Novel human proteins, polynucleotides encoding them and methods of using the same

FIELD OF THE INVENTION

[0002] The present invention relates to nucleic acids encoding proteins that are new members of the following protein families: FADD interacting protein-like; ATPase, H+ Transporting, Lysosomal (Vacuolar Proton Pump)-like; FGF 17-like; Single Pass Transmembrane-like; Beta-Ketoacyl Synthase-like; Neuralin 2-like; Glutamate Receptor Interacting Protein 2-like; ChR-Methyltransferase-like; NP25 Variant-like; GTPase-Activating Protein-like; ELKS-like; Sim2-like; RhoGAP-like; Phospholipase-like; Scavenger Receptor Domain Containing Protein-like; Metallothionein IA-like; NOGO receptor-like; FYVE-protein-like; NOELIN-like; Cyclin Regulatory Subunit-like; Tetratrico Peptide Repeat Protein-like; Immunoglobulin Domain Containing Protein-like; PA Domain Containing Protein-like; Phenylalanine And Histidine Ammonia-Lyase-like; Cellular Retinaldehyde-Binding Protein-like; Glutamine Repeat Containing Protein-like; TNF Receptor Associated Factor 2-like; Vacuolar Protein Sorting Homolog R-VPS33A; Bola Domain Containing Protein-like; Neurotrophin Receptor-like; RAL Guanine Nucleotide Dissociation Stimulator-like; Intracellular Protein-like; Protein Phosphatase Inhibitor 2-like; Armadillo/Beta-Catenin-like; Metalloprotease-like; T10 Ser/Thr-rich-like; Ring finger-like.

[0003] Included in the invention are polynucleotides and the polypeptides encoded by such polynucleotides, as well as vectors, host cells, antibodies and recombinant methods for producing the polypeptides and polynucleotides, as well as methods for using the same. Methods of use encompass diagnostic and prognostic assay procedures as well as methods of treating diverse pathological conditions.

BACKGROUND OF THE INVENTION

[0004] The invention generally relates to nucleic acids and polypeptides encoded therefrom. More specifically, the invention relates to nucleic acids encoding cytoplasmic, nuclear, membrane bound, and secreted polypeptides, as well as vectors, host cells, antibodies, and recombinant methods for producing these nucleic acids and polypeptides.

SUMMARY OF THE INVENTION

[0005] The present invention is based in part on nucleic acids encoding proteins that are members of the following protein families: FADD interacting protein-like; ATPase, H+ Transporting, Lysosomal (Vacuolar Proton Pump)-like; FGF 17-like; Single Pass Transmembrane-like; Beta-Ketoacyl Synthase-like; Neuralin 2-like; Glutamate Receptor Interacting Protein 2-like; ChR-Methyltransferase-like; NP25 Variant-like; GTPase-Activating Protein-like; ELKS-like; Sim2-like; RhoGAP-like; Phosphiolipase-like; Scavenger Receptor Domain Containing Protein-like; Metallothionein IA-like; NOGO receptor-like; FYVE-protein-like; NOELIN-like; Cyclin Regulatory Subunit-like; Tetratrico Peptide Repeat Protein-like; Immunoglobuliin Domain Containing Protein-like; PA Domain Containing Protein-like; Phenylalaninie And Histidine Ammonia-Lyase-like; Cellular Retinaldehyde-Binding Protein-like; Glutamine Repeat Containing Protein-like; TNF Receptor Associated Factor 2-like; Vacuolar Protein Sorting Homolog R-VPS33A; Bola Domain Containing Protein-like; Neurotrophin Receptor-like; RAL Guanine Nucleotide Dissociation Stimulator-like; Intracellular Protein-like; Protein Phosphatase Inhibitor 2-like; Armadillo/Beta-Catenin-like; Metalloprotease-like; T10 Ser/Thr-rich-like; Ring finger-like. The novel polynucleotides and polypeptides are referred to herein as NOV1a, NOV2a, NOV3a, NOV3b, NOV4a, NOV5a, NOV6a, NOV7a, NOV8a, NOV8b, NOV9a, NOV10a, NOV11a, NOV12a, NOV13a, NOV14a, NOV15a, NOV16a, NOV17a, NOV18a, NOV19a, NOV20a, NOV20b, NOV21a, NOV21b, NOV22a, NOV23a, NOV24a, NOV25a, NOV25b, NOV26a, NOV27a, NOV27b, NOV28a, NOV29a, NOV29b, NOV30a, NOV3 la, NOV32a, NOV33a, NOV34a, NOV34b, NOV35a, NOV36a, NOV36b, NOV36c, NOV37a, NOV37b, NOV37c, NOV37d and NOV37e.

[0006] These nucleic acids and polypeptides, as well as derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as “NOVX” nucleic acid or polypeptide sequences.

[0007] In one aspect, the invention provides an isolated NOVX nucleic acid disclosed in SEQ ID NO:2n−1, wherein n is an integer between 1 and 51. In some embodiments, the NOVX nucleic acid molecule will hybridize under stringent conditions to a nucleic acid sequence complementary to a nucleic acid molecule that includes a protein-coding sequence of a NOVX nucleic acid sequence. The invention also includes an isolated nucleic acid that encodes a NOVX polypeptide, or a fragment, homolog, analog or derivative thereof. For example, the nucleic acid can encode a polypeptide at least 80% identical to a polypeptide comprising the amino acid sequences of SEQ ID NO:2n, wherein n is an integer between 1 and 51. The nucleic acid can be, for example, a genomic DNA fragment or a cDNA molecule that includes the nucleic acid sequence of any of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51. Also included in the invention is an oligonucleotide, e g, an oligonucleotide which includes at least 6 contiguous nucleotides of a NOVX nucleic acid (e.g, SEQ ID NO:2n−1, wherein n is an integer between 1 and 51) or a complement of said oligonucleotide.

[0008] The invention also encompasses isolated NOVX polypeptides (SEQ ID NO:2n, wherein n is an integer between 1 and 51). In certain embodiments, the NOVX polypeptides include an amino acid sequence that is substantially identical to the amino acid sequence of a human NOVX polypeptide.

[0009] The invention also features antibodies that immunoselectively bind to NOVX polypeptides, or fragments, homologs, analogs or derivatives thereof.

[0010] In another aspect, the invention includes pharmaceutical compositions that include therapeutically- or prophylactically-effective amounts of a therapeutic and a pharmaceutically-acceptable carrier. The therapeutic can be, e.g., a NOVX nucleic acid, a NOVX polypeptide, or an antibody specific for a NOVX polypeptide. In a Further aspect, the invention includes, in one or more containers, a therapeutically- or prophylactically-effective amount of this pharmaceutical composition.

[0011] In a further aspect, the invention includes a method of producing a polypeptide by culturing a cell that includes a NOVX nucleic acid, under conditions allowing for expression of the NOVX polypeptide encoded by the DNA. If desired, the NOVX polypeptide can then be recovered.

[0012] In another aspect, the invention includes a method of detecting the presence of a NOVX polypeptide in a sample. In the method, a sample is contacted with a compound that selectively binds to the polypeptide under conditions allowing for formation of a complex between the polypeptide and the compound. The complex is detected, if present, thereby identifying the NOVX polypeptide within the sample.

[0013] The invention also includes methods to identify specific cell or tissue types based on their expression of a NOVX.

[0014] Also included in the invention is a method of detecting the presence of a NOVX nucleic acid molecule in a sample by contacting the sample with a NOVX nucleic acid probe or primer, and detecting whether the nucleic acid probe or primer bound to a NOVX nucleic acid molecule in the sample.

[0015] In a further aspect, the invention provides a method for modulating the activity of a NOVX polypeptide by contacting a cell sample that includes the NOVX polypeptide with a compound that binds to the NOVX polypeptide in an amount sufficient to modulate the activity of said polypeptide. The compound can be, e.g., a small molecule, such as a nucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, lipid or other organic (carbon containing) or inorganic molecule, as Further described herein.

[0016] In another embodiment, the invention involves a method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 51, the method including providing a cell expressing the polypeptide of the invention and having a property or function ascribable to the polypeptide; contacting the cell with a composition comprising a candidate substance; and determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition devoid of the substance, the substance is identified as a potential therapeutic agent.

[0017] In still another aspect, the invention provides the use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease that is associated with a NOVX polypeptide, such as those listed in Table A.

[0018] The therapeutic can be, e.g., a NOVX nucleic acid, a NOVX polypeptide, or a NOVX-specific antibody, or biologically-active derivatives or fragments thereof.

[0019] For example, the compositions of the present invention will have efficacy for treatment of patients suffering from the diseases and disorders disclosed below and/or other pathologies and disorders of the like. The polypeptides can be used as immunogens to produce antibodies specific for the invention, and as vaccines. They can also be used to screen for potential against and antagonist compounds. For example, a cDNA encoding NOVX may be useful in gene therapy, and NOVX may be useful when administered to a subject in need thereof.

[0020] The invention further includes a method for screening for a modulator of disorders or syndromes including, e.g., the diseases and disorders disclosed below and/or other pathologies and disorders of the like. The method includes contacting a test compound with a NOVX polypeptide and determining if the test compound binds to said NOVX polypeptide. Binding, of the test compound to the NOVX polypeptide indicates the test compound is a modulator of activity, or of latency or predisposition to the aforementioned disorders or syndromes.

[0021] Also within the scope of the invention is a method for screening for a modulator of activity, or of latency or predisposition to disorders or syndromes including, e g, the diseases and disorders disclosed below and/or other pathologies and disorders of the like by administering a test com pound to a test animal at increased risk for the aforementioned disorders or syndromes. The test animal expresses a recombinant polypeptide encoded by a NOVX nucleic acid. Expression or activity of NOVX polypeptide is then measured in the test animal, as is expression or activity of the protein in a control animal which recombinantly-expresses NOVX polypeptide and is not at increased risk for the disorder or syndrome. Next, the expression of NOVX polypeptide in both the test animal and the control animal is compared. A change in the activity of NOVX polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency of the disorder or syndrome.

[0022] In yet another aspect, the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a NOVX polypeptide, a NOVX nucleic acid, or both, in a subject (e.g., a human subject). The method includes measuring the amount of the NOVX polypeptide in a test sample from the subject and comparing the amount of the polypeptide in the test sample to the amount of the NOVX polypeptide present in a control sample. An alteration in the level of the NOVX polypeptide in the test sample as compared to the control sample indicates the presence of or predisposition to a disease in the subject. Preferably, the predisposition includes, e.g., the diseases and disorders disclosed below and/or other pathologies and disorders of the like. Also, the expression levels of the new polypeptides of the invention can be used in a method to screen for various cancers as well as to determine the stage of cancers.

[0023] In a further aspect, the invention includes a method of treating or preventing a pathological condition associated with a disorder in a mammal by administering to the subject a NOVX polypeptide, a NOVX nucleic acid, or a NOVX-specific antibody to a subject (e.g., a human subject), in an amount sufficient to alleviate or prevent the pathological condition. In preferred embodiments, the disorder, includes, e g, the diseases and disorders disclosed below and/or other pathologies and disorders of the like.

[0024] In yet another aspect, the invention can be used in a method to identity the cellular receptors and downstream effectors of the invention by any one of a number of techniques commonly employed in the art. These include but are not limited to the two-hybrid system, affinity purification, co-precipitation with antibodies or other specific-interacting molecules.

[0025] NOVX nucleic acids and polypeptides are further useful in the generation of antibodies that bind immuno-specifically to the novel NOVX substances for use in therapeutic or diagnostic methods. These NOVX antibodies may be generated according to methods known in the art, using prediction from hydrophobicity charts, as described in the “Anti-NOVX Antibodies” section below. The disclosed NOVX proteins have multiple hydrophilic regions, each of which can be used as an immunogen. These NOVX proteins can be used in assay systems for functional analysis of various human disorders, which will help in understanding of pathology of the disease and development of new drug targets for various disorders.

[0026] The NOVX nucleic acids and proteins identified here may be useful in potential therapeutic applications implicated in (but not limited to) various pathologies and disorders as indicated below. The potential therapeutic applications for this invention include, but are not limited to: protein therapeutic, small molecule drug target, antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), diagnostic and/or prognostic marker, gene therapy (gene delivery/gene ablation), research tools, tissue regeneration in vivo and in vitro of all tissues and cell types composing (but not limited to) those defined here.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0028] Other features and advantages of the invention will be apparent from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention provides novel nucleotides and polypeptides encoded thereby. Included in the invention are the novel nucleic acid sequences, their encoded polypeptides, antibodies, and other related compounds. The sequences are collectively referred to herein as “NOVX nucleic acids” or “NOVX polynucleotides” and the corresponding encoded polypeptides are referred to as “NOVX polypeptides” or “NOVX proteins.” Unless indicated otherwise, “NOVX” is meant to refer to any of the novel sequences disclosed herein. Table A provides a summary of the NOVX nucleic acids and their encoded polypeptides.

1TABLE ASequences and Corresponding SEQ ID NumbersSEQSEQID NOID NONovxInternal(nucleic(poly-AssignmentIdentificationacid)peptide)Homology 1aCG102232-01 1 2TADD interactingprotein-like 2aCG102931-01 3 4ATPase, H+Transporting,Lysosomal (VacuolarProton Pump)-like 3aCG104307-03 5 6FGF 17-like 3bCG104307-05 7 8FGF 17-like 4aCG105707-01 910Single PassTransmembrane-like 5aCG108369-011112Beta-KetoacylSynthase-like 6aCG110578-011314Neuralin 2-like 7aCG110646-011516Glutamate ReceptorInteracting Protein2-like 8aCG110998-011718ChR-Methyl-transferase-like 8bCG110998-021920ChR-Methyl-transferase-like 9aCG111347-012122NP25 Variant-like10aCG111446-012324GTPase-ActivatingProtein-like11aCG111464-012526ELKS-like12aCG111512-012728Sim2-like13aCG111646-012930RhoGAP-like14aCG111744-013132Phospholipase-like15aCG111815-013334Scavenger ReceptorDomain ContainingProtein-like16aCG112464-013536Metallothionein1A-like17aCG112475-013738NOGO receptor-like18aCG112713-013940FYVE-protein-like19aCG112731-014142NOELIN-like20aCG112749-014344Cyclin RegulatorySubunit-like20bCG112749-024546Cyclin RegulatorySubunit-like21aCG112758-014748Tetratrico PeptideRepeat Protein-like21bCG112758-024950Tetratrico PeptideRepeat Protein-like22aCG112892-015152ImmunoglobulinDomain ContainingProtein-like23aCG113794-015354PA DomainContainingProtein-like24aCG114814-015556Phenylalanine AndHistidine Ammonia-Lyase-like25aCG116840-015758CellularRetinaldehyde-BindingProtein-like25bCG116840-025960CellularRetinaldehyde-BindingProtein-like26aCG116903-016162Clutamine RepeatContaining Protein-like27aCG118634-016364TNF ReceptorAssociated Factor2-like27bCG118634-026566TNF ReceptorAssociated Factor2-like28aCG119215-016768Vacuolar ProteinSorting HomologR-VPS33A29aCG121501-016970Bola DomainContaining Protein-like29bCG121501-027172Bola DomainContaining Protein-like30aCG121894-017374NeurotrophinReceptor-like31aCG121954-017576RAL GuanineNucleotideDissociationStimulator-like32aCG122816-017778IntracellularProtein-like33aCG122825-017980Protein PhosphataseInhibitor 2-like34aCG122843-018182Armadillo/Beta-Catenin-like34bCG122843-028384Armadillo/Beta-Catenin-like35aCG124890-028586Metalloprotease-like36aCG59266-018788T10 Ser/Thr-rich-like36bCG59266-028990T10 Ser/Thr-rich-like36cCG59266-039192T10 Ser/Thr-rich-like37aCG97563-019394Ring Finger-like37bCG97563-029596Ring finger-like37cCG97563-039798Ring finger-like37dCG97563-0499100 Ring finger-like37cCG97563-05101 102 Ring finger-like

[0030] Table A indicates the homology of NOVX polypeptides to known protein families. Thus, the nucleic acids and polypeptides, antibodies and related compounds according to the invention corresponding to a NOVX as identified in column 1 of Table A will be useful in therapeutic and diagnostic applications implicated in, for example, pathologies and disorders associated with the known protein families identified in column 5 of Table A.

[0031] NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.

[0032] Consistent with other known members of the family of proteins, identified in column 5 of Table A, the NOVX polypeptides of the present invention show homology to, and contain domains that are characteristic of, other members of such protein families. Details of the sequence relatedness and domain analysis for each NOVX are presented in Example A.

[0033] The NOVX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVX activity or function. Specifically, the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit diseases associated with the protein families listed in Table A.

[0034] The NOVX nucleic acids and polypeptides are also useful for detecting specific cell types. Details of the expression analysis for each NOVX are presented in Example C. Accordingly, the NOVX nucleic acids, polypeptides, antibodies and related compounds according to the invention will have diagnostic and therapeutic applications in the detection of a variety of diseases with differential expression in normal vs. diseased tissues, e g. detection of a variety of cancers.

[0035] Additional utilities for NOVX nucleic acids and polypeptides according to the invention are disclosed herein.

[0036] NOVX Clones

[0037] NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.

[0038] The NOVX genes and their corresponding encoded proteins are useful for preventing, treating or ameliorating medical conditions, e.g., by protein or gene therapy. Pathological conditions can be diagnosed by determining the amount of the new protein in a sample or by determining the presence of mutations in the new genes. Specific uses are described for each of the NOVX genes, based on the tissues in which they are most highly expressed. Uses include developing products for the diagnosis or treatment of a variety of diseases and disorders.

[0039] The NOVX nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) a biological defense weapon.

[0040] In one specific embodiment, the invention includes an isolated polypeptide comprising, an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 51; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 51, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 51; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 51 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; and (e) a fragment of any of (a) through (d).

[0041] In another specific embodiment, the invention includes an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence given SEQ ID NO: 2n, wherein n is an integer between 1 and 51; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 51 wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 51; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 51, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 51 or any variant of said polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and (f) the complement of any of said nucleic acid molecules.

[0042] In yet another specific embodiment, the invention includes an isolated nucleic acid molecule, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n−1, wherein n is an integer between 1 and 51; (b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n−1, wherein n is an integer between 1 and 51 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; (c) a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO: 2n−1, wherein n is an integer between 1 and 51; and (d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n−1, wherein n is an integer between 1 and 51 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed.

[0043] NOVX Nucleic Acids and Polypeptides

[0044] One aspect of the invention pertains to isolated nucleic acid molecules that encode NOVX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify NOVX-encoding nucleic acids (e g, NOVX mRNAs) and fragments for use as PCR primers for the amplification and/or mutation of NOVX nucleic acid molecules. As used herein, the term “nucleic acid molecule” is intended to include DNA molecules (e g, cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNA generated using nucleotide analogs, and derivatives, fragments and homologs thereof. The nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double-stranded DNA.

[0045] A NOVX nucleic acid can encode a mature NOVX polypeptide. As used herein, a “mature” form of a polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. The product “mature” form arises, by way of nonlimiting, example, as a result of one or more naturally occurring processing steps that may take place within the cell (e.g., host cell) in which the gene product arises. Examples of such processing steps leading to a “mature” form of a polypeptide or protein include the cleavage of the N-terminal methionine residue encoded by the initiation codon of al ORF, or the proteolytic cleavage of a signal peptide or leader sequence. Thus a mature form arising from a precursor-polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N remaining after removal of the N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N-terminal signal sequence from residue 1 to residue M is cleaved, would have the residues from residue M+1 to residue N remaining. Further as used herein, a “mature” form of a polypeptide or protein may arise from a step of post-translational modification other than a proteolytic cleavage event. Such additional processes include, by way of non-limiting example, glycosylation, myristylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or a combination of any of them.

[0046] The term “probe”, as utilized herein, refers to nucleic acid sequences of variable length, preferably between at least about 10 nucleotides (nt), about 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences. Longer length probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single-stranded or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies.

[0047] The term “isolated” nucleic acid molecule, as used herein, is a nucleic acid that is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. Preferably, an “isolated” nucleic acid is free of sequences which naturally flank the nucleic acid (i e., sequences located at the 5′- and 3′-termini of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated NOVX nucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium, or of chemical precursors or other chemicals.

[0048] A nucleic acid molecule of the invention, e g, a nucleic acid molecule having the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, or a complement of this nucleotide sequence, can be isolated using standard molecular biology techniques and the sequence information provided herein. Using all or a portion of the nucleic acid sequence of SEQ ID NO:2-1, wherein n is an integer between 1 and 51, as a hybridization probe, NOVX molecules can be isolated using standard hybridization and cloning techniques (e.g, as described in Sambrook, et al., (eds.), MOLECULAR CLONING: A LABORATORY MANUAL. 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989; and Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, N.Y., 1993.)

[0049] A nucleic acid of the invention can be amplified using cDNA, mRNA or alternatively, genomic DNA, as a template with appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to NOVX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.

[0050] As used herein, the term “oligonucleotide” refers to a series of linked nucleotide residues. A short oligonucleotide sequence may be based on, or designed from, a genomic or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides comprise a nucleic acid sequence having about 10 nt, 50 fit, or 100 nt in length, preferably about 15 nt to 30 nt in length. In one embodiment of the invention, an oligonucleotide comprising a nucleic acid molecule less than 100 nt in length would Further comprise at least 6 contiguous nucleotides of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, or a complement thereof. Oligonucleotides may be chemically synthesized and may also be used as probes.

[0051] In another embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule that is a complement of the nucleotide sequence shown in SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer- or a fragment encoding a biologically-active portion of a NOVX polypeptide). A nucleic acid molecule that is complementary to the nucleotide sequence of SEQ ID NO:2t-1, wherein n is an integer between 1 and 51, is one that is sufficiently complementary to the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, that it can hydrogen bond with few or no mismatches to the nucleotide sequence shown in SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, thereby forming a stable duplex.

[0052] As used herein, the term “complementary” refers to Watson-Crick or Hoogsteen base pairing between nucleotides units of a nucleic acid molecule, and the term “binding” means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction can be either direct or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates.

[0053] A “fragment” provided herein is defined as a sequence of at least 6 (contiguous) nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, and is at most some portion less than a full length sequence. Fragments may be derived from any contiguous portion of a nucleic acid or amino acid sequence of choice.

[0054] A full-length NOVX clone is identified as containing an ATG translation start codon and an in-frame stop codon. Any disclosed NOVX nucleotide sequence lacking an ATG start codon therefore encodes a truncated C-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 5 direction of the disclosed sequence. Any disclosed NOVX nucleotide sequence lacking an in-frame stop codon similarly encodes a truncated N-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding mull-length cDNA extend in the 3′ direction of the disclosed sequence.

[0055] A “derivative” is a nucleic acid sequence or amino acid sequence formed from the native compounds either directly, by modification or partial substitution. An “analogy” is a nucleic acid sequence or amino acid sequence that has a structure similar to, but not identical to, the native compound, e.g. they differs from it in respect to certain components or side chains. Analogs may be synthetic or derived from a different evolutionary origin and may have a similar or opposite metabolic activity compared to wild type. A “homolog” is a nucleic acid sequence or amino acid sequence of a particular gene that is derived from different species.

[0056] Derivatives and analogs may be fill length or other than full length. Derivatives or analogs of the nucleic acids or proteins of the invention include, but are not limited to, molecules comprising regions that are substantially homologous to the nucleic acids or proteins of the invention, in various embodiments, by at least about 70%, 80%, or 95% identity (with a preferred identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to the complement of a sequence encoding the proteins under stringent, moderately stringent, or low stringent conditions. See e.g. Ausubel, et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, N.Y., 1993, and below.

[0057] A “homologous nucleic acid sequence” or “homologous amino acid sequence,” or variations thereof, refer to sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences include those sequences coding for isoforms of NOVX polypeptides. Isoforms can be expressed in different tissues of the same organism as a result of, for example, alternative splicing of RNA. Alternatively, isoforms can be encoded by different genes. In the invention, homologous nucleotide sequences include nucleotide sequences encoding for a NOVX polypeptide of species other than humans, including, but not limited to: vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and other organisms Homologous nucleotide sequences also include, but are not limited to, naturally occurring allelic variations and mutations of the nucleotide sequences set forth herein. A homologous nucleotide sequence does not, however, include the exact nucleotide sequence encoding human NOVX protein. Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, as well as a polypeptide possessing NOVX biological activity. Various biological activities of the NOVX proteins are described below.

[0058] A NOVX polypeptide is encoded by the open reading frame (“ORF”) of a NOVX nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be translated into a polypeptide. A stretch of nucleic acids comprising an ORF is uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG “start” codon and terminates with one of the three “stop” codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For an ORF to be considered as a good candidate for coding for a bona fide cellular protein, a minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more.

[0059] The nucleotide sequences determined from the cloning of the human NOVX genes allows for the generation of probes and primers designed for use in identifying and/or cloning NOVX homologues in other cell types, e.g. from other tissues, as well as NOVX homologues from other vertebrates. The probe/primer-typically comprises substantially purified oligonucleotide. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutive sense strand nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51; or an anti-sense strand nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51; or of a naturally occurring mutant of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51.

[0060] Probes based on the human NOVX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various embodiments, the probe has a detectable label attached, e.g. the label can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis-express a NOVX protein, such as by measuring a level of a NOVX-encoding nucleic acid in a sample of cells from a subject e.g, detecting NOVX mRNA levels or determining whether a genomic NOVX gene has been mutated or deleted.

[0061] “A polypeptide having a biologically-active portion of a NOVX polypeptide” refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide of the invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a “biologically-active portion of NOVX” can be prepared by isolating a portion of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, that encodes a polypeptide having a NOVX biological activity (the biological activities of the NOVX proteins are described below), expressing the encoded portion of NOVX protein (e.g., by recombinant expression in vitro) and assessing the activity of the encoded portion of NOVX.

[0062] NOVX Nucleic Acid and Polypeptide Variants

[0063] The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, due to degeneracy of the genetic code and thus encode the same NOVX proteins as that encoded by the nucleotide sequences of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a protein having an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 51.

[0064] In addition to the human NOVX nucleotide sequences of SEQ ID NO:2i-1, wherein n is an integer between 1 and 51, it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of the NOVX polypeptides may exist within a population (e g, the human population). Such genetic polymorphism in the NOVX genes may exist among individuals within a population due to natural allelic variation. As used herein, the terms “gene” and “recombinant gene” refer to nucleic acid molecules comprising an open reading frame (ORF) encoding a NOVX protein, preferably a vertebrate NOVX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the NOVX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the NOVX polypeptides, which are the result of natural allelic variation and that do not alter the functional activity of the NOVX polypeptides, are intended to be within the scope of the invention.

[0065] Moreover, nucleic acid molecules encoding NOVX proteins from other species, and thus that have a nucleotide sequence that differs from a human SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, are intended to be within the scope of the invention. Nucleic acid molecules corresponding to natural allelic variants and homologues of the NOVX cDNAs of the invention can be isolated based on their homology to the human NOVX nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.

[0066] Accordingly, in another embodiment, an isolated nucleic acid molecule of the invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51. In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule of the invention hybridizes to the coding region. As used herein, the term “hybridizes under stringent conditions” is intended to describe conditions for hybridization and washing under which nucleotide sequences at least about 65% homologous to each other typically remain hybridized to each other.

[0067] Homologs (i.e., nucleic acids encoding NOVX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or high stringency hybridization with all or a portion of the particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning.

[0068] As used herein, the phrase “stringent hybridization conditions” refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5° C. lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% of the probe's complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess, at Tm, 50% of the probes are occupied at equilibrium. Typically, stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30° C. for short probes, primers or oligonucleotides (e g., 10 nt to 50 nt) and at least about 60° C. for longer probes, primers and oligonucleotides. Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide.

[0069] Stringent conditions are known to those skilled in the art and can be found in Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6×SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65° C., followed by one or more washes in 0.2×SSC, 0.01% BSA at 50° C. An isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to a sequence of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, corresponds to a naturally-occurring nucleic acid molecule. As used herein, a “naturally-occurring” nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).

[0070] In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, or fragments, analogs or derivatives thereof, under conditions of moderate stringency is provided. A non-limiting example of moderate stringency hybridization conditions are hybridization in 6×SSC, 5×Renhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55° C., followed by one or more washes in 1×SSC, 0.1% SDS at 37° C. Other conditions of moderate stringency that may be used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Krieger, 1990; GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY.

[0071] In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide, 5×SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 02% BSA, 100 mg/ml denatured salmon sperm DNA, 10% (wt/vol) dextran sulfate at 40° C., followed by one or more washes in 2×SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDS at 50° C. Other conditions of low stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g, Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg, 1981. Proc Natl Acad Sci USA 78: 6789-6792.

[0072] Conservative Mutations

[0073] In addition to naturally-occurring allelic variants of NOVX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, thereby leading to changes in the amino acid sequences of the encoded NOVX protein, without altering the functional ability of that NOVX protein. For example, nucleotide substitutions leading to amino acid substitutions at “non-essential” amino acid residues can be made in the sequence of SEQ ID NO:2n, wherein 1 is all integer between 1 and 51. A “non-essential” amino acid residue is a residue that can be altered from the wild-type sequences of the NOVX proteins without altering their biological activity, whereas an “essential” amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the NOVX proteins of the invention are predicted to be particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well-known within the art.

[0074] Another aspect of the invention pertains to nucleic acid molecules encoding NOVX proteins that contain changes in amino acid residues that are not essential for activity. Such NOVX proteins differ in amino acid sequence from SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, yet retain biological activity. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least about 40% homologous to the amino acid sequences of SEQ ID NO:2n, wherein n is an integer between 1 and 51. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 51; more preferably at least about 70% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 51; still more preferably at least about 80% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 51; even more preferably at least about 90% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 51; and most preferably at least about 95% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 51.

[0075] An isolated nucleic acid molecule encoding a NOVX protein homologous to the protein of SEQ ID NO:2n, wherein n is an integer between 1 and 51, can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein.

[0076] Mutations can be introduced any one of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted, non-essential amino acid residues. A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the NOVX protein is replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of a NOVX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for NOVX biological activity to identify mutants that retain activity. Following mutagenesis of a nucleic acid of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, the encoded protein can be expressed by any recombinant technology known in the art and the activity of the protein can be determined.

[0077] The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved “strong” residues or fully conserved “weak” residues. The “strong” group of conserved amino acid residues may be any one of the following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the “weak” group of conserved residues may be any one of the following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, HFY, wherein the letters within each group represent the single letter amino acid code.

[0078] In one embodiment, a mutant NOVX protein can be assayed for (i) the ability to form protein:protein interactions with other NOVX proteins, other cell-surface proteins, or biologically-active portions thereof, (ii) complex formation between a mutant NOVX protein and a NOVX ligand; or (iii) the ability of a mutant NOVX protein to bind to an intracellular target protein or biologically-active portion thereof; (e.g. avidin proteins).

[0079] In yet another embodiment, a mutant NOVX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release).

[0080] Antisense Nucleic Acids

[0081] Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, or fragments, analogs or derivatives thereof. An “antisense” nucleic acid comprises a nucleotide sequence that is complementary to a “sense” nucleic acid encoding a protein (e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an in RNA sequence). In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire NOVX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of a NOVX protein of SEQ ID NO:2n, wherein n is an integer between 1 and 51, or antisense nucleic acids complementary to a NOVX nucleic acid sequence of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, are additionally provided.

[0082] In one embodiment, an antisense nucleic acid molecule is antisense to a “coding region” of the coding strand of a nucleotide sequence encoding a NOVX protein. The term “coding region” refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a “noncoding region” of the coding strand of a nucleotide sequence encoding the NOVX protein. The term “noncoding region” refers to 5′ and 3′ sequences which flank the coding region that are not translated into amino acids (i e., also referred to as 5′ and 3′ untranslated regions).

[0083] Given the coding strand sequences encoding the NOVX protein disclosed herein, antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of NOVX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of NOVX mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of NOVX mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e g., an antisense oligonucleotide) can be chemically synthesized using naturally-occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids (e.g, phosphorothioate derivatives and acridine substituted nucleotides can be used).

[0084] Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthilne, 4-acetylcytosine, 5-carboxymethylaminomethyl-2-thouridine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethlyluracil, dihydroulacil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 5-methoxyuracil, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, 2-thiouracil, 4-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 2-methylthio-N-6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

[0085] The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a NOVX protein to thereby inhibit expression of the protein (e.g., by inhibiting transcription and/or translation). The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface (e.g, by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens). The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient nucleic acid molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.

[0086] In yet another embodiment, the antisense nucleic acid molecule of the invention is an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other. See, e g, Gaultier, et al., 1987. Nucl. Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can also comprise a 2′-o-methylribonucleotide (See, e.g., Inoue, et al. 1987. Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (See, e.g., Inoue, et al., 1987. FEBS Lett 215: 327-330.

[0087] Ribozymes and PNA Moieties

[0088] Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.

[0089] In one embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammer-head ribozymes as described in Haselhoff and Gerlach 1988, Nature 334: 585-591) can be used to catalytically cleave NOVX mRNA transcripts to thereby inhibit translation of NOVX mRNA. A ribozyme having specificity for a NOVX-encoding nucleic acid can be designed based upon the nucleotide sequence of a NOVX cDNA disclosed herein (i.e., SEQ ID NO:2n−1, wherein n is an integer between 1 and 51). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a NOVX-encoding mRNA. See, e.g., U.S. Pat. No. 4,987,071 to Cech, et al. and U.S. Pat. No. 5,116,742 to Cech, et al. NOVX mRNA can also be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., (1993) Science 261:1411-1418.

[0090] Alternatively, NOVX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the NOVX nucleic acid (e.g., the NOVX promoter and/or enhancers) to form triple helical structures that prevent transcription of the NOVX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene, et al. 1992. Ann. N.Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15.

[0091] In various embodiments, the NOVX nucleic acids can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids. See, e.g., 1Hyrup, et al., 1996. Bioorg Med Chem 4: 5-23. As used herein, the terms “peptide nucleic acids” or “PNAs” refer to nucleic acid mimics (e.g., DNA mimics) in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleotide bases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomer can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al., 1996. supra; Perry-O'Keefe, et al., 1996. Proc. Natl. Acad. Sci. USA 93: 14670-14675.

[0092] PNAs of NOVX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of NOVX can also be used, for example, in the analysis of single base pair mutations in a gene (e g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e g, S1 nucleases (See Hyrup, et al., 1996. supra); or as probes or primers for DNA sequence and hybridization (See, Hyrup, et al., 1996, supra; Perry-O'Keefe, et al., 1996. supra).

[0093] In another embodiment, PNAs of NOVX can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras of NOVX can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes (e.g., RNase H and DNA polymerases) to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleotide bases, and orientation (see, Hyrup, et al., 1996. supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al., 1996. supra and Finn, et al., 1996. Nucl Acids Res 24: 3357-3363. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5′-(4-methoxytrityl)amino-5′-deoxy-thymidime phosphoramidite, can be used between the PNA and the 5′ end of DNA. See, e.g, Mag, et al., 1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5′ PNA segment and a 3′ DNA segment. See, e.g, Finn, et al., 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5′ DNA segment and a 3′ PNA segment. See, e g, Petersen, et al., 1975. Bioorg. Med. Chem. Lett 5: 1119-11124.

[0094] In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e g., Letsinger, et al., 1989. Proc. Natl. Acad Sci USA 86: 6553-6556; Lemaitre, et al., 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g, Krol, et al., 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988. Pharm. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, and the like.

[0095] NOVX Polypeptides

[0096] A polypeptide according to the invention includes a polypeptide including the amino acid sequence of NOVX polypeptides whose sequences are provided in any one of SEQ ID NO:2n, wherein n is an integer between 1 and 51. The invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residues shown in any one of SEQ ID NO:2n, wherein n is an integer between 1 and 51, while still encoding a protein that maintains its NOVX activities and physiological functions, or a functional fragment thereof.

[0097] In general, a NOVX variant that preserves NOVX-like function includes any variant in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues of the parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or deletion is encompassed by the invention. In favorable circumstances, the substitution is a conservative substitution as defined above.

[0098] One aspect of the invention pertains to isolated NOVX proteins, and biologically-active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise anti-NOVX antibodies. In one embodiment, native NOVX proteins can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, NOVX proteins are produced by recombinant DNA techniques. Alternative to recombinant expression, a NOVX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques.

[0099] An “isolated” or “purified” polypeptide or protein or biologically-active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the NOVX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language “substantially free of cellular material” includes preparations of NOVX proteins in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly-produced. In one embodiment, the language “substantially free of cellular material” includes preparations of NOVX proteins having less than about 30% (by dry weight) of non-NOVX proteins (also referred to herein as a “contaminating protein”), more preferably less than about 20% of non-NOVX proteins, still more preferably less than about 10% of non-NOVX proteins, and most preferably less than about 5% of non-NOVX proteins When the NOVX protein or biologically-active portion thereof is recombinantly-produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% of the volume of the NOVX protein preparation.

[0100] The language “substantially free of chemical precursors or other chemicals” includes preparations of NOVX proteins in which the protein is separated from chemical precursors or other chemicals that are involved in the synthesis of the protein. In one embodiment, the language “substantially free of chemical precursors or other chemicals” includes preparations of NOVX proteins having less than about 30% (by dry weight) of chemical precursors or non-NOVX chemicals, more preferably less than about 20% chemical precursors or non-NOVX chemicals, still more preferably less than about 10% chemical precursors or non-NOVX chemicals, and most preferably less than about 5% chemical precursors or non-NOVX chemicals.

[0101] Biologically-active portions of NOVX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences of the NOVX proteins (e.g., the amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 51) that include fewer amino acids than the full-length NOVX proteins, and exhibit at least one activity of a NOVX protein. Typically, biologically-active portions comprise a domain or motif with at least one activity of the NOVX protein. A biologically-active portion of a NOVX protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acid residues in length.

[0102] Moreover, other biologically-active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of a native NOVX protein.

[0103] In an embodiment, the NOVX protein has an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 51. In other embodiments, the NOVX protein is substantially homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 51, and retains the functional activity of the protein of SEQ ID NO:2n, wherein n is an integer between 1 and 51, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the NOVX protein is a protein that comprises an amino acid sequence at least about 45% homologous to the amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 51, and retains the functional activity of the NOVX proteins of SEQ ID NO:2n, wherein n is an integer between 1 and 51.

[0104] Determining Homology Between Two or More Sequences

[0105] To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid “homology” is equivalent to amino acid or nucleic acid “identity”).

[0106] The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs known in the art, such as GAP software provided in the GCG program package. See, Needleman and Wunsch, 1970. J Mol Biol 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP extension penalty of 0.3, the coding region of the analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, with the CDS (encoding) part of the DNA sequence of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51.

[0107] The term “sequence identity” refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the case of nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The term “substantial identity” as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison region.

[0108] Chimeric and Fusion Proteins

[0109] The invention also provides NOVX chimeric or fusion proteins. As used herein, a NOVX “chimeric protein” or “fusion protein” comprises a NOVX polypeptide operatively-linked to a non-NOVX polypeptide. An “NOVX polypeptide” refers to a polypeptide having an amino acid sequence corresponding to a NOVX protein of SEQ ID NO:2n, wherein n is an integer between 1 and 51, whereas a “non-NOVX polypeptide” refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially homologous to the NOVX protein, e g, a protein that is different from the NOVX protein and that is derived from the same or a different organism. Within a NOVX fusion protein the NOVX polypeptide can correspond to all or a portion of a NOVX protein. In one embodiment, a NOVX fusion protein comprises at least one biologically-active portion of a NOVX protein. In another embodiment, a NOVX fusion protein comprises at least two biologically-active portions of a NOVX protein. In yet another embodiment, a NOVX fusion protein comprises at least three biologically-active portions of a NOVX protein. Within the fusion protein, the term “operatively-linked” is intended to indicate that the NOVX polypeptide and the non-NOVX polypeptide are fused in-frame with one another. The non-NOVX polypeptide can be fused to the N-terminus or C-terminus of the NOVX polypeptide.

[0110] In one embodiment, the fusion protein is a GST-NOVX fusion protein in which the NOVX sequences are fused to the C-terminus of the GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant NOVX polypeptides.

[0111] In another embodiment, the fusion protein is a NOVX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of NOVX can be increased through use of a heterologous signal sequence.

[0112] In yet another embodiment, the fusion protein is a NOVX-immunoglobulin fusion protein in which the NOVX sequences are fused to sequences derived from a member of the immunoglobulin protein family. The NOVX-immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a NOVX ligand and a NOVX protein on the surface of a cell, to thereby suppress NOVX-mediated signal transduction in vivo. The NOVX-immunoglobulin fusion proteins can be used to affect the bioavailability of a NOVX cognate ligand. Inhibition of the NOVX ligand/NOVX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well as modulating (e.g. promoting or inhibiting) cell survival. Moreover, the NOVX-immunoglobulin fusion proteins of the invention can be used as immunogens to produce anti-NOVX antibodies in a subject, to purify NOVX ligands, and in screening assays to identify molecules that inhibit the interaction of NOVX with a NOVX ligand.

[0113] A NOVX chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g, by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g. Ausubel, et al. (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g, a GST polypeptide). A NOVX-encoding, nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the NOVX protein.

[0114] NOVX Agonists and Antagonists

[0115] The invention also pertains to variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists. Variants of the NOVX protein can be generated by mutagenesis (e.g, discrete point mutation or truncation of the NOVX protein). An agonist of the NOVX protein can retain substantially the same, or a subset of, the biological activities of the naturally occurring form of the NOVX protein. An antagonist of the NOVX protein can inhibit one or more of the activities of the naturally occurring form of the NOVX protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade which includes the NOVX protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. In one embodiment, treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the NOVX proteins.

[0116] Variants of the NOVX proteins that function as either NOVX agonists (i e., mimetics) or as NOVX antagonists can be identified by screening combinatorial libraries of mutants (e.g., truncation mutants) of the NOVX proteins for NOVX protein agonist or antagonist activity. In one embodiment, a variegated library of NOVX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of NOVX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential NOVX sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of NOVX sequences therein. There are a variety of methods which can be used to produce libraries of potential NOVX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential NOVX sequences. Methods for synthesizing degenerate oligonucleotides are well-known within the art. See, e.g., Narang, 1983. Tetrahedron 39: 3; Itakura, et al., 1984. Annu Rev Biochem. 53: 323; Itakura, et al., 1984. Science 198: 1056; Ike, et al., 1983. Nucl. Acids Res. 11: 477.

[0117] Polypeptide Libraries

[0118] In addition, libraries of fragments of the NOVX protein coding sequences can be used to generate a variegated population of NOVX fragments for screening and subsequent selection of variants of a NOVX protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of a NOVX coding sequence with a nuclease under conditions wherein nicking Occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double-stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with S1 nuclease, and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-terminal and internal fragments of various sizes of the NOVX proteins.

[0119] Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of NOVX proteins. The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify NOVX variants. See, e.g., Arkin and Yourvan, 1992. Proc Natl Acad. Sci USA 89: 7811-7815; Delgrave, et al., 1993. Protein Engineering 6:327-331.

[0120] Anti-NOVX Antibodies

[0121] Included in the invention are antibodies to NOVX proteins, or fragments of NOVX proteins. The term “antibody” as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab, Fab, and F(ab′)2 fragments, and an Fab expression library. In general, antibody molecules obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgG1, IgG2, and others. Furthermore, II humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.

[0122] An isolated protein of the invention intended to serve as an antigen, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of the full length protein, such as an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 51, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope. Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.

[0123] In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a regions of NOVX that is located on the surface of the protein, e.g., a hydrophilic region. A hydrophobicity analysis of the human NOVX protein sequence will indicate which regions of a NOVX polypeptide are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g, Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 3824-3828; Kyte and Doolittle 1982, J. Mol. Biol. 157: 105-142, each incorporated herein by reference in their entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.

[0124] The term “epitope” includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. A NOVX polypeptide or a fragment thereof comprises at least one antigenic epitope. An anti-NOVX antibody of the present invention is said to specifically bind to antigen NOVX when the equilibrium binding constant (KD) is ≦1 μM, preferably ≦100 nM, more preferably ≦10 nM, and most preferably ≦100 pM to about 1 pM, as measured by assays Such as radioligand binding assays or similar assays known to those skilled in the art.

[0125] A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.

[0126] Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., incorporated herein by reference). Some of these antibodies are discussed below.

[0127] Polyclonal Antibodies

[0128] For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerill and Corynebacterium parvum, or similar immunostimulatory agents. Additional examples of adjuvants which can be employed include MPL-TDM adjuvant (monophiosphoryl Lipid A, synthetic trelialose dicorynomycolate).

[0129] The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g, from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia Pa., Vol. 14, No. 8 (Apr. 17, 2000), pp. 25-28).

[0130] Monoclonal Antibodies

[0131] The term “monoclonal antibody” (MAb) or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.

[0132] Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro.

[0133] The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103). Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells.

[0134] Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, Calif. and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63).

[0135] The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980). It is an objective, especially important in therapeutic applications of monoclonal antibodies, to identify antibodies having a high degree of specificity and a high binding affinity for the target antigen.

[0136] After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods (Goding, 1986). Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Mediums and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.

[0137] The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0138] The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e g, by using oligonucleotide probes that are capable of biding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of Such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Pat. No 4,816,567; Morrison, Nature 368: 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.

[0139] Humanized Antibodies

[0140] The antibodies directed against the protein antigens of the invention can Further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)2 or other antigen-blinding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321: 522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S. Pat. No. 5,225,539.) In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fe), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)).

[0141] Human Antibodies

[0142] Fully human antibodies essentially relate to antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed “human antibodies”, or “fully human antibodies” herein. Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp.77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).

[0143] In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al. (Bio/Technology 10, 779-783 (1992)); Lonberg et al. (Nature 368 856-859 (1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al,(Nature Biotechnology 14,845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol 13 65-93 (1995)).

[0144] Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT publication WO94/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the Xenomouse™ disclosed in PCT publications WO-96/33715 and WO 96/3)4096. This animal produces B cells which secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be Further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.

[0145] An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Pat. No. 5,939,598. It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.

[0146] A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Pat. No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain.

[0147] In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049.

[0148] Fab Fragments and Single Chain Antibodies

[0149] According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Pat. No. 4,946,778). In addition, methods can be adapted for the construction of Fab expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F(ab′)2 fragment produced by pepsin digestion of an antibody molecule; (ii) an Fab fragment generated by reducing the disulfide bridges of an F(ab′)2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) Fv fragments.

[0150] Bispecific Antibodies

[0151] Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.

[0152] Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published May 13, 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991).

[0153] Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986).

[0154] According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory “cavities” of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.

[0155] Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e g F(ab′)2 bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab′)2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab′ fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives is then reconverted to the Fab′-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab′-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.

[0156] Additionally, Fab fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab′)2 molecule. Each Fab′ fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human Tr cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.

[0157] Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5): 1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab′ portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The “diabody” technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making, bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994).

[0158] Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).

[0159] Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).

[0160] Heteroconjugate Antibodies

[0161] Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Pat. No. 4,676,980.

[0162] Effector Function Engineering

[0163] It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) can be introduced into the Fe region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus (generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fe regions and can thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989).

[0164] Immunoconjugates

[0165] The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e g, an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e, a radioconjugate).

[0166] Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginiosa), ricin A chain, abrin A chain, modeccini A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenoinycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 212Bi, 131I, 131In, 90Y, and 186Re.

[0167] Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyidithiol) propionate (SPDP), immunothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (Such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026.

[0168] In another embodiment, the antibody can be conjugated to a “receptor” (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a “ligand” (e g, avidin) that is in turn conjugated to a cytotoxic agent.

[0169] Immunoliposomes

[0170] The antibodies disclosed herein can also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl. Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556.

[0171] Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphiatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab′ fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al., J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon et al., J. National Cancel Inst., 81(19): 1484 (1989).

[0172] Diagnostic Applications of Antibodies Directed Against the Proteins of the Invention

[0173] In one embodiment, methods for the screening of antibodies that possess the desired specificity include, but are not limited to, enzyme linked immunosorbent assay (ELISA) and other immunologically mediated techniques known within the art. In a specific embodiment, selection of antibodies that are specific to a particular domain of an NOVX protein is facilitated by generation of hybridomas that bind to the fragment of an NOVX protein possessing such a domain. Thus, antibodies that are specific for a desired domain within an NOVX protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.

[0174] Antibodies directed against a NOVX protein of the invention may be used in methods known within the art relating to the localization and/or quantitation of a NOVX protein (e.g., for use in measuring levels of the NOVX protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies specific to a NOVX protein, or derivative, fragment, analog or homolog thereof, that contain the antibody derived antigen binding domain, are utilized as pharmacologically active compounds (referred to hereinafter as “Therapeutics”).

[0175] An antibody specific for a NOVX protein of the invention (e.g., a monoclonal antibody or a polyclonal antibody) can be used to isolate a NOVX polypeptide by standard techniques, such as immunoaffinity, chromatography or immunoprecipitation. An antibody to a NOVX polypeptide can facilitate the purification of a natural NOVX antigen from cells, or of a recombinantly produced NOVX antigen expressed in host cells. Moreover, such an anti-NOVX antibody can be used to detect the antigenic NOVX protein (e g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the antigenic NOVX protein. Antibodies directed against a NOVX protein can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galaetosidase, or acetyleholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include 125I, 131I, 35S or 3H.

[0176] Antibody Therapeutics

[0177] Antibodies of the invention, including polyclonal, monoclonal, humanized and fully human antibodies, may used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology in a subject. An antibody preparation, preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Such an effect may be one of two kinds, depending on the specific nature of the interaction between the given antibody molecule and the target antigen in question. In the first instance, administration of the antibody may abrogate or inhibit the binding of the target with an endogenous ligand to which it naturally binds. In this case, the antibody binds to the target and masks a binding site of the naturally occurring ligand, wherein the ligand serves as an effector molecule. Thus the receptor mediates a signal transduction pathway for which ligand is responsible.

[0178] Alternatively, the effect may be one in which the antibody elicits a physiological result by virtue of binding to an effector binding site on the target molecule. In this case the target, a receptor having an endogenous ligand which may be absent or defective in the disease or pathology, binds the antibody as a surrogate effector ligand, initiating a receptor-based signal transduction event by the receptor.

[0179] A therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target, and in other cases, promotes a physiological response. The amount required to be administered will Furthermore depend on the binding affinity of the antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered. Common ranges for therapeutically effective dosing, of an antibody or antibody fragment of the invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week.

[0180] Pharmaceutical Compositions of Antibodies

[0181] Antibodies specifically binding a protein of the invention, as well as other molecules identified by the screening assays disclosed herein, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington: The Science And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa.: 1995; Drug Absorption Enhancement: Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York.

[0182] If the antigenic protein is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein can also contain more than one active compound as necessary for the particular indication being, treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

[0183] The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions.

[0184] The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

[0185] Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.

[0186] ELISA Assay

[0187] An agent for detecting an analyte protein is an antibody capable of binding to an analyte protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e g., Fab or F(ab)2) can be used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e, physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term “biological sample” is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term “biological sample”, therefore, is blood and a fi-action or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting immunoassays are described, for Example in “ELISA: Theory and Practice: Methods in Molecular Biology”, Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, N.J., 1995; “Immunoassay”, E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, Calif., 1996; and “Practice and Thory of Enzyme Immunoassays”, P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-an analyte protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

[0188] NOVX Recombinant Expression Vectors and Host Cells

[0189] Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a NOVX protein, or derivatives, fragments, analogs or homologs thereof. As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid”, which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e g, non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as “expression vectors”. In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, “plasmid” and “vector” can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

[0190] The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably-linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).

[0191] The term “regulatory sequence” is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., NOVX proteins, mutant forms of NOVX proteins, fusion proteins, etc.).

[0192] The recombinant expression vectors of the invention can be designed for expression of NOVX proteins in prokaryotic or eukaryotic cells. For example, NOVX proteins can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed Further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for Example using T7 promoter regulatory sequences and T7 polymerase.

[0193] Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: (i) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (lit) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathione S-transferase (GsST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.

[0194] Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al., (1988) Gene 69:301-315) and pET 11d (Studier et al., GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89).

[0195] One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E coli (see, e.g, Wada, et al., 1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques.

[0196] In another embodiment, the NOVX expression vector is a yeast expression vector. Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSec1 (Baldari, et al., 1987. EMBO. J. 6: 229-234), pMFa (Kurjan and Herskowitz, 1982. Cell 30: 933-943), pJRY88 (Schultz et al., 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and picZ (In Vitrogen Corp, San Diego, Calif.).

[0197] Alternatively, NOVX can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g, SF9 cells) include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39).

[0198] In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING;: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor N.Y.; 1989.

[0199] In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Banerji, et al., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, e g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the α-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546).

[0200] The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to NOVX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see, e g., Weintraub, et al., “Antisense RNA as a molecular tool for genetic analysis,” Reviews-Trends in Genetics, Vol. 1(1) 1986.

[0201] Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms “host cell” and “recombinant host cell” are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the tern as used herein.

[0202] A host cell can be any prokaryotic or eukaryotic cell. For example, NOVX protein can be expressed in bacterial cells such as E coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.

[0203] Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms “transformation” and “transfection” are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.

[0204] For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding NOVX or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).

[0205] A host cell of the invention, such as a prokaryote or eukaryotic host cell in culture, can be used to produce (i.e., express) NOVX protein. Accordingly, the invention further provides methods for producing NOVX protein using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding NOVX protein has been introduced) in a suitable medium such that NOVX protein is produced. In another embodiment, the method Further comprises isolating NOVX protein from the medium or the host cell.

[0206] Transgenic NOVX Animals

[0207] The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which NOVX protein-coding sequences have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous NOVX sequences have been introduced into their genome or homologous recombinant animals in which endogenous NOVX sequences have been altered. Such animals are useful for studying the function and/or activity of NOVX protein and for identifying and/or evaluating modulators of NOVX protein activity. As used herein, a “transgenic animal” is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a “homologous recombinant animal” is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous NOVX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.

[0208] A transgenic animal of the invention can be created by introducing NOVX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by microinjection, retroviral infection) and allowing the oocyte to develop in a pseudopregnant female foster animal. The human NOVX cDNA sequences, i.e, any one of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, can be introduced as a transgene into the genome of a non-human animal. Alternatively, a non-human homologue of the human NOVX gene, such as a mouse NOVX gene, can be isolated based on hybridization to the human NOVX cDNA (described further supra) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequences) can be operably-linked to the NOVX transgene to direct expression of NOVX protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866; 4,870,009; and 4,873,191; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the NOVX transgene in its genome and/or expression of NOVX mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene-encoding NOVX protein can further be bred to other transgenic animals carrying other transgenes.

[0209] To create a homologous recombinant animal, a vector is prepared which contains at least a portion of a NOVX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the NOVX gene. The NOVX gene can be a human gene (e.g., the cDNA of any one of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51), but more preferably, is a non-human homologue of a human NOVX gene. For example, a mouse homologue of human NOVX gene of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, can be used to construct a homologous recombination vector suitable for altering an endogenous NOVX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous recombination, the endogenous NOVX gene is functionally disrupted (i e, no longer encodes a functional protein; also referred to as a “knock out” vector).

[0210] Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous NOVX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous NOVX protein). In the homologous recombination vector, the altered portion of the NOVX gene is flanked at its 5′- and 3′-termini by additional nucleic acid of the NOVX gene to allow for homologous recombination to occur between the exogenous NOVX gene carried by the vector and an endogenous NOVX gene in an embryonic stem cell. The additional flanking NOVX nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5′- and 3′-termini) are included in the vector. See, e.g., Thomas, et al., 1987. Cell 51: 503 for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stein cell line (e.g., by electroporation) and cells in which the introduced NOVX gene has homologously-recombined with the endogenous NOVX gene are selected. See, e.g., Li, et al., 1992. Cell 69: 915.

[0211] The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras. See, e g., Bradley, 1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously-recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously-recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described Further in Bradley, 1991. Curr. Opin. Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354; WO 91/01140; WO 92/0968; and WO 93/04169.

[0212] In another embodiment, transgenic non-humans animals can be produced that contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. For a description of the cre/loxP recombinase system, See, e.g, Lakso, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 6232-6236. Another Example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See. O'Gorman, et al., 1991. Science 251: 1351-1355. If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of “double” transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

[0213] Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al., 1997. Nature 385: 810-813. In brief, a cell (e g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G0 phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone of the animal from which the cell (e.g., the somatic cell) is isolated.

[0214] Pharmaceutical Compositions

[0215] The NOVX nucleic acid molecules, NOVX proteins, and anti-NOVX antibodies (also referred to herein as “active compounds”) of the invention, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0216] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e, topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass of plastic.

[0217] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0218] Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a NOVX protein or anti-NOVX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0219] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following, ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent Such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0220] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0221] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0222] The compounds can also be prepared in the form of suppositories (e.g., with conventional Suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0223] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal Suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0224] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0225] The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Pat. No. 5,328,470) or by stereotactic injection (see, e.g., Chen, et al., 1994. Proc. Natl. Acad. Sci USA 91: 3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system.

[0226] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0227] Screening and Detection Methods

[0228] The isolated nucleic acid molecules of the invention can be used to express NOVX protein (e.g, via a recombinant expression vector in a host cell in gene therapy applications), to detect NOVX mRNA (e.g, in a biological sample) or a genetic lesion in a NOVX genie, and to modulate NOVX activity, as described Further, below. In addition, the NOVX proteins can be used to screen drugs or compounds that modulate the NOVX protein activity or expression as well as to treat disorders characterized by insufficient or excessive production of NOVX protein or production of NOVX protein forms that have decreased or aberrant activity compared to NOVX wild-type protein (e.g.; diabetes (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting disorders associated with chronic diseases and various cancers, and infectious disease (possesses anti-microbial activity) and the various dyslipidemias. In addition, the anti-NOVX antibodies of the invention can be used to detect and isolate NOVX proteins and modulate NOVX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absorption of nutrients and the disposition of metabolic substrates in both a positive and negative fashion.

[0229] The invention Further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra

[0230] Screening Assays

[0231] The invention provides a method (also referred to herein as a “screening assay”) for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to NOVX proteins or have a stimulatory or inhibitory effect on, e.g., NOVX protein expression or NOVX protein activity. The invention also includes compounds identified in the screening assays described herein.

[0232] In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity of the membrane-bound form of a NOVX protein or polypeptide or biologically-active portion thereof. The test compounds of-the invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the “one-bead one-compound” library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other foul approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 1997. Anticancer Drug Design 12: 145.

[0233] A “small molecule” as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention.

[0234] Examples of methods for the synthesis of molecular libraries can be found in the art, for Example in: DeWitt, et al., 1993. Proc. Natl. Acad. Sci USA. 90: 6909; Erb, et al., 1994. Proc. Natl. Acad Sci. U.S.A. 91: 11422; Zuckermann, et al., 1994. J. Med. Chem. 37: 2678; Cho, et al., 1993. Science 261: 1303; Carrell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33:2059; Carell, et al., 1994. Angew Chem Int. Ed. Engl. 33:2061; and Gallop, et al., 1994. J. Med. Chem. 37:1233.

[0235] Libraries of compounds may be presented in solution (e g, Houghten, 1992. Biotechniques 13:412-421), or on beads (Lam, 1991. Nature 354:82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Pat. No. 5,223,409), spores (Ladner, U.S. Pat. No. 5,233,409), plasmids (Cull, et al., 1992. Proc. Nucl. Acad. Sci. USA 89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249:386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al., 1990. Proc. Natl. Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol. Biol 222:301-310; Ladner, U.S. Pat. No. 5,233,409.).

[0236] In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof on the cell surface is contacted with a test compound and the ability of the test compound to bind to a NOVX protein determined. The cell, for example, can of mammalian origin or a yeast cell. Determining the ability of the test compound to bind to the NOVX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding, of the test Compound to the NOVX protein or biologically-active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with 125I, 35S, 14C, or 3H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a known Compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining, the ability of the test compound to interact with a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX protein or a biologically-active portion thereof as compared to the known compound.

[0237] In another embodiment, an assay is a cell-based assay comprising contacting a cell expressing a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX or a biologically-active portion thereof can be accomplished, for example, by determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule. As used herein, a “target molecule” is a molecule with which a NOVX protein binds or interacts in nature, for example, a molecule on the surface of a cell which expresses a NOVX interacting protein, a molecule on the Surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal surface of a cell membrane or a cytoplasmic molecule. A NOVX target molecule can be a non-NOVX molecule or a NOVX protein or polypeptide of the invention. In one embodiment, a NOVX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of a compound to a membrane-bound NOVX molecule) through the cell membrane and into the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with NOVX.

[0238] Determining, the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by one of the methods described above for determining direct binding. In one embodiment, determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by determining the activity of the target molecule. For example, the activity of the target molecule can be determined by detecting induction of a cellular second messenger of the target (i.e. intracellular Ca2+, diacylglycerol, IP3, etc), detecting catalytic/enzymatic activity of the target an appropriate substrate, detecting the induction of a reporter gene (comprising a NOVX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or detecting a cellular response, for example, cell survival, cellular differentiation, or cell proliferation.

[0239] In yet another embodiment, an assay of the invention is a cell-free assay comprising contacting a NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to bind to the NOVX protein or biologically-active portion thereof. Binding of the test compound to the NOVX protein can be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX or biologically-active portion thereof as compared to the known compound.

[0240] In still another embodiment, an assay is a cell-free assay comprising contacting NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to modulate (e.g stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining, the ability of the test compound to modulate the activity of NOVX can be accomplished, for example, by determining the ability of the NOVX protein to bind to a NOVX target molecule by one of the methods described above for determining direct binding. In an alternative embodiment, determining the ability of the test compound to modulate the activity of NOVX protein can be accomplished by determining the ability of the NOVX protein further modulate a NOVX target molecule. For example, the catalytic/enzymatic activity of the target molecule on an appropriate substrate can be determined as described, supra.

[0241] In yet another embodiment, the cell-free assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the NOVX protein to preferentially bind to or modulate the activity of a NOVX target molecule.

[0242] The cell-free assays of the invention are amenable to use of both the soluble form or the membrane-bound forth of NOVX protein. In the case of cell-free assays comprising the membrane-bound form of NOVX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of NOVX protein is maintained in solution. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X-100, Triton® X-114, Thesit®, Isotridecypoly(ethylene glycol ether)n, N-dodecyl-N,N-dimethyl-3-ammonio-1-propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1-propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate (CHAPSO).

[0243] In more than one embodiment of the above assay methods of the invention, it may be desirable to immobilize either NOVX protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Binding of a test compound to NOVX protein, or interaction of NOVX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix. For example, GST-NOVX fusion proteins or GST-target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or NOVX protein, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra. Alternatively, the complexes can be dissociated from the matrix, and the level of NOVX protein binding or activity determined using standard techniques.

[0244] Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either the NOVX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated NOVX protein or tar-get molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with NOVX protein or target molecules, but which do not interfere with binding of the NOVX protein to its target molecule, can be derivatized to the wells of the plate, and unbound target or NOVX protein trapped in the wells by antibody conjugation. Methods for detecting, such complexes, in addition to those described above for the GS-immobilized complexes, include immunodetection of complexes using antibodies reactive with the NOVX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the NOVX protein or target molecule.

[0245] In another embodiment, modulators of NOVX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of NOVX mRNA or protein in the cell is determined. The level of expression of NOVX mRNA or protein in the presence of the candidate compound is compared to the level of expression of NOVX mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of NOVX mRNA or protein expression based upon this comparison. For example, when expression of NOVX mRNA or protein is greater (i.e., statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of NOVX mRNA or protein expression. Alternatively, when expression of NOVX mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of NOVX mRNA or protein expression. The level of NOVX mRNA or protein expression in the cells can be determined by methods described herein for detecting NOVX mRNA or protein.

[0246] In yet another aspect of the invention, the NOVX proteins can be used as “bait proteins” in a two-hybrid assay or three hybrid assay (see, e g, U.S. Pat. No. 5,283,317; Zervos, et al., 1993. Cell 72: 223-232; Madura, et al., 1993. J. Biol. Chem. 268: 12046-12054; Bartel, et al., 1993. Biotechniques 14: 920-924; Iwabuchi, et al., 1993. Oncogene 8: 1693-1696; and Brent WO 94/10300), to identify other proteins that bind to or interact with NOVX (“NOVX-binding proteins” or “NOVX-bp”) and modulate NOVX activity. Such NOVX-binding proteins are also involved in the propagation of signals by the NOVX proteins as, for example, upstream or downstream elements of the NOVX pathway.

[0247] The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for NOVX is fused to a gene encoding the DNA bindings domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein (“prey” or “sample”) is fused to a gene that codes for the activation domain of the known transcription factor. If the “bait” and the “prey” proteins are able to interact, in vivo, forming a NOVX-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein which interacts with NOVX.

[0248] The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein.

[0249] Detection Assays

[0250] Portions or fragments of the cDNA sequences identified herein (and the corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: (i) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (ii) identity an individual from a minute biological sample (tissue typing); and (iii) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below.

[0251] Chromosome Mapping

[0252] Once the sequence (or a portion of the sequence) of a gene has been isolated, this sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments of the NOVX sequences of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, or fragments or derivatives thereof, can be used to map the location of the NOVX genes, respectively, on a chromosome. The mapping, of the NOVX sequences to chromosomes is an important first step in correlating these sequences with genes associated with disease.

[0253] Briefly, NOVX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the NOVX sequences. Computer analysis of the NOVX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing, the human gene corresponding to the NOVX sequences will yield an amplified fragment

[0254] Somatic cell hybrids are prepared by fusing somatic cells from different mammals (e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, et al., 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions.

[0255] PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using, a single thermal cycler. Using the NOVX sequences to design oligonucleotide primers, sub-localization can be achieved with panels of fragments from specific chromosomes.

[0256] Fluorescence in Situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can Further be used to provide a precise chromosomal location in one step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a DNA sequence as short as 500 or 600 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al., HUMAN CHROMOSOMES: A MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988).

[0257] Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.

[0258] Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, e.g., in McKusick, MENDELIAN INHERITANCE IN MAN, available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland, et al., 1987. Nature, 325: 783-787.

[0259] Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the NOVX gene, can be determined. If a mutation is observed in some or all of the affected individuals but not any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are visible from chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms.

[0260] Tissue Typing

[0261] The NOVX sequences of the invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences of the invention are useful as additional DNA markers for RFLP (“restriction fragment length polymorpilsnis,” described in U.S. Pat. No. 5,272,057).

[0262] Furthermore, the sequences of the invention can be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the NOVX sequences described herein can be used to prepare two PCR primers from the 5′- and 3′-termini of the sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it.

[0263] Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences of the invention can be used to obtain such identification sequences from individuals and from tissue. The NOVX sequences of the invention uniquely represent portions of the human genome Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Much of the allelic variation is due to single nucleotide polymorphisms (SNPs), which include restriction fragment length polymorphisms (RFLPs).

[0264] Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If coding sequences, such as those of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, are used, a more appropriate number of primers for positive individual identification would be 500-2,000.

[0265] Predictive Medicine

[0266] The invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the invention relates to diagnostic assays for determining NOVX protein and/or nucleic acid expression as well as NOVX activity, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, associated with aberrant NOVX expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. For example, mutations in a NOVX gene can be assayed in a biological sample. Such assays can be used for prognostic or predictive purpose to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with NOVX protein, nucleic acid expression, or biological activity.

[0267] Another aspect of the invention provides methods for determining NOVX protein, nucleic acid expression or activity in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (referred to herein as “pharmacogenomics”). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual examined to determine the ability of the individual to respond to a particular agent.)

[0268] Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs, Compounds) on the expression or activity of NOVX in clinical trials.

[0269] These and other agents are described in Further detail in the following, sections.

[0270] Diagnostic Assays

[0271] An exemplary method for detecting the presence or absence of NOVX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting, NOVX protein or nucleic acid (e.g, mRNA, genomic DNA) that encodes NOVX protein such that the presence of NOVX is detected in the biological sample. An agent for detecting NOVX mRNA or (genomic DNA is a labeled nucleic acid probe capable of hybridizing to NOVX mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length NOVX nucleic acid, such as the nucleic acid of SEQ ID NO:2n−1, wherein n is an integer between 1 and 51, or a portion thereof such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to NOVX mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein.

[0272] An agent for detecting NOVX protein is an antibody capable of binding to NOVX protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab′)2) can be used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by Coupling (i e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term “biological sample” is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect NOVX mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of NOVX mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of NOVX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of NOVX genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of NOVX protein include introducing into a subject a labeled anti-NOVX antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

[0273] In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject.

[0274] In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting NOVX protein, mRNA, or genomic DNA, such that the presence of NOVX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of NOVX protein, mRNA or genomic DNA in the control sample with the presence of NOVX protein, mRNA or genomic DNA in the test sample.

[0275] The invention also encompasses kits for detecting the presence of NOVX in a biological sample. For example, the kit can comprise: a labeled compound or agent capable of detecting, NOVX protein or mRNA in a biological sample; means for determining the amount of NOVX in the sample; and means for comparing the amount of NOVX in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can Further comprise instructions for using the kit to detect NOVX protein or nucleic acid.

[0276] Prognostic Assays

[0277] The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant NOVX expression or activity in which a test sample is obtained from a subject and NOVX protein or nucleic acid (e.g, mRNA, genomic DNA) is detected, wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. As used herein, a “test sample” refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., serum), cell sample, or tissue.

[0278] Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant NOVX expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder. Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with aberrant NOVX expression or activity in which a test sample is obtained and NOVX protein or nucleic acid is detected (e.g., wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant NOVX expression or activity).

[0279] The methods of the invention can also be used to detect genetic lesions in a NOVX gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding a NOVX-protein, or the misexpression of the NOVX gene. For example, such genetic lesions can be detected by ascertaining the existence of at least one of (i) a deletion of one or more nucleotides from a NOVX gene; (ii) an addition of one or more nucleotides to a NOVX gene; (iii) a substitution of one or more nucleotides of a NOVX gene, (iv) a chromosomal rearrangement of a NOVX gene; (v) an alteration in the level of a messenger RNA transcript of a NOVX gene, (vi) aberrant modification of a NOVX gene, such as of the methylation pattern of the genomic DNA, (vii) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of a NOVX gene, (viii) a non-wild-type level of a NOVX protein, (ix) allelic loss of a NOVX gene, and (x) inappropriate post-translational modification of a NOVX protein. As described herein, there are a large number of assay techniques known in the art which can be used for detecting lesions in a NOVX gene A preferred biological sample is peripheral blood leukocyte sample isolated by conventional means from a subject. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

[0280] In certain embodiments, detection of the lesion involves the use of a probe/primer II a polymerase chain reaction (PCR) (see, e.g., U.S. Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran, et al., 1988. Science 241: 1077-1080; and Nakazawa, et al., 1994. Proc Natl. Acad, Sci. USA 91: 360-364), the latter of which can be particularly useful for detecting point mutations in the NOVX-gene (see, Abravaya, et al., 1995. Nucl Acids Res. 23: 675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to a NOVX gene under conditions such that hybridization and amplification of the NOVX gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.

[0281] Alternative amplification methods include: self sustained sequence replication (see, Guatelli, et al., 1990. Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (see, Kwoh, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 1173-1177); Qβ Replicase (see, Lizardi, et al, 1988. BioTechnology 6: 1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.

[0282] In an alternative embodiment, mutations in a NOVX gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, e g., U.S. Pat. No. 5,493,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.

[0283] In other embodiments, genetic mutations in NOVX can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high-density arrays containing hundreds or thousands of oligonucleotides probes. See, e.g., Cronin, et al., 1996. Human Mutation 7: 244-255; Kozal, et al., 1996. Nat. Med. 2: 753-759. For example, genetic mutations in NOVX can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, et al., supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.

[0284] In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the NOVX gene and detect mutations by comparing the sequence of the sample NOVX with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl. Acad. Sci. USA 74: 560 or Sanger, 1977. Proc. Natl. Acad. Sci. USA 74: 5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays (,see, e.g., Naeve, et al., 1995. Biotechniques 19: 448), including sequencing by mass spectrometry (see, e.g, PCT International Publication No. WO 94/16101; Cohen, et al., 1996. Adv. Chromatography 36: 127-162; and Griffin, et al., 1993. Appl Biochem. Biotechnol. 38: 147-159).

[0285] Other methods for detecting mutations in the NOVX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers, et al., 1985. Science 230: 1242. In general, the art technique of “mismatch cleavage” starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type NOVX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with S1 nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine tile site of mutation. See, e.g., Cotton, et al., 1988. Proc. Natl. Acad. Sci. USA 85: 4397; Saleeba, et al, 1992. Methods Enzymol. 217: 286-295. In an embodiment, the control DNA or RNA can be labeled for detection.

[0286] In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called “DNA mismatch repair” enzymes) in defined systems for detecting and mapping point mutations in NOVX cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves Tat G/T mismatches. See, e.g., list, et al., 1994. Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, a probe based on a NOVX sequence, e.g., a wild-type NOVX sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g, U.S. Pat. No. 5,459,039.

[0287] In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in NOVX genes. For example, single strand conformation polymorphisim (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids. See, e.g., Orita, et al., 1989. Proc. Natl. Acad. Sci. USA: 86: 2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Appl. 9: 73-79. Single-stranded DNA fragments of sample and control NOVX nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility. See, e.g., Keen, et al., 1991. Trends Genet 7: 5.

[0288] In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE). See, e.g, Myers, et al., 1985. Nature 313: 495. When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for Example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a Further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA. See, e.g., Rosenbaum and Reissner, 1987. Biophys. Chem. 265: 12753.

[0289] Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al., 1986. Nature 324: 163; Saiki, et al., 1989. Proc Natl. Acad. Sci. USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.

[0290] Alternatively, allele specific amplification technology that depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, et al., 1989. Nucl. Acid Res. 17: 2437-2448) or at the extreme 3′-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 11: 238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection. See, e.g., Gasparin, et al., 1992. Mol. Cell Probes 6: 1. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification. See, e.g., Barany, 1991. Proc Natl. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3′-terminus of the 5′ sequence, making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.

[0291] The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a NOVX gene

[0292] Furthermore, any cell type or tissue, preferably peripheral blood leukocytes, in which NOVX is expressed may be utilized in the prognostic assays described herein. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

[0293] Pharmacogenomics

[0294] Agents, or modulators that have a stimulatory or inhibitory effect on NOVX activity (e.g., NOVX gene expression), as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) disorders. The disorders include but are not limited to, e g., those diseases, disorders and conditions listed above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table A.

[0295] In conjunction with such treatment, the pharmacogenomics (I e, the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) of the individual may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics of the individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can Further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual.

[0296] Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol., 23: 983-985; Linder, 1997. Clin. Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

[0297] As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome pregnancy zone protein precursor enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among, different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.

[0298] Thus, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping, of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an Individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a NOVX modulator, such as a modulator identified by one of the exemplary screening assays described herein.

[0299] Monitoring of Effects During Clinical Trials

[0300] Monitoring the influence of agents (e.g, drugs, compounds) on the expression or activity of NOVX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase NOVX gene expression, protein levels, or upregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting decreased NOVX gene expression, protein levels, or downregulated NOVX activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease NOVX gene expression, protein levels, or downregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting increased NOVX gene expression, protein levels, or upregulated NOVX activity. In such clinical trials, the expression or activity of NOVX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a “read out” or markers of the immune responsiveness of a particular cell.

[0301] By way of example, and not of limitation, genes, including NOVX, that are modulated in cells by treatment with an agent (e g, compound, drug or small molecule) that modulates NOVX activity (e.g, identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of NOVX and other genes implicated in the disorder. The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of NOVX or other genies. In this manner, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent.

[0302] In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of a NOVX protein, mRNA, or genomic DNA in the preadministration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the pre-administration sample with the NOVX protein, mRNA, or genomic DNA in the post administration sample or samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased administration of the agent may be desirable to increase the expression or activity of NOVX to higher levels than detected, i.e., to increase the effectiveness of the agent. Alternatively, decreased administration of the agent may be desirable to decrease expression or activity of NOVX to lower levels than detected, i.e., to decrease the effectiveness of the agent.

[0303] Methods of Treatment

[0304] The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant NOVX expression or activity. The disorders include but are not limited to, e g., those diseases, disorders and conditions listed above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table A.

[0305] These methods of treatment will be discussed more fully, below.

[0306] Diseases and Disorders

[0307] Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that antagonize (i e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to: (i) an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (it) antibodies to an aforementioned peptide; (iii) nucleic acids encoding an aforementioned peptide; (iv) administration of antisense nucleic acid and nucleic acids that are “dysfunctional” (i.e., due to a heterologous insertion within the coding sequences of coding sequences to an aforementioned peptide) that are utilized to “knockout” endogenous function of an aforementioned peptide by homologous recombination (see, e.g., Capeechi, 1989. Science 244: 1288-1292); or (v) modulators (i e, inhibitors, agonists and antagonists, including additional peptide mimetic of the invention or antibodies specific to a peptide of the invention) that alter the interaction between an aforementioned peptide and its binding partner.

[0308] Diseases and disorders that are characterized by decreased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability.

[0309] Increased or decreased levels can be readily detected by quantifying peptide and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or peptide levels, structure and/or activity of the expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot blots, in situ hybridization, and the like).

[0310] Prophylactic Methods

[0311] In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant NOVX expression or activity, by administering to the subject an agent that modulates NOVX expression or at least one NOVX activity. Subjects at risk for a disease that is caused or contributed to by aberrant NOVX expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the NOVX aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending upon the type of NOVX aberrancy, for example, a NOVX agonist or NOVX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections.

[0312] Therapeutic Methods

[0313] Another aspect of the invention pertains to methods of modulating NOVX expression or activity for therapeutic purposes. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of NOVX protein activity associated with the cell. An agent that modulates NOVX protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of a NOVX protein, a peptide, a NOVX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more NOVX protein activity. Examples of such stimulatory agents include active NOVX protein and a nucleic acid molecule encoding NOVX that has been introduced into the cell. In another embodiment, the agent inhibits one or more NOVX protein activity. Examples of such inhibitory agents include antisense NOVX nucleic acid molecules and anti-NOVX antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e g., by administering the agent to a subject). As such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of a NOVX protein or nucleic acid molecule. In one embodiment, the method involves administering an a gent (e g, an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) NOVX expression or activity. In another embodiment, the method involves administering a NOVX protein or nucleic acid molecule as therapy to compensate for reduced or aberrant NOVX expression or activity.

[0314] Stimulation of NOVX activity is desirable in situations in which NOVX is abnormally downregulated and/or in which increased NOVX activity is likely to have a beneficial effect. One Example of such a situation is where a subject has a disorder characterized by aberrant cell proliferation and/or differentiation (e.g, cancer or immune associated disorders). Another Example of such a situation is where the subject has a gestational disease (e.g., preclampsia).

[0315] Determination of the Biological Effect of the Therapeutic

[0316] In various embodiments of the invention, suitable in vitro or in vivo assays are performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue.

[0317] In various specific embodiments, in vitro assays may be performed with representative cells of the type(s) involved in the patient's disorder, to determine if a given Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects. Similarly, for in vivo testing, any of the animal model system known in the art may be used prior to administration to human subjects.

[0318] Prophylactic and Therapeutic Uses of the Compositions of the Invention

[0319] The NOVX nucleic acids and proteins of the invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders. The disorders include but are not limited to, e.g., those diseases, disorders and conditions listed above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table A.

[0320] As an example, a cDNA encoding the NOVX protein of the invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof by way of non-limiting example, the compositions of the invention will have efficacy for treatment of patients suffering from diseases, disorders, conditions and the like, including but not listed to those listed herein.

[0321] Both the novel nucleic acid encoding the NOVX protein, and the NOVX protein of the invention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. A further use could be as an anti-bacterial molecule (i.e., some peptides have been found to possess anti-bacterial properties). These materials are Further useful in the generation of antibodies, which immunospecifically-bind to the novel substances of the invention for use in therapeutic or diagnostic methods.

[0322] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

EXAMPLES

Example A

Polynucleotide and Polypeptide Sequences, and Homology Data

Example 1

[0323] The NOV1 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 1A.

2TABLE 1ANOV1 Sequence AnalysisSEQ ID NO: 12584 bpNOV1a,GGAGCAGGAGCTCCGCCTAGCTCTGCGCCCTGGAGCGAGGTGTAGAAAGAGGTACATGCG102232-01DNA SequenceGAGAACAAGTTTGTCAATCCGTCTCAACTTCAGTTGCCTTACCTGTAAGGCAGCCGTGTCTGTGTTTTTGTCTCGCAGAATTAGAGCCCATTGGGAACGATGCCACCACCGTCAGACATTGTCAAAGTGGCCATTGAGTGGCCAGGTGCTAACGCCCAGCTCCTTGAAATCGACCACAAACCGCCCCTGGCATCCATTATCAAGGAAGTTTGTGATGGGTGGTCGTTGCCAAACCCAGACTATTATACCCTCCGTTATGCAGATCGTCCTCAGCTGTACATCACCGAACAGACTCGCACTGACATTAAGAATGGGACAATCTTACAACTGGCTATCTCCCCGTCCCGGGCTGCGCGCCAGCTGATGGAGAGGACCCAGTCATCCAACATGGAGACCCGGCTGGATGCCATGAAGGAGCTGGCCAAGCTCTCTGCCGACGTGACTTTCGCTACTGAGTTCATCAACATGGATGGCATCATTGTGCTGACAAGGCTCGTGGAAAGTGGAACCAAGCTCTTGTCCCACTACAGTGAGATGCTGGCATTCACCCTGACTGCCTTCCTAGACCTCATCGACCATGGCATTGTCTCCTGGGACATGGTTTCAATCACCTTTATTAAGCAGATTGCAGGGTATGTGAGCCAGCCCATGGTGGACGTGTCAATCCTTCAGAGGTCCCTCGCCATCCTGGACAGCATGGTCTTCAACAGCCAGAGTCTGTACCACAAGATAGCCGACGAAATCACCGTGGGACAGCTCATCTCACACCTCCAGGTCTCCAACCAGGAGATTCAGACCTACGCCATTGCACTGATTAATGCACTTTTTCTCAAGCCTCCTGAGGACAAACGACACGATATCGCAAATGCATTTGCACAGAAGCATCTCCGGTCTATAATCCTGAATCATGTGATCCGAGGGAACCGCCCCATCAAAACTGAGATGGCCCATCAGCTATATGTCCTTCAAGTCCTAACCTTTAACCTTCTGGAAGAAAGGATGATGACCAAGATGGACCCCAATGACCAGGCTCAAAGGGACATCATATTTGAACTGAGGAGGATTGCATTTGACGCAGAGTCTGATCCTAGCAATGCCCCTGGGAGTGGGACCGAAAAACGCAAAGCCATGTACACAAAGGACTACAAAATGCTGGGATTTACCAACCACATCAATCCAGCCATGGACTTTACCCAGACTCCTCCTGGAATGCTGGCCTTGGACAACATGCTGTACTTGGCTAAAGTCCACCAGGACACCTACATCCGGATTGTCTTGGAGAACAGTAGCCGGGAAGACAAACATGAATGCCCCTTTGGCCGCAGTGCCATTGAGCTCACCAAAATGCTCTGTGAAATCCTGCAGGTTGGGGAACTACCAAATGAAGGACGCAATGACTACCACCCGATGTTCTTTACCCATGACCGAGCCTTTGAAGAGCTCTTTGGAATCTGCATCCAGCTGTTGAACAAGACCTGGAAGGAGATGAGGGCAACAGCAGAGGACTTCAACAAGGTTATGCAAGTCGTCCGAGAGCAAATCACTCGAGCTTTGCCCTCCAAACCCAACTCTTTGGATCAGTTCAAGAGCAAATTGCGTAGCCTGAGTTACTCTGAGATTCTACGACTGCGCCAGTCTGAGAGGATGAGTCAGGATGACTTCCAGTCCCCGCCAATTGTGGAGCTGAGGGAGAAGATCCAGCCCGAGATCCTTGAGCTGATCAAGCAGCAGCGCCTGAACCGGCTCTGTGAGGGCAGCAGCTTCCGAAAGATTGGGAACCGCCGAAGGCAAGAACGGTTCTGGTACTGCCGGTTGGCACTGAACCACAAGGTCCTTCACTATGGTGACTTGGATGACAACCCACAAGGGGAGGTGACATTTGAATCCCTGCAGGAGAAAATTCCTGTTGCAGACATTAAGGCCATTGTCACTGGGAAAGATTGTCCCCACATGAAAGAGAAAAGTGCTCTGAAACAGAACAAGGAGGTGTTGGAATTGGCCTTCTCCATCCTGTATGACCCTGATGAGACCTTAAACTTCATCGCACCTAATAAATATGAGTACTGCATCTGGATTGACGGCCTCAGTGCCCTTCTGGGGAAGGACATGTCCAGTGAGCTGACCAAGAGTGACCTGGACACCcTCCTGAGCATGGAGATGAAGCTGCGGCTCCTGCACCTGGACAACATCCAGATTCCCGPAGCCCCACCCCCCATCCCCAAGGAGCCCAGCAGCTATGACTTTGTCTATCACTATGCCTGAGCCTGGAGCCAGAAACCACCGTACCCAGGAGAAGGGATTTTGGGCCCAGGAGAAACACTTACATTCTGGTGCCTTGTCTTTTCCTTGTACAGAATCTGTAGTGATTTTGGTGGCCAGTAAATGCCAGCCATTTCTCAAACCCACCTCCGACCACCCAGAGTTTCCTCTTGGTCCCTGTCTACTAAGAGTCATGAACGCAGGTTGCTCTGCCCACTCCATCACCATGAAGCCTGGGATTGGGCCACGAGGAACAAACACCAGATGORF Start: ATG at 158ORF Stop: TGA at 2318SEQ ID NO:2720 aaMW at 82614.1DaNOV1a,MPPPSDIVKVAIEWPGANAQLLEIDQKRPLASIIKEVCDGWSLPNPEYYTLRYADGPQCG102232-01Protein SequenceLYITEQTRSDIKNGTILQLAISPSRAARQLMERTQSSNMETRLDAMKELAKLSADVTFATEFINMDGIIVLTRLVESGTKLLSHYSEMLAFTLTAFLELMDHGIVSWDMVSITFIKQIAGYVSQPMVDVSILQRSLAILESMVLNSQSLYQKIAEEITVGQLISHLQVSNQEIQYTAIALINALFLKAPEDKRQDMANAFAQKHLRSIILNHVIRGNRPIKTEMAHQLYVLQVLTFNLLEERMMTKMDPNDQAQRDIIFELRRIAFDAESDPSNAPGSGTEKRKAMYTKDYKMLGFTNHINPAMDFTQTPPGMLALDNMLYLAKVHQDTYIRIVLENSSREDKHECPFGRSAIELTKMLCEILQVGELPNEGRNDYHPMFFTHDRAFEELFGICIQLLNKTWKEMRATAEDFNKVMQVVREQITRALPSKPNSLDQFKSKLRSLSYSEILRLRQSERMSQDDFQSPPIVELREKIQPEILELIKQQRLNRLCEGSSFRKIGNRRRQERFWYCRLALNHKVLHYGDLDDNPQGEVTFESLQEKIPVADIKAIVTGKDCPHMKEKSALKQNKEVLELAFSILYDPDETLNFIAPNKYEYCIWIDGLSALLGKDMSSELTKSDLDTLLSMEMKLRLLDLENIQIPEAPPPIPKEPSSYDFVYHYG

[0324] Further analysis of the NOV1a protein yielded the following properties shown in Table 1B.

3TABLE 1BProtein Sequence Properties NOV1aPSort0.4500 probability located in cytoplasm; 0.3000 probabilityanalysis:located in microbody (peroxisome); 0.1000 probability locatedin mitochondrial matrix space; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0325] A search of the NOV1a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 1C.

4TABLE 1CGenseq Results for NOV1aNOV1aIdentities/Protein/Residues/Similarities forGenseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAW96153Human FADD- 1 . . . 717548/7250.0interacting protein (75%)(FIP)—Homo 1 . . . 724643/725sapiens, 727 aa. (88%)[WO9900499-A1,07 JAN. 1999]AAB93788Human protein282 . . . 720437/4390.0sequence SEQ ID (99%)NO: 13537— 1 . . . 439437/439Homo sapiens, (99%)439 aa.[EP1074617-A2,07 FEB. 2001]AAM41711Human poly-297 . . . 720424/4240.0peptide SEQ ID(100%)NO 6642—Homo 2 . . . 425424/424sapiens, 425 aa.(100%)[WO200153312-A1, 26 JUL.2001]AAM39925Human poly-301 . . . 720420/4200.0peptide SEQ ID(100%)NO 3070—Homo 1 . . . 420420/420sapiens, 420 aa.(100%)[WO200153312-A1, 26 JUL.2001]AAB94432Human protein351 . . . 720370/3700.0sequence SEQ ID(100%)NO: 15049— 1 . . . 370370/370Homo sapiens,(100%)370 aa.[EP1074617-A2,07 FEB. 2001]

[0326] In a BLAST search of public sequence datbases, the NOV1a protein was found to have homology to the proteins shown in the BLASTP data in Table 1D.

5TABLE 1DPublic BLASTP Results for NOV1aNOV1aIdentities/ProteinResidues/SimilaritiesAccessionProtein/Matchfor theExpectNumberOrganism/LengthResiduesMatched PortionValueQ96JJ3KIAA1834 protein1 . . . 720720/720 (100%)0.0(ELMO2) (PH6 . . . 725720/720 (100%)domain proteinCED12A)—Homosapiens (Human),725 aa (fragment).Q91ZU2ELMO2—Mus1 . . . 720709/720 (98%) 0.0musculus (Mouse),1 . . . 718717/720 (99%) 718 aa.Q9NQQ6BA394O2.2 (novel1 . . . 720698/720 (96%) 0.0protein similar to1 . . . 699699/720 (96%) KIAA0281 andDrosophilaCG5336)—Homosapiens (Human),699 aa.Q96PB0ELMO1—Homo1 . . . 717548/725 (75%) 0.0sapiens (Human),1 . . . 724643/725 (88%) 727 aa.Q91ZU3ELMO1—Mus1 . . . 717547/725 (75%) 0.0musculus (Mouse),1 . . . 724642/725 (88%) 727 aa.

Example 2

[0327] The NOV2 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 2A

6TABLE 2ANOV2 Sequence AnalysisSEQ ID NO:31478 bpNOV2a,GTGGTGAGGCGGGGATATCTGACACATCTCTCCTTCTGTTTCTGTTTGTGTATGTTTGCG102931-01DNA SequenceTCCTGGTTCTGGGCAGTCACTGGGTAAGAGAAGACTGGAAGCATGTCGGAGTTTTGGTTAATTTCTGCCCCTGGCGATAAGGAAAATTTGCAAGCTCTGGAGAGGATGAATACTGTAACCTCCAAGTCCAACCTGTCTTATAATACCAAATTCGCTATTCCTGACTTCAAGGTGGGGACCTTGGATTCCCTGGTTGGCCTCTCTGATGAGTTGGGGAAACTCGACACCTTTGCTGAAAGCCTCATAAGGAGAATGGCTCAGAGCGTGGTGGAAGTCATGGAGGACTCAAAGGGGAAGGTCCAGGAGCACCTCCTGGCAAACGGAGTTGACTTAACATCCTTTGTGACCCACTTTGAATGGGACATGGCCAAATATCCTGTCAAGCAGCCGCTCGTGAGTGTGGTGGACACAATAGCCAAGCAGCTGGCGCAGATCGAGATGGACCTGAAGTCCCGAACGGCCGCCTACGACACTCTGAAGACAAACCTGGAGAACCTGGAAAAGAAATCCATGGGGAACCTCTTCACCCGGACACTGAGTGATATTGTGAGCAAAGAGGACTTCGTGCTGGATTCTGAATATCTCGTCACACTTCTGGTCATCGTCCCCAAGCCAAACTACTCACAATGGCAAAAAACCTACGAATCTCTCTCAGACATGGTGGTCCCTCGATCAACCAAGCTCATTACTGAGGACAAGGAAGGGGGCCTTTTCACTGTGACTCTGTTTCGAAAAGTGATTGAAGATTTCAAAACCAAGGCCAAAGAAAACAAGACTGTTCGTGAATTTTACTATGATGAGAAGGAAATTGAAAGGGAAAGGGAGGAGATGGCCAGATTGCTGTCTGATAAGAAGCAACAGTATCCCACTTCCTGTGTTGCTCTTAAAAAGGGATCATCCACCTTCCCGGACCACAAGGTTAAGGTAACCCCGCTAGGTAACCCTGATAGGCCTGCTGCGGGGCAGACCGACAGAGAGAGAGAGAGTGAGGGCGAGGGTGAGGGCCCCCTGCTGCGCTGGCTCAAGGTGAACTTCAGTGAAGCCTTCATTGCCTGGATCCACATCAAGGCCCTGAGAGTGTTTGTGGAGTCCGTGCTCAGGTATGGACTACCAGTGAACTTCCAGGCAGTGCTCCTGCAGCCGCATAAGAAGTCATCCACCAAGCGTTTAAGAGAGGTTCTAAACTCTGTCTTCCGACATCTGGATGAAGTAGCCGCTACAAGTATACTGGATGCATCTGTGGAGATCCCGGGACTGCAACTCAATAACCAAGACTATTTTCCTTATGTCTACTTCCATATTGACCTTAGTCTTCTTGACTAGAAAGGCCAGCTGGCACCTCTGTCTCATGTTCGTGCAGATTATTACAGACACCTCTTTCCTTTAGCCAGAGAATGGTTCAAATGTCTTACAGAACTAAORF Start: ATG at 101ORF Stop: TAG at 1379SEQ ID NO: 4426 aaMW at 48581.0DaNOV2a,MSEFWLISAPGDKENLQALERMNTVTSKSNLSYNTKFAIPDFKVGTLDSLVGLSDELGCG102931-01Protein SequenceKLDTFAESLIRRMAQSVVEVMEDSKGKVQEHLLANGVDLTSFVTHFEWDMAKYPVKQPLVSVVDTIAKQLAQIEMDLKSRTAAYDTLKTNLENLEKKSMGNLFTRTLSDIVSKEDFVLDSEYLVTLLVIVPKPNYSQWQKTYESLSDMVVPRSTKLITEDKEGGLFTVTLFRKVIEDFKTKAKENKTVREFYYDEKEIEREREEMARLLSDKKQQYPTSCVALKKGSSTFPDHHVKVTPLGNPDRPAAGQTDRERESEGEGEGPLLRWLKVNFSEAFIAWIHIKALRVFVESVLRYGLPVNFQAVLLQPHKKSSTKRLREVLNSVFRHLDEVAATSILDASVEIPGLQLNNQDYFPYVYFHIDLSLLD

[0328] Further analysis of the NOV2a protein yielded the following properties shown in Table 2B.

7TABLE 2BProtein Sequence Properties NOV2aPSort0.4500 probability located in cytoplasm; 0.3604 probabilityanalysis:located in microbody (peroxisome); 0.1000 probability locatedin mitochondrial matrix space; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0329] A search of the NOV2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 2C.

8TABLE 2CGeneseq Results for NOV2aNOV2aIdentities/Protein/Residues/Similarities forGenseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAB98620Human vacuolar1 . . . 426378/427 (88%)0.0H{circumflex over ( )}+-ATPase C1 . . . 381379/427 (88%)subunit 42—Homosapiens, 381 aa.[WO200131032-A1,03 MAY 2001]ABB67011Drosophila1 . . . 426216/430 (50%) e−117melanogaster poly-2 . . . 384293/430 (67%)peptide SEQ ID NO27825—Drosophilamelanogaster,388 aa.[WO200171042-A2,27 SEP. 2001]ABB63641Drosophila1 . . . 426203/484 (41%)5e−92 melanogaster poly-2 . . . 438281/484 (57%)peptide SEQ ID NO17715—Drosophilamelanogaster,442 aa.[WO200171042-A2,27 SEP. 2001]AAG27623Arabidopsis2 . . . 423145/426 (34%)9e−59 thaliana protein3 . . . 375226/426 (53%)fragment SEQ IDNO: 32533—Arabidopsisthaliana, 375 aa.[EP1033405-A2,06 SEP. 2000]AAG10023Arabidopsis2 . . . 423145/426 (34%)1e−58 thaliana protein3 . . . 375225/426 (52%)fragment SEQ IDNO: 8180—Arabidopsisthaliana, 375 aa.[EP1033405-A2,06 SEP. 2000]

[0330] In a BLAST search of public sequence datbases, the NOV2a protein was found to have homology to the proteins shown in the BLASTP data in Table 2D.

9TABLE 2DPublic BLASTP Results for NOV2aNOV2aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ99L60Similar to ATPase,1 . . . 426392/427 (91%)0.0H+ transporting,1 . . . 427406/427 (94%)lysosomal (vacuolarproton pump) 42 kD—Mus musculus(Mouse), 427 aa.Q96EL8Unknown (protein for1 . . . 426380/427 (88%)0.0MGC: 20253)—Homo1 . . . 381380/427 (88%)sapiens (Human),381 aa.Q91Z42RIKEN cDNA1 . . . 426236/428 (55%)e−1291700025B18 gene−1 . . . 380320/428 (74%)Mus musculus(Mouse), 382 aa.P21283Vacuolar ATP1 . . . 426236/428 (55%)e−129synthase subunit C1 . . . 380319/428 (74%)(EC 3.6.3.14) (V-ATPase C subunit)(Vacuolar protonpump C subunit)—Homo sapiens(Human), 382 aa.P21282Vacuolar ATP1 . . . 426235/428 (54%)e−129synthase subunit C1 . . . 380319/428 (73%)(EC 3.6.3.14) (V-ATPase C subunit)(Vacuolar protonpump C subunit)—Bos taurus (Bovine),382 aa.

Example 3.

[0331] The NOV3 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 3A.

10TABLE 3ANOV3 Sequence AnalysisSEQ ID NO:5750 bpNOV3a,CAAGCAGATGGGAGCCGCCCGCCTGCTGCCCAACCTCACTTTGTGCTTACAGCTGCTGACG104307-03DNA SequenceTTCTCTGCTGTCAAACTCAGGGGGAGAATCACCCGTCTCCTAATTTTAACCAGTACGTGAGGGACCAGGGCGCCATGACCGACCAGCTGAGCAGGCGGCAGATCCGCGAGTACCAACTCTACAGCAGGACCAGTGGCAAGCACGTGCAGGTCACCGGGCGTCGCATCTCCGCCACCGCCGAGGACGGCAACAAGTTTGCCAAGCTCATAGTGGAGACGGACACGTTTGGCAGCCGGGTTCGCATCAAAGGGGCTGAGAGTGAGAAGTACATCTGTATGAACAAGAGGGGCAAGCTCATCGGGAAGCCCAGCGGGAAGAGCAAAGACTGCGTGTTCACGGAGATCGTGCTGGAGAACAACTATACGGCCTTCCAGAACGCCCGGCACGAGGGCTGGTTCATGGCCTTCACGCGGCAGCCGCCAGAACCAGCGCGAGGCCCACTTCATCAAGCGCCTCTACCAAGGCCAGCTGCCCTTCCCCAACCACGCCGAGAAGCAGAAGCAGTTCGAGTTTGTGGGCTCCGCCCCCACCCGCCGGACCAAGCGCACACGGCGGCCCCAGCCCCTCACGTAGTCTGGGAGGCAGGGGGCAGCAGCCCCTGGGCCGCCTCCCCACCCCTTTCCCTTCTTAATCCAAGGACTGGGCTGGGGTGGCGGGAGGGGAGCCAGATCCCCGAGGGAGGACCCTGAGGGORF Start: ATG at 7ORF Stop: TGA at 745SEQ ID NO: 6246 aaMW at 27146.6DaNOV3a,MGAARLLPNLTLCLQLLILCCQTQGENHPSPNFNQYVRDQGAMTDQLSRRQIREYQLYCG104307-03Protein SequenceSRTSGKHVQVTGRRISATAEDGNKFAKLIVETDTFGSRVRIKGAESEKYICMNKRGKLIGKPSGKSKDCVFTEIVLENNYTAFQNARHEGWFMAFTRQPPEPARGPLHQAPLPRPAALPQPRREAEAVRVCGLRPHPPDQAHTAAPAPHVVWEAGGSSPWAASPPLSLLNPRTGLGWREGSQIPEGGPSEQ ID NO: 7749 bpNOV3b,CAAGCGATGGGAGCCGCCCGCCTGCTGCCCAACCTCACTTTGTGCTTACAGCTGCTGACG104307-05DNA SequenceTTCTCTGCTGTCAAACTCAGGGGGAGAATCACCCGTCTCCTAATTTTAACCAGTACGTGAGGGACCAGGGCGCCATGACCGACCAGCTGAGCAGGCGGCAGATCCGCGAGTACCAACTCTACAGCAGGACCAGTGGCAAGCACGTGCAGGTCACCGGGCGTCGCATCTCCGCCACCGCCGAGGACGGCAACAAGTTTGCCAAGCTCATAGTGGAGACGGACACGTTTGGCAGCCGGGTTCGCATCAAAGGGGCTGAGAGTGAGAAGTACATCTGTATGAACAAGAGGGGCAAGCTCATCGGGAAGCCCAGCGGGAAGAGCAAAGACTGCGTGTTCACGGAGATCGTGCTGGAGAACAACTATACGGCCTTCCAGAACGCCCGGCACGAGGGCTGGTTCATGGCCTTCACGCGGCAGCGCCAGAACCAGCGCGAGGCCCACTTCATCAAGCGCCTCTACCAAGGCCAGCTGCCCTTCCCCAACCACGCCGAGAAGCAGAAGCAGTTCGAGTTTGTGGGCTCCGCCCCCACCCGCCGGACCAAGCGCACACGGCGGCCCCAGCCCCTCACGTAGTCTGGGAGGCAGGGGGCAGCAGCCCCTGGGCCGCCTCCCCACCCCTTTCCCTTCTTAATCCAAGGACTGGGCTGGGGTGGCGGGAGGGGAGCCAGATCCCCGAGGGAGGACCCTGAGGGORF Start: ATG at 7ORF Stop: TAG at 628SEQ ID NO: 8207 aaMW at 23895.1DaNOV3b,MGAARLLPNLTLCLQLLILCCQTQGENHPSPNFNQYVRDQGAMTDQLSRRQIREYQLYCG104307-05Protein SequenceSRTSGKHVQVTGRRISATAEDGNKFAKLIVETDTFGSRVRIKGAESEKYICMNKRGKLIGKPSGKSKDCVFTEIVLENNYTAFQNARHEGWFMAFTRQRQNQREAHFIKRLYQGQLPFPNHAEKQKQFEFVGSAPTRRTKRTRRPQPLT

[0332] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 3B.

11TABLE 3BComparison of NOV3a against NOV3b.ProteinNOV3a Residues/Identities/SimilaritiesSequenceMatch Residuesfor the Matched RegionNOV3b1 . . . 173142/177 (80%)1 . . . 177143/177 (80%)

[0333] Further analysis of the NOV3a protein yielded the following properties shown in Table 3C.

12TABLE 3CProtein Sequence Properties NOV3aPSort0.4992 probability located in outside; 0.1278 probabilityanalysis:located in microbody (peroxisome); 0.1000 probability locatedin endoplasmic reticulum (membrane); 0.1000 probabilitylocated in endoplasmic reticulum (lumen)SignalPCleavage site between residues 26 and 27analysis:

[0334] A search of the NOV3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3D.

13TABLE 3DGeneseq Results for NOV3aNOV3aIdentities/Protein/Residues/Similarities forGenseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAE18822Human FGF-171 . . . 167159/169 (94%)6e−88protein—Homo5 . . . 173162/169 (95%)sapiens, 220 aa.[US2002001825-A1, 03 JAN. 2002]AAB50272Human fibroblast1 . . . 167159/169 (94%)6e−88growth factor1 . . . 169162/169 (95%)FGF-13 SEQ IDNO: 2—Homosapiens, 216 aa.[WO200071567-A2,30 NOV. 2000]AAG65663Human fibroblast1 . . . 167159/169 (94%)6e−88growth factor5 . . . 173162/169 (95%)(FGF)-17—Homosapiens, 220 aa.[WO200172957-A2,04 OCT. 2001]AAW70330Fibroblast growth1 . . . 167158/169 (93%)2e−87factor-13—Homo1 . . . 169161/169 (94%)sapiens, 216 aa.[WO9823749-A1,04 JUN. 1998]AAW37915Fibroblast growth1 . . . 167157/169 (92%)9e−87factor 13—Homo1 . . . 169160/169 (93%)sapiens, 216 aa.[WO9814467-A1,09 APR. 1998]

[0335] In a BLAST search of public sequence datbases, the NOV3a protein was found to have homology to the proteins shown in the BLASTP data in Table 3E.

14TABLE 3EPublic BLASTP Results for NOV3aNOV3aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueO70627Fibroblast growth1 . . . 167159/169 (94%)1e−87factor-171 . . . 169162/169 (95%)precursor(FGF-17)—Musmusculus(Mouse), and,216 aa.O60258Fibroblast growth 1 . . . 167159/169 (94%)1e−87factor-17 1 . . . 169162/169 (95%)precursor(FGF-17)—Homosapiens (Human),216 aa.G02092fibroblast growth12 . . . 184111/176 (63%)4e−55factor 811 . . . 186132/176 (74%)precursor—human, 215 aa.Q9DE51Fibroblast growth12 . . . 186110/184 (59%)7e−53factor 8—12 . . . 195133/184 (71%)Ambystomamexicanum(Axolotl), 212 aa.AAM22684Fibroblast growth12 . . . 184106/176 (60%)1e−52factor-8 isoform11 . . . 186129/176 (73%)b—Xenopuslaevis (Africanclawed frog), 211aa (fragment).

[0336] PFam analysis predicts that the NOV3a protein contains the domains shown in the Table 3F.

15TABLE 3FDomain Analysis of NOV3aIdentities/PfamNOV3aSimilarities forExpectDomainMatch Regionthe Matched RegionValueFGF51 . . . 15539/122 (32%)2.2e−4598/122 (80%)

Example 4

[0337] The NOV4 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 4A.

16TABLE 4ANOV4 Sequence AnalysisSEQ ID NO:92403 bpNOV4a,GGATCTCAGCACTCTGACCCAAGGGGAAGCATGTCGAAGAAAGGCCGGAGCAAGGGCGCG105707-01DNA SequenceAGAAGCCCGAGATGGAGAACGGACGCGGTGCAGATGGCCAACGAGGAGCTGCGGGCCAAAGCTGACCAGCATTCAGATCGAGTTCCAGCAGGAAAAAGCAAGGTGGGCAAACTGCGCGAGCGGCTGCAGGAGGCGAAGCTGGAGCGCGAGCAGGAGCAGCGACGGCACACGGCCTACATTTCGGAGCTCAAGGCCAAGCTGCATGAGGAGAAGACCAAGGAGCTGCAGGCGCTGCGCGAGGGGCTCATCCGGCAGCACGAGCAGGAGGCGGCGCGCACCGCCAAGATCAAGGAGGGCGAGCTGCAGCGGCTGCAGGCCACGCTGAACGTGCTGCGCGACGGCGCGGCCGACAAGGTCAAGACGGCGCTGCTGACCGAGGCGCGCGAGGAGGCGCGCAGGGCCTTCGATGGAGAGCGCCTGCGGCTGCAGCAGGAGATCCTGGAGCTCAAGGCAGCGCGCAAGCAGGCAGAGGAGGCGCTCAGTAACTGCATGCAGGCTGACAAGACCAAGGCAGCCGACCTGCGTGCCGCCTACCAGGCGCACCAAGACGAGGTGCACCGCATCAAGCGCGAGTGCGAGCGGCACATCCGCAGGCTGATGGATGAGATCAAAGGGAAAGACCGTGTGATTCTGGCCTTGGAGAAGGAACTTGGCGTGCAGGCTGGGCAGACCCAGAAGCTGCTTCTGCAGAAAGAGGCTTTGGATGAGCAGCTGGTTCAGGTCAAGGAGGCCGAGCGGCACCACAGTAGTCCAAACAGAGAGCTCCCGCCCGGGATCGGGGACATGGTGGAGCTCATGGGCGTCCAGGATCAACATATGGACGAGCGAGATGTGAGGCGATTTCCACTAAAAATTGCTGAACTGAATTCAGTGATACGGAAGCTGGAAGACAGAAATACGCTGTTGGCAGATGAGAGGAATGAACTGCTGAAACGCTCACGAGAGACCGAGGTTCAGCTGAAGCCCCTGGTGGAGAAGAACAAGCGGATGAACAAGAAGAATGAGGATCTGTTGCAGAGTATCCAGAGGATGGAGGAGAAAATCAAGAACCTCACGCGGGAAAACGTGGAAATGCTGTCAGCGCAGGCGTCTCTGAAGCGGCATACCTCCTTGAATGACCTCAGCCTGACGAGGGATGAGCAGGAGATCGAGTTCCTGAGGCTGCAGGTGCTGGAGCAGCAGCACGTCATTGACGACCTCTCACTGGAGAGAGAACGGCTGTTGCGCTCCAAAAGGCATCGAGGGAAAAGTCTGAAACCGCCCAAGAAGCATGTTGTGGAGACATTTTTTGGATTTGATGAGGAGTCTGTGGACTCAGAAACGTTGTCCGAAACATCCTACAACACAGACAGGACAGACAGGACCCCAGCCACGCCCGAAGAAGACTTGGACGATAAGGCCACAGCCCGAGAGGAGGCTGACCTGCGCTTCTGCCAGCTGACCCGGGAGTACCAGGCCCTGCAACGCGCCTACGCCCTGCTCCAGGAGCAGGTGGGAGGCACGCTGGACGCTGAGAGGGAGGCCCGGACTCGGGAGCAGCTACAAGCTGATCTGCTGAGGTGTCAGGCCAAAATCGAAGATTTGGAGAAGTTACTGGTTGAGAAGGGACAGGTGAGCAGGAGTGATATGGAAGAGAACCAGCTGAAGAATGAAATGCAAGACGCCAAGGATCAGAACGAGCTGTTAGAATTCAGAGTGCTAGAACTCGAAGAGAGAGAGAGGAGGTCGCCAGCATTTAACCTCCAAATCACCACCTTCCCCGAGAACCACAGCAGCGCTCTCCAGCTGTTCTGTCACCAGGAAGGAGTTAAGGATGTGAATGTTTCTGAACTTATGAAGAAATTAGATATCCTTGGCGATAACGGGAATTTGAGAAATGAAGAACAGGTTGCAATAATCCAAGCTGGAACTGTGCTTGCCCTGTGTGAAAAGTGGCTGAAGCAAATAGAGGGGACCGAGGCCGCCCTGACCCAGAAGATGCTGGACCTGGAGAAGGAGAAATCCCAAGACCTGGAGGCCACACTGTACACAGCGCTGCAGCAGGAGCCGGGGCGGAGGGCCGGTGAGGCGCTGAGCGAGGGCCAGCGGGAGGACCTGCAGGCTGCTGTGGAAAAGGTGCGCAGGCAGATCCTCAGGCAGAGCCGCGAGTTCGACAGCCAGATCCTGCGGGAGCGCATGGAGCTGCTGCAGCAGGCCCAGCAGAGAATCCGAGAACTGGAGGACAAACTGGAGTTTCAGAAGCGGCACCTGAAAGAACTGGAGGAAAAGTTTTTGTTCCTTTTTTTGTTTTTCTCACTAGCATTCATTCTGTGGCCTTGATGACTTCAGTGAGCCAAGAACTCGGGTORF Start: ATG at 31ORF Stop: TGA at 2374SEQ ID NO: 10781 aaMW at 91150.4DaNOV4a,MSKKGRSKGEKPEMETDAVQMANEELRAKLTSIQIEFQQEKSKVGKLRERLQEAKLERCG105707-01Protein SequenceEQEQRRHTAYISELKAKLHEEKTKELQALREGLIRQHEQEAARTAKIKEGELQRLQATLNVLRDGAADKVKTALLTEAREEARRAFDGERLRLQQEILELKAARKQAEEALSNCMQADKTKAADLRAAYQAHQDEVHRIKRECERDIRRLMDEIKGKDRVILALEKELGVQACQTQKLLLQKEALDEQLVQVKEAERHHSSPKRELPPGIGDMVELMGVQDQHMDERDVRRFQLKIAELNSVIRKLEDRNTLLADERNELLKRSRETEVQLKPLVEKNKRMNKKNEDLLQSIQRMEEKIKNLTRENVEMLSAQASLKRHTSLNDLSLTRDEQEIEFLRLQVLEQQHVIDDLSLERERLLRSKRHRGKSLKPPKKHVVETFFGFDEESVDSETLSETSYNTDRTDRTPATPEEDLDDKATAREEADLRFCQLTREYQALQRAYALLQEQVGGTLDAEREARTREQLQADLLRCQAKIEDLEKLLVEKGQVSRSDMEENQLKNEMQDAKDQNELLEFRVLELEERERRSPAFNLQITTFPENHSSALQLFCHQEGVKDVNVSELMKKLDILGDNGNLRNEEQVAIIQAGTVLALCEKWLKQIEGTEAALTQKMLDLEKEKSQDLEATLYTALQQEPGRRAGEALSEGQREDLQAAVEKVRRQILRQSREFDSQILRERMELLQQAQQRIRELEDKLEFQKRHLKELEEKFLFLFLFFSLAFILWP

[0338] Further analysis of the NOV4a protein yielded the following properties shown in Table 4B.

17TABLE 4BProtein Sequence Properties NOV4aPSort0.8500 probability located in endoplasmic reticulumanalysis:(membrane); 0.4400 probability located in plasma membrane;0.3000 probability located in microbody (peroxisome); 0.1000probability located in mitochondrial inner membraneSignalPNo Known Signal Sequence Predictedanalysis:

[0339] A search of the NOV4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 4C.

18TABLE 4CGeneseq Results for NOV4aIdentities/NOV4aSimilaritiesProtein/Residues/for theGeneseqOrganism/LengthMatchMatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueABB04608Human xylose173 . . . 582 323/431 e−162isomerase 43(74%)protein SEQ ID 1 . . . 366332/431NO: 2—Homo(76%)sapiens, 387 aa.[CN1307130-A,Aug. 8, 2001]AAB42436Human ORFX194 . . . 431238/241 e−128ORF2200 poly-(98%)peptide sequence 1 . . . 241238/241SEQ ID NO:(98%)4400—Homosapiens, 241 aa.[WO200058473-A2, Oct. 5,2000]AAM85650Human immune/445 . . . 781 217/390 e−107haematopoietic(55%)antigen SEQ ID 4 . . . 388274/390NO: 13243—(69%)Homo sapiens,388 aa.[WO200157182-A2, Aug. 9, 2001]ABB61173Drosophila 6 . . . 765174/8513e−23 melanogaster(20%)polypeptide SEQ423 . . . 1246356/851ID NO 10311—(41%)Drosophilamelanogaster,1690 aa.[WO200171042-A2, Sep. 27,2001]ABB61144Drosophila 6 . . . 765174/8513e−23 melanogaster(20%)polypeptide SEQ423 . . . 1246356/851ID NO 10224—(41%)Drosophilamelanogaster,1690 aa.[WO200171042-A2, Sep. 27,2001]

[0340] In a BLAST search of public sequence datbases, the NOV4a protein was found to have homology to the proteins shown in the BLASTP data in Table 4D.

19TABLE 4DPublic BLASTP Results for NOV4aNOV4aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ96N16CDNA FLJ31564 1 . . . 582575/606 (94%)0.0fis, clone 1 . . . 605578/606 (94%)NT2R12001450,weakly similar totrichohyalin—Homosapiens (Human),626 aa.T00331hypothetical protein 1 . . . 781508/812 (62%)0.0KIAA0555— 1 . . . 799633/812 (77%)human, 799 aa.Q96AA8Hypothetical protein 1 . . . 765492/817 (60%)0.0KIAA0555—Homo 1 . . . 804617/817 (75%)sapiens (Human),810 aa.Q9CU416330417G02Rik 1 . . . 418262/436 (60%) e−139protein—Mus 1 . . . 435333/436 (76%)musculus (Mouse),437 aa (fragment).Q9BGP2Hypothetical 23.9609 . . . 781127/200 (63%)3e−62 kDa protein— 2 . . . 201153/200 (76%)Macaca fascicularis(Crab eatingmacaque)(Cynomolgusmonkey), 201 aa.

Example 5

[0341] The NOV5 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 5A.

20TABLE 5ANOV5 Sequence AnalysisSEQ ID NO:111872 bpNOV5a,ATGCCTCCGCCGCAGGGTGACGTGACCGCCTTGTTCCTGGGGCCTCCGGGCTTGGGGACG108369-01DNA SequenceAGTCCGCGCTGATCGCAGCGCTGTGCGACAAGGATGTGGAGACGCTCGAGGCCCCCGAGGGACGGCCGGACTCCGGGGTTCCCAGCCTAAGAGCTGCGGGCCCAGGCCTTTTTCTGGGCGAGCTGAGCTGCCCACCCGCAGCGCCGGGGCCCTGGGCGGCGGAAGCCAACGTGCTGGTACTGGTGCTGCCCGGACCCGAGGGGAACGGGGAACCGTTGGCTCCAGCCCTGGGAGAGGCAGCGCTGGCCGCCCTGGCCCGAGGGACCCCGCTACTGGCTGTGCGGAACCTCCGTCCTGGGGATTCACAGACTGCCGCCCAGGCCCGTGATCAGACAGCAGCTCTGCTGAACAGCGCGGGGTTAGGAGCTGCGGATCTGTTTGTGCTACCGGCGAACTGCGGCAGCAGCGACGGCTGCGAGGAGCTAGAGCGCCTCCGGGCGGCGCTGCAGAGCCAGGCAGAAGCGCTGCGGAGGCTCCTGCCACCGGCGCAGGATGGCTTCGAGGTGTTGGGTGCAGCAGAGCTAGAGGCTGTGCGTGAGGCCTTTGAGACCGGCGGCCTTGAGGCTGCGCTGTCGTGGGTGCGCTCAGGCCTGGAGCGCCTGGGCAGCGCACGGCTAGACCTGGCCGTGGCTGGCAAGGCTGACGTGGGCCTTGTGGTGGACATGCTGCTTGGATTGGATCCTGGCGACCCAGGCGCTGCGCCTGCTTCGGTCCCCACAGCACCCACTCCCTTCCCAGCCCCAGAGCGCCCGAATGTGGTGCTCTGGACCGTGCCTCTGGGCCACACGGGCACTGCCACCACCGCGGCCGCCGCCTCTCACCCAACGCACTACGACGCCCTCATCCTCGTCACCCCTGGGGCCCCCACTGAGAAGGACTGGGCCCAGGTCCAGGCCTTGCTGCTACCAGATGCGCCTCTTGTCTGCGTGCGCACAGACGGCGAGGGCGAGGATCCGGAGTGTCTGGGAGAAGGCAAGATGGAGAATCCCAAGGGCGAGAGCTTAAAGAACGCAGGTGGAGGGGGATTGGAGAATGCACTCAGTAAGGGAAGGGAGAAATGTAGCGCTGGATCGCAGAAAGCAGGCAGCGGGGAAGGTCCTGGGAAAGCTGGCAGCGAGGGTTTGCAGCAGGTTGTCGGCATGAAGAAATCAGGTGGTGGCGACTCAGAGCGGGCCGCTGCGTTAAGCCCGGAGGACGAGACGTGGGAGGTGCTGGAGGAGGCGCCGCCGCCAGTGTTCCCCCTACGGCCTGGCGGACTCCCAGGGCTATGCGAATGGCTGCGGCGAGCGCTCCCCCCAGCCCAGGCAGGGGCACTGCTGCTGGCGTTGCCACCAGCATCTCCCAGCGCTGCCCGAACCAAGGCTGCGGCGTTGCGAGCCGGGGCGTGGAGGCCAGCTCTGCTGGCTAGTCTGGCGGCGGCGGCGGCACCACTCCCAGGGCTGGGCTGGGCATGCGACGTGGCACTTCTGCGGGGTCAGCTGGCGGAGTGGCGACGGGGCCTGGGGCTGGAACCCACGGCACTGGCTCGACGTGAGCGTGCCCTGGGCCTGGCTTCTGGAGAGCTGGCAGCGCGCGCTCATTTCCCAGGCCCGGTGACGCGCGCCGAGGTGGAAGCAAGACTGGGCGCCTGGGCGGGCGAGGGCACTGCTGGGGGCGCAGCACTGGGGGCTCTCTCCTTCCTGTGGCCTGCGGGTGGTGCAGCGGCGACAGGTGGCCTGGGCTACCGAGCGGCTCACGGCGTCCTGCTGCAGGCTCTCGATGAGATGCGGGCTGATGCTGAGGCTGTGCTGGCACCCCCTGAGCCTGCCCAGTGAORF Start: ATG at 1ORF Stop: TGA at 1870SEQ ID NO: 12623 aaMW at 62716.3DaNOV5a,MPPPQGDVTALFLGPPGLGKSALIAALCDKDVETLEAPEGRPDSGVPSLRAAGPGLFLCG108369-01Protein SequenceGELSCPPAAPGPWAAEANVLVLVLPGPEGNGEPLAPALGEAALAALARGTPLLAVRNLRPGDSQTAAQARDQTAALLNSAGLGAADLFVLPANCGSSDGCEELERLRAALQSQAEALRRLLPPAQDGFEVLGAAELEAVREAFETGGLEAALSWVRSGLERLGSARLDLAVAGKADVGLVVDMLLGLDPGDPGAAPASVPTAPTPFPAPERPNVVLWTVPLGHTGTATTAAAASHPTHYDALILVTPGAPTEKDWAQVQALLLPDAPLVCVRTDGEGEDPECLGEGKMENPKGESLKNAGGGGLENALSKGREKCSAGSQKAGSGEGPGKAGSEGLQQVVGMKKSGGGDSERAAALSPEDETWEVLEEAPPPVFPLRPGGLPGLCEWLRRALPPAQAGALLLALPPASPSAARTKAAALRAGAWRPALLASLAAAAAPLPGLGWACDVALLRGQLAEWRRGLGLEPTALARRERALGLASGELAARAHFPGPVTRAEVEARLGAWAGEGTAGGAALGALSFLWPAGGAAATGGLGYRAAHGVLLQALDEMRADAEAVLAPPEPAQ

[0342] Further analysis of the NOV5a protein yielded the following properties shown in Table 5B.

21TABLE 5BProtein Sequence Properties NOV5aPSort0.7600 probability located in nucleus; 0.3000 probabilityanalysis:located in microbody (peroxisome); 0.2813 probability locatedin lysosome (lumen); 0.1000 probability located inmitochondrial matrix spaceSignalPNo Known Signal Sequence Predictedanalysis:

[0343] A search of the NOV5a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 5C.

22TABLE 5CGeneseq Results for NOV5aNOV5aIdentities/Protein/Residues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAE06678Human nuclear 1 . . . 623623/6230.0 hormone receptor(100%)(NHREC)-1 1 . . . 623623/623protein—Homo(100%)sapiens, 623 aa.[WO200155392-A2, Aug. 2,2001]AAB42434Human ORFX178 . . . 615115/4468e−20ORF2198 poly- (25%)peptide sequence 8 . . . 399180/446SEQ ID NO: (39%)4396—Homosapiens, 463 aa.[WO200058473-A2, Oct. 5,2000]ABB89799Human poly-178 . . . 594107/4253e−16peptide SEQ ID (25%)NO 2175—Homo 8 . . . 378168/425sapiens, 394 aa. (39%)[WO200190304-A2, Nov. 29,2001]AAU82954Human homo-349 . . . 501 48/1554e−04logue of MPTI (30%)protein target 45 . . . 177 60/155for antifungal (37%)compound—Homo sapiens,1023 aa.[WO200202055-A2, Jan. 10,2002]AAE13147Human retinitis332 . . . 42229/910.004pigmentosa (31%)GTPase regulator247 . . . 33343/91(RPGR) exon (46%)ORF15—Homosapiens, 567 aa.[WO200177380-A2, Oct. 18,2001]

[0344] In a BLAST search of public sequence datbases, the NOV5a protein was found to have homology to the proteins shown in the BLASTP data in Table 5D.

23TABLE 5DPublic BLASTP Results for NOV5aNOV5aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ8WZA9FKSG27—Homo 1 . . . 623623/6230.0sapiens (Human),(100%) 623 aa. 1 . . . 623623/623(100%) Q8VIM9FKSG27—Mus 1 . . . 623488/6240.0musculus(78%)(Mouse), 583 aa. 1 . . . 583519/624(82%)AAC34467R30953_1—178 . . . 615115/4462e−19Homo sapiens(25%)(Human), 463 aa. 8 . . . 399180/446(39%)Q9AD50Putative ATP/333 . . . 41935/953e−04GTP-binding(36%)Gly/Ala-rich296 . . . 38547/95protein—(48%)Streptomycescoelicolor,811 aa.Q9RX57Hypothetical247 . . . 593 96/3664e−04protein(26%)DR0458—253 . . . 566127/366Deinococcus(34%)radiodurans,839 aa.

[0345] PFam analysis predicts that the NOV5a protein contains the domains shown in the Table 5E.

24TABLE 5EDomain Analysis of NOV5aIdentities/PfamNOV5aSimilarities forExpectDomainMatch Regionthe Matched RegionValueketoacyl-synt_C145 . . . 29437/189 (20%)0.2193/189 (49%)

Example 6

[0346] The NOV6 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 6A.

25TABLE 6ANOV6 Sequence AnalysisSEQ ID NO:131411 bpNOV6a,CTTCTCCGACCCCGCTCTAGCAGCAGACCTCCTGGGGTCTGTGGGTTGATCTGTGGCCCG100578-01DNA SequenceCCTGTGCCTCCGTGTCCTTTTCGTCTCCCTTCCTCCCGACTCCGCTCCCGGACCAGCGGCCTGACCCTGGGGAAAGGATGGTTCCCGAGGTGAGGGTCCTCTCCTCCTTGCTGGGACTCGCGCTGCTCTGGTTCCCCCTGGACTCCCACGCTCGAGCCCGTTGCCTTTTCCATGGGAAGAGATACTCCCCCGGCCACAGCTCCCACCCCTACTTGGAGCCACAAGGCCTGATGTACTGCCTGCGCTGTACCTGCTCAGAGGTAGGTTCCTCTGGCCACCTGACCACCTGTGTCAGGGATGTCCCTCCTGCCTGTTATTTTCCAGTCTCTTCCCCTTGGGGCTGCTGCCCTTCCCCCACTGCAGAACCTCACACTCCCTCTGGACTCCGGGCCCCACCAAAGTCCTGCCAGCACAACGGGACCATGTACCAACACGGAGAGATCTTCAGTGCCCATGAGCTGTTCCCCTCCCGCCTGCCCAACCAGTGTGTCCTCTGCAGCTGCCAGGAGGGCCAGATCTACTGCGGCCTCACAACCTGCCCCGAACCAGGCTGCCCAGCACCCCTCCCGCTGCCAGACTCCTGCTGCCAGGCCTGCAAAGGTGAGTCTGTCCCTCCATCTGCTAGAAACAAACTTCGCCAACTTCAGAATTGTGAAAGACATCCTCAGGATCCATGTTCCAGTGATGCTGGGAGAAAGAGAGGCCCGGGCACCCCAGCCCCCACTGGCCTCAGCGCCCCTCTGAGCTTCATCCCTCGCCACTTCAGACCCAAGGGAGCAGGCAGCACAACTGTCAAGATCATCCTCCTTCCTTCTCACCCTCCTTATTCAGCCTGTGTGCATGGCGGGAAGACGTACTCCCACGGGGAGGTGTGGCACCCGGCCTTCCGTGCCTTCGGCCCCTTGCCCTGCATCCTATGCACCTGTGAGGATGGCCGCCAGGACTGCCAGCGTGTGACCTGTCCCACCGAGTACCCCTGCCGTCACCCCGAGAAAGTGGCTGGGAAGTGCTGCAAGATTTGCCCAGAGGACAAAGCAGACCCTGGCCACAGTGAGATCAGTTCTACCAGGTGTCCCAAGGCACCGGGCCGGGTCCTCGTCCACACATCGGTATCCCCAAGCCCAGACAACCTGCGTCGCTTTGCCCTGGAACACGAGGCCTCGGACTTGGTGGAGATCTACCTCTGGAAGCTGGTAAAAGGTATCTTCCACTTGACTCAGATCAAGAAAGTCAGGAAGCAAGACTTCCAGAAAGAGGCACAGCACTTCCGACTGCTCGCTGGCCCCCACGAAGGTAGGAGCTTGGGCTGAe,uns GGAATGGGGCCGGGGCAGGAAGAAGGCAAGGACACGGGCCAGAORF Start: ATG at 136ORF Stop: TGA at 1366NOV6a,MVPEVRVLSSLLGLALLWFPLDSHARARCLFHGKRYSPGESWHPYLEPQGLMYCLRCTCG110578-01Protein SequenceCSEVGSSGHLTTCVRDVPPACYFPVSSPWGCCPSPTAEPHTPSGLRAPPKSCQHNGTMYQHGEIFSAHELFPSRLPNQCVLCSCQEGQIYCGLTTCPEPGCPAPLPLPDSCCQACKGESVPPSARNKLRQLQNCERHPQDPCSSDAGRKRGPGTPAPTGLSAPLSFIPRHFRPKGAGSTTVKIILLPSHPPYSACVHGGKTYSHGEVWHPAFRAFGPLPCILCTCEDGRQDCQRVTCPTEYPCRHPEKVAGKCCKICPEDKADPGHSEISSTRCPKAPGRVLVHTSVSPSPDNLRRFALEHEASDLVEIYLWKLVKGIFHLTQIKKVRKQDFQKEAQHFRLLAGPHEGRSLG

[0347] Further analysis of the NOV6a protein yielded the following properties shown in Table 6B.

26TABLE 6BProtein Sequence Properties NOV6aPSort0.5500 probability located in endoplasmic reticulumanalysis:(membrane); 0.1900 probability located in lysosome (lumen);0.1000 probability located in endoplasmic reticulum (lumen);0.1000 probability located in outsideSignalPCleavage site between residues 26 and 27analysis:

[0348] A search of the NOV6a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 6C.

27TABLE 6CGeneseq Results for NOV6aNOV6aIdentities/Protein/Residues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAU78172Human chordin 1 . . . 406359/412 (87%)0.0homologue 1 . . . 405364/412 (88%)LP226—Homosapiens, 429 aa.[WO200208277-A2, Jan. 31,2002]AAU02750Novel Human 1 . . . 406359/412 (87%)0.0Protein, NHP 1 . . . 405364/412 (88%)#2—Homosapiens, 429 aa.[WO200129084-A2, Apr. 26,2001]AAE12886Human chordin- 1 . . . 406359/412 (87%)0.0like-2 (CHL-2) 1 . . . 405364/412 (88%)protein—Homosapiens, 429 aa.[WO200164885-A1, Sep. 7,2001]AAB68074Amino acid 1 . . . 406355/430 (82%)0.0sequence of a93 . . . 515361/430 (83%)human chordin-like homologuesplice variant—Homo sapiens,539 aa.[WO200134796-A1, May 17,2001]AAE12887Human chordin-22 . . . 406338/391 (86%)0.0like-2 (CHL-2) 1 . . . 384343/391 (87%)mature protein—Homo sapiens,408 aa.[WO200164885-A1, Sep. 7,2001]

[0349] In a BLAST search of public sequence datbases, the NOV6a protein was found to have homology to the proteins shown in the BLASTP data in Table 6D.

28TABLE 6DPublic BLASTP Results for NOV6aNOV6aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueCAC88239Sequence 4 from1 . . . 406359/412 (87%)0.0Patent1 . . . 405364/412 (88%)WO0164885—Homo sapiens(Human), 429 aa.CAD23759Sequence 5 from1 . . . 374327/380 (86%)0.0Patent1 . . . 373332/380 (87%)WO0208277—Homo sapiens(Human), 451 aa.Q8VEA6Hypothetical 47.81 . . . 406272/411 (66%)e−165kDa protein—Mus1 . . . 401305/411 (74%)musculus (Mouse),426 aa.CAC88238Sequence 1 from1 . . . 406271/411 (65%)e−164Patent1 . . . 401304/411 (73%)WO0164885—Musmusculus (Mouse),426 aa.Q92513Chordin-related1 . . . 392260/397 (65%)e−157protein neuralin-2—1 . . . 387292/397 (73%)Mus musculus(Mouse), 406 aa.

[0350] PFam analysis predicts that the NOV6a protein contains the domains shown in the Table 6E.

29TABLE 6EDomain Analysis of NOV6aIdentities/PfamNOV6aSimilarities forExpectDomainMatch Regionthe Matched RegionValuevwc29 . . . 9322/84 (26%)0.001543/84 (51%)vwc110 . . . 17322/93 (24%)1.9e−0645/93 (48%)vwc253 . . . 31526/84 (31%)2.2e−1445/84 (54%)

Example 7

[0351] The NOV7 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 7A.

30TABLE 7ANOV7 Sequence AnalysisSEQ ID NO:153165 bpNOV7a,GAGGGCACAATGCTGGCGGTGTCACTCAAGTGGCGGCTGGGCGTGGTGAGGCGGCGTCCG110646-01DNA SequenceTCAAAGACGATGGGCCCTACTCCAAAGGAGGCAAGGACGCAGGAGGGGCCGACGTTTCCCTGGCGTGCCGCAGACAGAGCATTCCAGAGGAGTTCCGAGGGATCACTGTGGTGGAGCTGATCAAGAAAGAAGGCAGCACGCTGGGCCTGACTATCTCAGGTGGCACCGACAAGGATGGAAAGCCCAGGGTCTCCAACCTGAGACCTGGGGGACTTGCAGCCAGGAGTGATCTGCTGAACATTGGTGACTATATTCGGTCTGTGAACGGGATCCACCTGACCAGGCTCCGCCACGATGAGATCATCACCCTGCTCAAGAATGTGGGCGAGCGCGTGGTGCTGGAGGTGGAGTATGAGCTGCCCCCGCCCGCTCCTGAGAATAACCCCAGGATCATTTCAAAGACAGTGGACGTCTCCCTCTACAAGGAGGGCAATAGCTTTGGCTTTGTCCTTAGAGGAGGTGCCCATGAAGATGGGCACAAGTCCCGCCCGCTTGTCCTGACCTACGTGCGGCCCGGTGGCCCTGCCGACAGGGAGGGCTCCCTGAAGGTGGGCGACAGGCTGCTCAGCGTCGATGGAATCCCGCTGCACGGGGCCAGCCATGCCACCGCCCTGGCCACCCTGCGGCAGTGCAGCCACGAGGCACTCTTTCAGGTGGAGTATGATGTGGCCACCCCTGACACGGTGGCTAATGCTTCGGGACCCTTGATGGTGGAAATAGTCAAGACGCCAGGGTCTGCCCTGGGGATCTCGCTCACCACCACCTCCCTCCGGAACAAGTCAGTCATTACCATCGACCGCATCAAGCCAGCCAGCGTGGTGGACAGGAGCGGAGCCCTGCACCCTGGAGACCACATCCTGTCCATCGATGGCACCAGCATGGAACACTGCTCGCTGCTTGAGGCCACCAAGCTCCTGGCCAGCATTTCAGAGAAGGTGCGGCTGGAGATCCTGCCTGTGCCCCAGAGTCAGCGGCCACTGAGGCCCTCAGAGGCAGTGAAAGTGCAGAGGAGTGAGCAGCTGCACCGCTGGGACCCCTGCGTGCCCTCCTGCCACAGCCCCCGGCCCGGCCACTGCAGGATGCCCACCTGGGCCACACCTGCTGGCCAGGACCAAAGCCGATCCTTGTCTTCAACTCCCTTTTCCTCGCCGACCTTGAACCACGCCTTTTCCTGCAACAACCCCAGCACCCTTCCCCGTGGATCCCAGCCCATGAGTCCTCGAACTACAATGGGGCGGAGGAGGCAGCGAAGAAGGGAACACAAGAGCTCGTTGTCGCTAGCCTCCAGCACGGTGGGGCCGGGCGGGCAGATTGTGCACACGGAGACCACGGAGGTCGTGCTCTGTGGAGACCCCCTCAGCGGCTTTGGCCTCCAGCTCCAGGGCGGCATCTTCGCCACCGAGACCCTGTCCTCCCCACCCCTCGTGTGCTTCATCGAGCCTGACAGCCCGGCTGAGAGGTGTGGGCTGCTGCAGGTGGGGGACCGTGTCCTGTCCATCAATGGCATTGCCACCGAGGACGGGACTATGGAGGAAGCCAACCAGCTCCTGCGGGACGCCGCGCTGGCCCACAAGGTCGTGCTGGAGGTGGAGTTCGATGTGGCGGAGTCCGTCATCCCAAGCAGTGGCACCTTCCACGTGAAGCTGCCCAAGAAGCGCAGCGTGGAGCTGGGCATCACCATCAGCTCGGCCAGCAGGAAACGAGGGGAGCCCTTGATCATCTCCGACATCAAGAAAGGCAGCGTGGCACACAGGACGGGCACCCTGGAGCCAGGCGACAAGCTACTGGCCATTGACAATATCCGCCTGGACAACTGCCCCATGGAGGACGCCGTGCAAATCCTGCGGCAGTGCGAGGACCTGGTGAAGCTGAAGATCCGGAAGGACGAGGACAACTCTGATGAGCTGGAGACCACAGGTGCCGTCAGCTACACAGTGGAGCTGAAGCGCTACGGGGGTCCCCTGGGCATCACCATTTCGGGCACGGAGGAACCTTTTGACCCCATTGTCATCTCAGGCCTCACCAAGCGTGGCCTGGCTGAGAGGACTGGTGCCATCCACGTGGGGGACCGCATTCTGGCCATCAACAACGTTAGCCTCAAGGGCCGGCCGCTGAGCGAGGCCATCCACCTCCTGCAGGTGGCTGGAGAGACCGTCACACTGAAGATCAAGAAGCAACTAGACCGTCCCCTCCTACCCCGCAAGTCGGGCAGCCTCAGTGAGACCAGTGATGCTGATGAGGACCCAGCAGATGCCCTGAAAGGAGGCCTGCCAGCAGCCCGCTTCTCGCCGGCTGTGCCCAGTGTGGACAGTGCTGTGGAGTCTTGGGACAGCTCGGCCACCGAGGGTGGCTTTGGGGGCCCAGGGTCCTATACACCACAGGCAGCAGCCCGGGGCACGACCCCCCAGGAGCGGAGGCCTGGCTGGCTGAGGGGCAGCCCCCCACCCACCGAGCCCCGGAGGACGAGCTATACCCCAACCCCAGCTGACGAGAGCTTTCCAGAGGAGGAGGAGGGGGATGATTGGGAGCCGCCAACGAGCCCAGCCCCTGGCCCTGCCCGAGAGGAGGGCTTCTGGCGCATGTTTGGAGAAGCTCTCGAAGACCTGGAGTCATGTGGTCAGTCAGAGCTGCTGAGGGAACTGGAGGCATCCATCATGACGGGCACCGTGCAGAGGGTGGCCCTCGAGGGCAGGCCTGGCCACCGGCCTTGGCAGAGGGGCCGGGAGGTACGAGCCTCTCCTGCAGAAATGGAGGAGCTGTTGCTGCCTACACCCTTGGAGATGCACAAGGTGACCCTGCACAAGGACCCCATGCGGCATGACTTTGGTTTCAGCGTCTCAGATGGCCTCCTGGAAAAAGGTGTCTATGTCCACACTGTGCGCCCTGATGGGCCAGCCCACCGTGGAGGCCTCCAGCCCTTCGACAGGGTCCTGCAGGTCAACCACGTCCGTACACGGGACTTCGACTGCTGCCTGGCGGTGCCACTCCTGGCCGAGGCGGGTGATGTCTTGGAGCTGATCATCAGCCGCAAGCCGCACACGGCACACAGCAGCCGGGCCCCCCGATCGCCAGGCCCCAGCAGTCCCCGGATGCTCTGAAGTCAGCATORF Start: ATG at 10ORF Stop: TGA at 3154SEQ ID NO: 161048 aaMW at 113318.0DaNOV7a,MLAVSLKWRLGVVRRRLKDDGPYSKGGKDAGGADVSLACRRQSIPEEFRGITVVELIKCG110646-01Protein sequenceKEGSTLGLTISGGTDKDGKPRVSNLRPGGLAARSDLLNIGDYIRSVNGIHLTRLRHDEIITLLKNVGERVVLEVEYELPPPAPENNPRIISKTVDVSLYKEGNSFGFVLRGGAHEDGHKSRPLVLTYVRPGGPADREGSLKVGDRLLSVDGIPLHGASHATALATLRQCSHEALFQVEYDVATPDTVANASGPLMVEIVKTPGSALGISLTTTSLRNKSVITIDRIKPASVVDRSGALHPGDHILSIDGTSMEHCSLLEATKLLASISEKVRLEILPVPQSQRPLRPSEAVKVQRSEQLHRWDPCVPSCHSPRPGHCRMPTWATPAGQDQSRSLSSTPFSSPTLNHAFSCNNPSTLPRGSQPMSPRTTMGRRRQRRREHKSSLSLASSTVGPGGQIVHTETTEVVLCGDPLSGFGLQLQGGIFATETLSSPPLVCFIEPDSPAERCGLLQVGDRVLSINGIATEDGTMEEANQLLRDAALAHKVVLEVEFDVAESVIPSSGTFHVKLPKKRSVELGITISSASRKRGEPLIISDIKKGSVAHRTGTLEPGDKLLAIDNIRLDNCPMEDAVQILRQCEDLVKLKIRKDEDNSDELETTGAVSYTVELKRYGGPLGITISGTEEPFDPIVISGLTKRGLAERTGAIHVGDRILAINNVSLKGRPLSEAIHLLQVAGETVTLKIKKQLDRPLLPRKSGSLSETSDADEDPADALKGGLPAARFSPAVPSVDSAVESWDSSATEGGFGGPGSYTPQAAARGTTPQERRPGWLRGSPPPTEPRRTSYTPTPADESFPEEEEGDDWEPPTSPAPGPAREEGFWRMFGEALEDLESCGQSELLRELEASIMTGTVQRVALEGRPGHRPWQRGREVRASPAEMEELLLPTPLEMHKVTLHKDPMRHDFGFSVSDGLLEKGVYVHTVRPDGPAHRGGLQPFDRVLQVNHVRTRDFDCCLAVPLLAEAGDVLELIISRKPHTAHSSRAPRSPGPSSPRML

[0352] Further analysis of the NOV7a protein yielded the following properties shown in Table 7B.

31TABLE 7BProtein Sequence Properties NOV7aPSort0.6923 probability located in mitochondrial matrix space;analysis:0.6736 probability located in nucleus; 0.3787 probabilitylocated in mitochondrial inner membrane; 0.3787 probabilitylocated in mitochondrial intermembrane spaceSignalPCleavage site between residues 16 and 17analysis:

[0353] A search of the NOV7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 7C.

32TABLE 7CGeneseq Results for NOV7aIdentities/NOV7aSimilaritiesProtein/Residues/for theGeneseqOrganism/LengthMatchMatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAW73062Rat GRIP2— 1 . . . 1015885/10150.0Rattus sp,(87%)1049 aa. 36 . . . 1046934/1015[WO9841541-A1,(91%)Sep. 24, 1998]AAW73061Rat GRIP— 1 . . . 1034644/10900.0Rattus sp,(59%)1112 aa. 1 . . . 1076799/1090[WO9841541-A1,(73%)Sep. 24, 1998]AAB64404Amino acid 1 . . . 1034642/10900.0sequence of(58%)human intra- 1 . . . 1077797/1090cellular signalling(72%)moleculeINTRA36—Homo sapiens,1113 aa.[WO200077040-A2, Dec. 21,2000]ABB11493Human GRIP1266 . . . 1044471/8380.0protein homo-(56%)logue, SEQ ID 1 . . . 826580/838NO: 1863—(69%)Homo sapiens,851 aa.[WO200157188-A2, Aug. 9,2001]ABB11122Human AMPA-409 . . . 543 134/1351e−71receptor binding(99%)protein homo- 1 . . . 135134/135logue, SEQ ID(99%)NO: 1492—Homo sapiens,135 aa.[WO200157188-A2, Aug. 9,2001]

[0354] In a BLAST search of public sequence datbases, the NOV7a protein was found to have homology to the proteins shown in the BLASTP data in Table 7D.

33TABLE 7DPublic BLASTP Results for NOV7aIdentities/NOV7aSimilaritiesProteinResidues/for theAccessionProtein/MatchMatchedExpectNumberOrganism/LengthResiduesPortionValueBAB21810KIAA1719 19 . . . 10481030/10300.0protein—Homo(100%)sapiens (Human), 21 . . . 10501030/10301050 aa(100%)(fragment).Q9WTW1Glutamate 1 . . . 1048 926/10480.0receptor (88%)interacting protein 1 . . . 1043 974/10482—Rattus (92%)norvegicus(Rat), 1043 aa.Q9C0E4KIAA1719153 . . . 1048896/8960.0protein—Homo(100%)sapiens (Human), 1 . . . 896896/896896 aa(100%)(fragment).O88961AMPA receptor53 . . . 861729/8090.0binding protein— (90%)Rattus norvegicus 1 . . . 805759/809(Rat), 822 aa. (93%)P97879AMPA receptor 1 . . . 1034 644/10900.0interacting (59%)protein GRIP— 1 . . . 1076 799/1090Rattus norvegicus (73%)(Rat), 1112 aa.

[0355] PFam analysis predicts that the NOV7a protein contains the domains shown in the Table 7E.

34TABLE 7EDomain Analysis of NOV7aIdentities/PfamNOV7aSimilarities forExpectDomainMatch Regionthe Matched RegionValuePDZ 53 . . . 13529/85 (34%)2.3e−1163/85 (74%)PDZ153 . . . 23827/89 (30%) 3e−1266/89 (74%)PDZ253 . . . 33621/86 (24%)1.1e−0860/86 (70%)PDZ461 . . . 54925/91 (27%)9.2e−0965/91 (71%)PDZ562 . . . 64522/86 (26%)1.3e−1467/86 (78%)PDZ661 . . . 74223/85 (27%)7.5e−1767/85 (79%)PDZ 946 . . . 102726/84 (31%)6.5e−0761/84 (73%)

Example 8

[0356] The NOV8 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 8A.

35TABLE 8ANOV8 Sequence AnalysisSEQ ID NO: 17868 bpNOV8a,AGATGGCTTCTTTGCAAAGGAAAGGGCTGCAGGCAAGGATTCTCACCTCTGAAGAAGACG110998-01DNA SequenceGGAGAAACTGAAAAGAGACCAAACTTTGGTGTCTGATTTTAAACAGCAGAAATTGGAACAAGAGGCTCAGAAAAATTGGGATCTTTTTTACAAAAGAAATAGCACTAATTTCTTCAAAGACAGACACTGGACCACCAGAGAGTTTGAGGAGCTAAGATCATGTAGAGAGTTTGAAGATCAAAAGTTAACAATGCTTGAAGCTGGCTGTGGGGTTGGAAACTGTTTATTCCCACTTTTAGAAGAAGATCCGAATATCTTTGCCTATGCCTGTGATTTTTCTCCAAGAGCCATTGAATATGTTAAGCAAAATCCTTTATATGATACAGAAAGATGCAAGGTATTCCAGTGTGATCTGACTAAAGATGATCTTCTGGATCATGTACCGCCAGAGTCTGTGGATGTTGTTATGTTGATATTTGTGCTGTCAGCTGTTCATCCTGATAAGATGCACCTTGTCTTACAAAACATTTACAAGGTTTTAAAACCAGGCAAAAGTGTCTTGTTTCGTGACTACGGACTGTATGATCATGCCATGCTTAGGTTTAAAGCCAGCAGCAAACTTGGAGAAAACTTTTATGTTAGACAAGATGGGACCAGATCATATTTTTTTACTGATGACTTCCTGGCTCAGCTCTTTATGGACACAGGTTATGAAGAAGTGGTAAACGAGTATGTGTTTCGAGAGACGGTGAATAAAAAAGAAGGCCTGTGTGTGCCAAGAGTTTTCCTTCAGAGCAAATTTCTAAAGCCTCCTAAGAACCCATCTCCTGTGGTCCTGGGCCTGGATCCTAAGTCCTGACCTTTCATGAGORF Start: ATG at 3ORF Stop: TGA at 855SEQ ID NO: 18284 aaMW at 33250.7DaNOV8a,MASLQRKGLQARILTSEEEEKLKRDQTLVSDFKQQKLEQEAQKNWDLFYKRNSTNFFKCG110998-01Protein SequenceDRHWTTREFEELRSCREFEDQKLTMLEAGCGVGNCLFPLLEEDPNIFAYACDFSPRAIEYVKQNPLYDTERCKVFQCDLTKDDLLDHVPPESVDVVMLIFVLSAVHPDKMHLVLQNIYKVLKPGKSVLFRDYGLYDHAMLRFKASSKLGENFYVRQDGTRSYFFTDDFLAQLFMDTGYEEVVNEYVFRETVNKKEGLCVPRVFLQSKFLKPPKNPSPVVLGLDPKSSEQ ID NO: 19865 bpNOV8b,AGATGGCTTCTTTGCAAAGGAAAGGGCTGCAGGCAAGGATTCTCACCTCTGAAGAAGACG110998-02DNA SequenceGGAGAAACTGAAAAGAGACCAAACTTTGGTGTCTGATTTTAAACAGCAGAAATTGGAACAAGAGGCTCAGAAAAATTGGGATCTTTTTTACAAAAGAAATAGCACTAATTTCTTCAAAGACAGACACTGGACCACCAGAGAGTTTGAGGAGCTAAGATCATGTAGAGAGTTTGAAGATCAAAAGTTAACAATGCTTGAAGCTGGCTGTGGGGTTGGAAACTGTTTATTCCCACTTTTAGAAGAAGATCCGAATATCTTTGCCTATGCCTGTGATTTTTCTCCAAGAGCCATTGAATATGTTAAGCAAAATCCTTTATATGATACAGAAAGATGCAAGGTATTCCAGTGTGATCTGACTAAAGATGATCTTCTGGATCATGTACCGCCAGAGTCTGTGGATGTTGTTATGTTGATATTTGTGCTGTCAGCTGTTCATCCTGATAAGATGCACCTTGTCTTACAAAACATTTACAAGGTATTAAAACCAGGCAAAAGTGTCTTGTTTCGTGACTACGGACTGTATGATCATGCCATGCTTAGGTTTAAAGCCAGCAGCAAACTTGGAGAAAACTTTTATGTTAGACAAGATGGGACCAGATCATATTTTTTTACTGATGGCTTCCTGGCTCAGCTCTTTATGGACACAGGTTATGAAGAAGTGGTAAACGAGTATGTGTTTCGAGAGACGGTGAATAAAAAAGAAGGCCTGTGTGTGCCAAGAGTTTTCCTTCAGAGCAAATTTCTAAAGCCTCCTAAGAACCCATCTCCTGTGGTCCTGGGCCTGGATCCTAAGTCCTGACCTTTCATORF Start ATG at 3ORF Stop: TGA at 855SEQ ID NO: 20284 aaMW at 33192.7DaNOV8b,MASLQRKGLQARILTSEEEEKLKRDQTLVSDFKQQKLEQEAQKNWDLFYKRNSTNFFKCG110998-02Protein SequenceDRHWTTREFEELRSCREFEDQKLTMLEAGCGVGNCLFPLLEEDPNIFAYACDFSPRAIEYVKQNPLYDTERCKVFQCDLTKDDLLDHVPPESVDVVMLIFVLSAVHPDKMHLVLQNIYKVLKPGKSVLFRDYGLYDHAMLRFKASSKLGENFYVRQDGTRSYFFTDDFLAQLFMDTGYEEVVNEYVFRETVNKKEGLCVPRVFLQSKFLKPPKNPSPVVLGLDPKS

[0357] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 8B.

36TABLE 8BComparison of NOV8a against NOV8b.ProteinNOV8a Residues/Identities/SimilaritiesSequenceMatch Residuesfor the Matched RegionNOV8b1 . . . 284283/284 (99%)1 . . . 284283/284 (99%)

[0358] Further analysis of the NOV8a protein yielded the following properties shown in Table 8C.

37TABLE 8CProtein Sequence Properties NOV8aPSort0.4877 probability located in microbody (peroxisome); 0.4500analysis:probability located in cytoplasm; 0.1000 probability located inmitochondrial matrix space; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0359] A search of the NOV8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 8D.

38TABLE 8DGeneseq Results for NOV8aNOV8aIdentities/Protein/Residues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueABB61164Drosophila14 . . . 266148/264 (56%)1e−84melanogaster 7 . . . 269192/264 (72%)polypeptide SEQID NO 10284—Drosophilamelanogaster,274 aa.[WO200171042-A2, Sep. 27,2001]AAG31804Arabidopsis14 . . . 275117/263 (44%)6e−57thaliana protein36 . . . 287158/263 (59%)fragment SEQ IDNO: 38256—Arabidopsisthaliana, 581 aa.[EP1033405-A2,Sep. 6, 2000]ABB68788Drosophila33 . . . 269103/241 (42%)5e−49melanogaster 5 . . . 245142/241 (58%)polypeptide SEQID NO 33156—Drosophilamelanogaster,246 aa.[WO200171042-A2, Sep. 27,2001]ABB66750Drosophila33 . . . 269103/241 (42%)5e−49melanogaster 5 . . . 245142/241 (58%)polypeptide SEQID NO 27042—Drosophilamelanogaster,246 aa.[WO200171042-A2, Sep. 27,2001]AAB93705Human protein38 . . . 269117/302 (38%)4e−47sequence SEQ ID 6 . . . 307147/302 (47%)NO: 13289—Homo sapiens,313 aa.[EP1074617-A2,Feb. 7, 2001]

[0360] In a BLAST search of public sequence datbases, the NOV8a protein was found to have homology to the proteins shown in the BLASTP data in Table 8E.

39TABLE 8EPublic BLASTP Results for NOV8aNOV8aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ8TCB7Hypothetical 30.11 . . . 255255/255 (100%) e−149kDa protein—1 . . . 255255/255 (100%)Homo sapiens(Human), 255 aa.Q9DAX61600013P15Rik1 . . . 275243/275 (88%) e−145protein—Mus1 . . . 275261/275 (94%) musculus(Mouse), 282 aa.Q9D9M61600013P15Rik 1 . . . 275205/275 (74%) e−113protein—Mus 1 . . . 230218/275 (78%)musculus(Mouse), 237 aa.Q96LU4CDNA FLJ25062 1 . . . 177176/177 (99%) e−101fis, clone 1 . . . 177176/177 (99%)CBL04765—Homo sapiens(Human), 240 aa.Q9V872CG498914 . . . 266148/264 (56%)3e−84 protein— 7 . . . 269192/264 (72%)Drosophilamelanogaster(Fruit fly),274 aa.

Example 9

[0361] The NOV9 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 9A.

40TABLE 9ANOV9 Sequence AnalysisSEQ ID NO: 21915 bpNOV9a,ATGGCTAACAGGGGCCCGAGCTATGGCTTAAGCCGAGAGGTGCAGGAGAAGATCGAGCCG111347-01DNA SequenceAGAAGTATGATGCGGACCTGGAGAACAAGCTGGTGGACTGGATCATCCTGCAGTGCGCCGAGGACATAGAGCACCCGCCCCCCGGCAGGGCCCATTTTCAGAAATGGTTAATGGACGGGACGGTACTGTGCAAGCTGATAAATAGTTTATACCCACCAGGACAAGAGCCCATACCCAAGATCTCAGAGTCAAAGATGGCTTTTAAGCAGATGGAGCAAATCTCCCAGTTCCTAAAAGCTGCGGAGACCTATGGTGTCAGAACCACCGACATCTTTCAGACGGTGGATCTATGGGAAGGTAAAGACATGGCAGCTGTGCAGAGGACCCTGATGGCTTTAGGCAGCGTTGCAGTCACCAAGGATGATGGCTGCTATCGGGGAGAGCCATCCTGGTTTCACAGGAAAGCCCAGCAGAATCGGAGAGGCTTTTCCGAGGAGCAGCTTCGCCAGGGACAGAACGTAATAGGCCTGCAGATGGGCAGCAACAAGGGAGCCTCCCAGGCGGGCATGACAGGGTACGGGATGCCCAGGCAGATCATGGGACGCGGCATCCTGCCCCTGGTAGAGAGGACGAATGTTCCACACCATGGTCTCTACGAAAAAGAAATAGTTAGTCACCTTCTGACCTTCTCCTCTTTCTCAAAGCCTTCTGTCCCTGGTTTTTGCAAGTGCTGCATTTCCGCCGAGAATCCGCGTTGCCTACTGCTGCCACCTCCTGTTCATTTAGAACTATGCAAAGACTCCGCTTCCGTTTTCCTGAGCTCCTCGGGCCCCAGAGTCTCTGTTTGATTATTTATTTATTTATTTATTTATTTGCCAAAAATTCTTCCTCTTCAACTTATAGAATGCACCTAATAAAORF Start: ATG at 1ORF Stop: TGA at 844SEQ ID NO: 22281 aaMW at 31340.7DaNOV9a,MANRGPSYGLSREFQEKIEQKYDADLENKLVDWIILQCAEDIEHPPPGRAHFQKWLMDCG111347-01Protein SequenceGTVLCKLINSLYPPGQEPIPKISESKMAFKQMEQISQFLKAAETYGVRTTDIFQTVDLWEGKDMAAVQRTLMALGSVAVTKDDGCYRGEPSWFHRKAQQNRRGFSEEQLRQGQNVIGLQMGSNKGASQAGMTGYGMPRQIMGRGILPLVERTNVPHHGLYEKEIVSHLLTFSSFSKPSVPGFCKCCISAENPRCLLLPPPVHLELCKDSASVFLSSSGPRVSV

[0362] Further analysis of the NOV9a protein yielded the following properties shown in Table 9B.

41TABLE 9BProtein Sequence Properties NOV9aPSort0.4500 probability located in cytoplasm; 0.3000 probabilityanalysis:located in microbody (peroxisome); 0.1000 probability locatedin mitochondrial matrix space; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0363] A search of the NOV9a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 9C.

42TABLE 9CGeneseq Results for NOV9aNOV9aIdentities/Protein/Residues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAB81003Human neuronal1 . . . 281281/282 (99%) e−165protein 251 . . . 282281/282 (99%) (hNP25) aminoacid sequence—Homo sapiens,282 aa.[CN1272546-A,08 NOV. 2000]AAY93187Human NP251 . . . 221212/221 (95%) e−123protein—Homo1 . . . 221215/221 (96%) sapiens, 221 aa.[CN1251860-A,03 MAY 2000]AAB81004Rat neuronal1 . . . 217205/219 (93%) e−116protein 251 . . . 219207/219 (93%) (hNP25) aminoacid sequence—Rattus sp, 219 aa.[CN1272546-A,08 NOV. 2000]AAM41226Human poly-1 . . . 199199/199 (100%)e−115peptide SEQ ID1 . . . 199199/199 (100%)NO 6157—Homosapiens, 206 aa.[WO200153312-A1, 26 JUL.2001 ]AAM39440Human poly-1 . . . 199199/199 (100%)e−115peptide SEQ ID1 . . . 199199/199 (100%)NO 2585—Homosapiens, 199 aa.[WO200153312-A1, 26 JUL.2001]

[0364] In a BLAST search of public sequence datbases, the NOV9a protein was found to have homology to the proteins shown in the BLASTP data in Table 9D.

43TABLE 9DPublic BLASTP Results for NOV9aNOV9aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ9UI15Neuronal protein1 . . . 281281/282 (99%) e−165NP25—Homo1 . . . 282281/282 (99%) sapiens (Human),282 aa.P37805Neuronal protein1 . . . 217205/219 (93%) e−116NP25—Rattus1 . . . 219207/219 (93%) norvegicus (Rat),219 aa.Q96A74Neuronal protein1 . . . 199199/199 (100%)e−11522 (Similar to1 . . . 199199/199 (100%)neuronalprotein)—Homosapiens (Human),199 aa.Q9R1Q8Neuronal protein1 . . . 199198/199 (99%) e−114NP25—Mus1 . . . 199198/199 (99%) musculus(Mouse), 199 aa.Q8VHH3Neuronal protein1 . . . 199197/199 (98%) e−11422—Rattus1 . . . 199197/199 (98%) norvegicus (Rat),199 aa.

[0365] PFam analysis predicts that the NOV9a protein contains the domains shown in the Table 9E.

44TABLE 9EDomain Analysis of NOV9aIdentities/PfamNOV9aSimilarities forExpectDomainMatch Regionthe Matched RegionValueCH 24 . . . 13328/124 (23%) 3.7e−1578/124 (63%) calponin174 . . . 199 20/26 (77%) 1.1e−14 26/26 (100%)

Example 10

[0366] The NOV10 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 10A.

45TABLE 10ANOV10 Sequence AnalysisSEQ ID NO: 233631 bpNOV10a,CGGCCGCCCATGTGATCAAACGGTATACAGCCCAGGCGCCAGATGAGCTGTCCTTTGACG111446-01DNA SequenceGGTGAGGCTGTGGGGAAGCAGATTCCAGCTGGGCTCCCCACACCCCCTGCTCCTTCTGACCCTTCTCTTCCCACCCGCCCTCTCCCAGGTGGGAGACATTGTCTCGGTGATCGACATGCCACCCACAGAGGATCGGAGCTGGTGGCGGGGCAAGCGAGGCTTCCAGGTCGGGTTCTTCCCCAGTGAGTGTGTGGAACTCTTCACAGAGCGGCCAGGTCCGGGCCTGAAGGCGGCAGATGCCGATGGCCCCCCATGTGGCATCCCGGCTCCCCAGGGTATCTCGTCTCTGACCTCAGCTGTGCCACGGCCTCGTGGGAAGCTGGCCGGCCTGCTCCGCACCTTCATGCGCTCCCGCCCTTCTCGGCAGCGGCTGCGGCAGCGGGGAATCCTGCGACAGAGGGTGTTTGGCTGCGATCTTGGCGAGCACCTCAGCAACTCAGGCCAGGATGTGCCCCAGGTGCTGCGCTGCTGCTCCGAGTTCATTGAGGCCCACGGGGTGGTGGATGGGATCTACCGGCTCTCAGGCGTGTCTTCCAACATCCAGAGGCTTCGGCACGAGTTTGACAGTGAGAGGATCCCGGAGCTGTCTGGCCCTGCATTCCTGCAGGACATCCACAGCGTGTCCTCCCTCTGCAAGCTCTACTTCCGAGAGCTTCCGAACCCTCTGCTCACCTACCAGCTCTATGGGAAGTTCAGTGAGGCCATGTCAGTGCCTGGGGAGGAGGAGCGTCTGGTGCGGGTGCACGATGTCATCCAGCAGCTGCCCCCACCACATTACAGGACCCTGGAGTACCTGCTGAGGCACCTGGCCCGCATGGCGAGACACAGTGCCAACACCAGCATGCATGCCCGCAACCTGGCCATTGTCTGGGCACCCAACCTGCTACGGTCCATGGAGCTGGAGTCAGTGGGAATGGGTGGCGCGGCGGCGTTCCGGGAAGTTCGGGTGCAGTCGGTGGTGGTGGAGTTTCTGCTCACCCATGTGGACGTCCTGTTCAGCGACACCTTCACCTCCGCCGGCCTCGACCCTGCAGGCCGCTGCCTGCTCCCCAGGCCCAAGTCCCTTGCGGGCAGCTGCCCCTCCACCCGCCTGCTGACGCTGGAGGAAGCCCAGGCACGCACCCAGGGCCGGCTGGGGACGCCCACGGAGCCCACAACTCCCAAGGCCCCGGCCTCACCTGCGGAAAGGAGGAAAGGGGAGAGAGGGGAGAAGCAGCGGAAGCCAGGGGGCAGCAGCTGGAAGACGTTCTTTGCACTGGGCCGGGGCCCCAGTGTCCCTCGAAAGAAGCCCCTGCCCTGGCTGGGGGGCACCCGTGCCCCACCGCAGCCTTCAGGCAGCAGACCCGACACCGTCACACTGAGATCTGCCAAGAGCGAGGAGTCTCTGTCATCGCAGGCCAGCGGGGCTGGCCTCCAGAGGCTGCACAGGCTGCGGCGACCCCACTCCAGCAGCGACGCTTTCCCTGTGGGCCCAGCACCTGCTGGCTCCTGCGAGAGCCTGTCCTCGTCCTCCTCCTCCGAGTCCTCCTCCTCTGAGTCCTCCTCTTCCTCCTCTGAGTCCTCAGCAGCTGGGCTGGGGGCACTCTCTGGGTCTCCCTCACACCGTACCTCAGCCTGGCTAGATGATGGTGATGAGCTGGACTTCAGCCCACCCCGCTGCCTGGAGGGACTCCGGGGGCTGGACTTTGATCCCTTAACCTTCCGCTGCAGCAGCCCCACCCCAGGGGATCCCGCACCTCCCGCCAGCCCAGCACCCCCCGCCCCTGCCTCTGCCTTCCCACCCAGGGTGACCCCCCAGGCCATCTCGCCCCGGGGGCCCACCAGCCCCGCCTCGCCTGCTGCCCTAGACATCTCAGAGCCCCTGGCTGTATCAGTGCCACCCGCTGTCCTAGAACTGCTGGGGGCTGGGGGAGCACCTGCCTCAGCCACCCCAACACCAGCTCTCAGCCCCGGCCGGAGCCTGCGCCCCCATCTCATACCCCTGCTGCTGCGAGGAGCCGAGGCCCCGCTGACTGACGCCTGCCAGCAGGAGATGTGCAGCAAGCTCCGGGGAGCCCAGGGCCCACTCGGTCCTGATATGGAGTCACCACTGCCACCCCCTCCCCTGTCTCTCCTGCGCCCTGGGGGTGCCCCACCCCCGCCCCCTAAGAACCCAGCACGCCTCATGGCCCTGGCCCTGGCTGAGCGGGCTCAGCAGGTGGCCGAGCAACAGAGCCAGCAGGAGTGTGGGGGCACCCCACCTGCTTCCCAATCCCCCTTCCACCGCTCGCTGTCTCTGGAGGTGGGCGGGGAGCCCCTGGGGACCTCAGGGAGTGGGCCACCTCCCAACTCCCTAGCACACCCGGGTGCCTGGGTCCCGGGACCCCCACCCTACTTACCAAGGCAACAAAGTGATGGGAGCCTGCTGAGGAGCCAGCGGCCCATGGGGACCTCAAGGAGGGGACTCCGAGGCCCTGCCCAGGTCAGTGCGCAGCTCAGGGCAGGTGGCGGGGGCAGGGATGCGCCAGAGGCAGCAGCCCAGTCCCCATGTTCTGTCCCCTCACAGGTTCCTACCCCCGGCTTCTTCTCCCCAGCCCCCAGGGAGTGCCTGCCACCCTTCCTCGGGGTCCCCAAGCCAGGCTTGTACCCCCTGGGCCCCCCATCCTTCCAGCCCAGTTCCCCAGCCCCAGTCTGGAGGAGCTCTCTGGGCCCCCCTGCACCACTCGACAGGGGAGAGAACCTGTACTATGAGATCGGGGCAAGTGAGGGGTCCCCCTATTCTGGCCTCACCCGCTCCTGGAGTCCCTTTCGCTCCATGCCCCCCGACAGGCTCAATGCCTCCTACGGCATGCTTGGCCAATCACCCCCACTCCACAGGTCCCCCGACTTCCTGCTCAGCTACCCGCCAGCCCCCTCCTGCTTTCCCCCTGACCACCTTGGCTACTCAGCCCCCCAGCACCCTGCTCGGCGCCCTACACCGCCTGAGCCCCTCTACGTCAACCTAGCTCTAGGGCCCAGGGGTCCCTCACCTGCCTCTTCCTCCTCCTCTTCCCCTCCTGCCCACCCCCGAAGCCGTTCAGATCCCGGTCCCCCAGTCCCCCGCCTTCCCCAGAAACAACGGGCACCCTGGGGACCCCGTACCCCTCATAGGGTGCCGGGTCCCTGGGGCCCTCCTGAGCCTCTCCTGCTCTACAGGGCAGCCCCGCCAGCCTACGGAAGGGGGGGCGAGCTCCACCGAGGGTCCTTGTACAGAAATGGAGGGCAAAGAGGGGAGGGGGCTGGTCCCCCACCCCCTTACCCCACTCCCAGCTGGTCCCTCCACTCTGAGGGCCAGACCCGAAGCTACTGCTGAGCACCAGCTGGGAGGGGCCGTCCTTCCTTCCCTTCACCCTCACTGGATCTTGGCCCAACCAAATCCCTTGTTTTGTATTTTCTTGAACCCCGACCACTACCCCAGGTTTCTAACTTTGTAACTTGCTTCTGATGTGGGTCCCTAACCTATAATCTCAGCTTCCCTACCCTGGACTGAAGGGTCTGCCCATCCCCCCACCACCCTCCATCCTGGGGGCCCTCGCACAAATCTGGGGTGGGAGGORF Start: ATG at 174ORF Stop: TGA at 3387SEQ ID NO: 241071 aaMW at 113672.9DaNOV10a,MPPTEDRSWWRGKRGFQVGFFPSECVELFTERPGPGLKAADADGPPCGIPAPQGISSLCG111446-01Protein SequenceTSAVPRPRGKLAGLLRTFMRSRPSRQRLRQRGILRQRVFGCDLELGEHLSNSGQDVPQVLRCCSEFIEAHGVVDGIYRLSGVSSNIQRLRHEFDSERIPELSGPAFLQDIHSVSSLCKLYFRELPNPLLTYQLYGKFSEAMSVPGEEERLVRVHDVIQQLPPPHYRTLEYLLRHLARMARHSANTSMHARNLAIVWAPNLLRSMELESVGMGGAAAFREVRVQSVVVEFLLTHVDVLFSDTFTSAGLDPAGRCLLPRPKSLAGSCPSTRLLTLEEAQARTQGRLGTPTEPTTPKAPASPAERRKGERGEKQRKPGGSSWKTFFALGRGPSVPRKKPLPWLGGTRAPPQPSGSRPDTVTLRSAKSEESLSSQASGAGLQRLHRLRRPHSSSDAFPVGPAPAGSCESLSSSSSSESSSSESSSSSSESSAAGLGALSGSPSHRTSAWLDDGDELDFSPPRCLEGLRGLDFDPLTFRCSSPTPGDPAPPASPAPPAPASAFPPRVTPQAISPRGPTSPASPAALDISEPLAVSVPPAVLELLGAGGAPASATPTPALSPGRSLRPHLIPLLLRGAEAPLTDACQQEMCSKLRGAQGPLGPDMESPLPPPPLSLLRPGGAPPPPPKNPARLMALALAERAQQVAEQQSQQECGGTPPASQSPFHRSLSLEVGGEPLGTSGSGPPPNSLAHPGAWVPGPPPYLPRQQSDGSLLRSQRPMGTSRRGLRGPAQVSAQLRAGGGGRDAPEAAAQSPCSVPSQVPTPGFFSPAPRECLPPFLGVPKPGLYPLGPPSFQPSSPAPVWRSSLGPPAPLDRGENLYYEIGASEGSPYSGLTRSWSPFRSMPPDRLNASYGMLGQSPPLHRSPDFLLSYPPAPSCFPPDHLGYSAPQHPARRPTPPEPLYVNLALGPRGPSPASSSSSSPPAHPRSRSDPGPPVPRLPQKQRAPWGPRTPHRVPGPWGPPEPLLLYRAAPPAYGRGGELHRGSLYRNGGQRGEGAGPPPPYPTPSWSLHSEGQTRSYC

[0367] Further analysis of the NOV10a protein yielded the following properties shown in Table 10B.

46TABLE 10BProtein Sequence Properties NOV10aPSort0.6000 probability located in nucleus; 0.3000 probabilityanalysis:located in microbody (peroxisome); 0.1834 probability locatedin lysosome (lumen); 0.1000 probability located inmitochondrial matrix spaceSignalPNo Known Signal Sequence Predictedanalysis:

[0368] SignalP No Known Signal Sequence Predicted analysis:

[0369] A search of the NOV10a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 10C.

47TABLE 10CGeneseq Results for NOV10aIdentities/GeneseqProtein/Organism/LengthNOV10a Residues/Similarities forExpectIdentifier[Patent #, Date]Match Residuesthe Matched RegionValueAAB42952Human ORFX ORF2716 210 . . . 1071861/862 (99%)0.0polypeptide sequence SEQ ID 2 . . . 863861/862 (99%)NO:5432-Homo sapiens, 863 aa.[WO200058473-A2, Oct. 5, 2000]AAB42926Human ORFX ORF2690 487 . . . 1071546/585 (93%)0.0polypeptide sequence SEQ ID350 . . . 903547/585 (93%)NO:5380-Homo sapiens, 903 aa.[WO200058473-A2, Oct. 5, 2000]AAE13842Human lung tumour-specific protein115 . . . 698280/698 (40%)e−11120129-Homo sapiens, 1702 aa. 3 . . . 672375/698 (53%)[WO200172295-A2, Oct. 4, 2001]AAE13842Human lung tumour-specific protein115 . . . 698280/698 (40%)e−11120129-Homo sapiens, 1702 aa. 3 . . . 672375/698 (53%)[WO200172295-A2, Oct. 4, 2001]AAM50136Human GTPase activating molecule 82 . . . 572217/513 (40%)e−87GAP-5-Homo sapiens, 1101 aa. 3 . . . 497282/513 (53%)[WO200175106-A1, Oct. 11, 2001]

[0370] In a BLAST search of public sequence datbases, the NOV10a protein was found to have homology to the proteins shown in the BLASTP data in Table 10D.

48TABLE 10DPublic BLASTP Results for NOV10aIdentities/NOV10aSimilaritiesProteinResidues/for theAccessionProtein/MatchMatchedExpectNumberOrganism/LengthResiduesPortionValueQ9NT23Hypothetical 90.3210 . . . 1071862/8620.0kDa protein—(100%)Homo sapiens 1 . . . 862862/862(Human), 862 aa(100%)(fragment).O14560F25965_3—487 . . . 1071546/5850.0Homo sapiens (93%)(Human), 903 aa.350 . . . 903 547/585 (93%)Q96CP3Hypothetical 31.6777 . . . 1071294/2950.0kDa protein— (99%)Homo sapiens 4 . . . 298294/295(Human), 298 aa (99%)(fragment).CAD10299Sequence 1 from82 . . . 572217/5136e−87Patent (42%)WO0175106— 3 . . . 497282/513Homo sapiens (54%)(Human),1101 aa.Q9ULL6KIAA120477 . . . 877289/8625e−86protein—Homo (33%)sapiens (Human), 2 . . . 806398/8621445 aa(45%)(fragment).

[0371] PFam analysis predicts that the NOV10a protein contains the domains shown in the Table 10E.

49TABLE 10EDomain Analysis of NOV10aPfamNOV10aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValueRhoGAP113 . . . 265 68/171 (40%)1.6e−50125/171 (73%)

Example 11

[0372] The NOV11 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 11A.

50TABLE 11ANOV11 Sequence Analysis6126 bpSEQ ID NO: 25NOV11a,GCCGGCTCCTGCTCCTCCTGGCCGCCCGGGGCCAAGGCGACGAGAGGTTGTAAAAATCCG111464-01DNA SequenceCATGTGGGACGGCCCCGGGGCGAGCATCGGAAAGATCTCTGAGTGGAGTTATTTTCTGGTACGGACTGTGAAAAGAATGCGGTCAAAATTCTGGACAATCGTGGAAATATTAGCTCAAACCCCAACTTAATATAGCATTTCTTCTCTTCAGTAACACCTCATAATACAAGAAAAATGTATCGAAGTGCAAGAACAATCACCAATCTGGAAGGTAGCCCTTCCAGATCCCCTCGTTTGCCAAGCTCTCCTCGTTTGGGCCACCGAAGAACAAGTAGTGGGCGAGGTGGAGGAACAGGCAAGACTCTGTCTATGGAGAATATCCAGTCCCTCAATGCAGCCTATGCTACGTCTGGACCCATGTATCTGAGTGATCATGAAGGGGTGGCTTCACCAACCTACCCAAAGGGTACTATGACTCTGGGAAGGGCTACAAATCGAGCTGTATATGGAGGCCGTGTCACAGCCATGGGGAGTAGTCCCAATATTGCTTCTGCTGGACTTTCCCACACAGATGTCCTTTCATACACAGATCAACATGGTGGGCTGACTGGCTCATCCCATCATCACCACCACCAGGTCCCCTCCATGTTGAGGCAGGTAAGAGACAGCACAATGTTAGATCTTCAGGCCCAGCTGAAACAACTGCACAGAGAGAATCACCTCCTCCGGAAAGAGCTAGACATCAAGGACAGCAAATTGGGATCTTCCATGAACACTATTAAGACTTTCTCGAGTCCTGAGCTTAAGAAGGAGAGAGTCTTGAGGAAAGAAGAGGCAGCGCGGATGTCTGTCCTCAAGGAGCAGATGAGGGTTTCCCATGAAGAAAATCAGCACCTACAGTTGACAATCCAGGCCCTTCAAGATGAGCTGCGAACCCAGAGAGACCTCAACCACCTCCTCCAGCAAGACAGTGGCAACCGAGCAGCGGAGCACTTCACCATCGAGCTGACCGAGGACAACTTTAGGCGGCTCCAAGCCGAGCATCACAGGCAGGCTAAGGAGCTGTTCCTTTTGAGGAAGACATTAGAGGAAATGGAGCTGAGAATTGAAACGCAGAAACAAACCCTCAATGCCCGAGATGAGTCAATTAAAAAACTTCTTGAGATGTTGCAAAGTAAAGGCTTGCCATCCAAAAGCCTGGAGCATGACAATGAGCGAACGCGGCGGATGGCAGAGGCTGAGTCTCAGGTCAGCCACTTGGAAGTGATTTTAGATCAGAAAGAGAAGGAAAACATACATCTTAGAGAGGAATTGCACCGAAGAAGCCAACTTCAGCCGGAGCCAGCCAAGACGAACGCTCTCCAGACTGTCATCCAAATGAAGCACACAAAAATCGCTTCATTCCAACGAAACATAACGGATCTTGAGGATGAGATCCAGATGTTAAAAGCCAATGGTGTGCTGAACACTCAGGACCGCGAAGAAGAGATCAAACAAATTCAGGTTTACAAAAGTCACTCCAAGTTTATGAAGACCAAGATTGATCAGCTGAAGCAGGAACTTTCAAAGAAAGAGTCGCAACTTCTTGCCTTACAAACAAAGCTTGAAACCCTCAGCAATCAAAATTCAGATTGCAAGCAACACATTGAAGTGCTCAAAGAGTCACTTACTGCCAAAGAACAGAGGGCTGCCATCCTTCACACTGACGTAGATCCGCTGAGATTACGACTGGAAGAAAAAGAATCTTTCCTCAATAAAAAAACAAAACAGCTACAGAACCTCACAGAAGAGAAGGGGACACTGGCCGGTGAAATTCGTGACATCAAAGATATCTTACAACTGAAGCAAAGAAAAATCAATGTTCTTCAGAAAAAGATTGAAAACTTGCAAGAACAACTTAGGGATAAAGACAAGCAACTGACCAACCTGAAAGACAGAGTCAACTCCTTGCAGACGCATTCCAGTAATACAGATACTGCACTGGCGACGCTAGAGGAAGCTCTGTCAGACAAGGAGAGAATAATTGAGCGCTTGAAAGAACAGCGAGAAAGAGATGATCGGCAAAGACTAGAAGAGATAGAATCCTTCCGAAAAGACAACAAAGACCTGAAAGAGAACGTCAATGCTTTACAGGCTGAACTGACTGAGAAAGAGTCTAGTTTAATTGACCTCAAAGAACATGCATCTTCATTAGCCTCTGCGCGGCTCAAAAGGGATTCCAAATTAAAATCTCTAGAAATAGCCATTGAACAAAAGAAAGAGGAATGTAGCAAATTGGAAGCACAGTTAAAAAAGGCACATAATATTGAACATGACTCCAGGATGAACCCTGAGTTTGCAGACCAAATAAAACAGCTCGATAAAGAGGCGTCTTACTACCGCGACGAGTGTCGCAAGGCCCAAGCCGAAGTGGACCGGTTGCTGGAGATCCTCAAGGAGGTGGAGAATGAGAAGAATGACAAGGACAAGAAGATCGCAGAACTGGACACCTTGACTCTCAGGCATATGAAAGATCAGAATAAGAAGGTGGCCAACCTCAACCACAATCAACAGTTGGAAAAGAAGAAAAATGCTCAGTTACTACAAGAAGTGCGCAGGCGAGAAGACAGCATGGCTGACAACTCACAGCATTTGCAGATAGAGGAACTCATGAATGCACTGGAGAAGACCAGACAGGAACTGGATGCCACCAAAGCACGCCTCGCCTCCACACAACAGTCCCTGGCCGAAAAAGAAGCGCACTTGGCCAACCTCCGGATTGAGAGGAGGAAACAGCTAGAGGAGATCCTGGAGATGAAACAGGAAGCACTACTTGCAGCCATCAGTGAAAAAGATGCAAACATTGCCTTGCTGGAATTGTCTGCCTCCAAAAAGAAAAAGACGCAGCAAGAAGTCATGGCCCTCAAGCGGGAAAAAGACCGACTAGTACATCAATTAAAGCAGCAGACCCAGAACAGAATGAAGTTGATGGCAGACAACTATCATGATGACCATCACCATTACCACCACCACCACCATCACCACCACCATCGATCTCCTGGGAGGTCGCAACATTCCAATCACAGGCCCTCTCCGGACCAGGATGACGAGCAGGGCATATGGGCATAGCCGGGCCTGTAAACCAAAGTTCCAGTTTTGTTTTGAGGGCTATTAGAAGGGCTGAATAAAGCGAACATGCAGCTCTGCACCAATATTCTGATAATGTATTGCAGTGCGGCTCACATCACTGTCCACCACCACCTGGAGCGGCTCATCAGAACTGAAGGCGAGTTTTCACTTACCTTATTGAGCGTGATTCTGTTCTACTTGATATTTCCTTCACCACCTCATGTCATTTCTCATGGATTTGGTTATGATGGAAAGGAAGAATGCAGAGGAGGAGAAAAGTGACAGATCCTCCATTTTTGTTGGGATGCGGGCATTTTGAATGTCATCATCTTTGCTGAATGTCATTATTTCATAACATTTTGTTTATGTTACTTAAACATCATTGGATAAATTTCAACTCCATGGGATTTTATCTGTGCATTCAGCTTCTGTTGGACAACTACCCTCATCTCCAGTATCCTGCTGGTTCACTCTAATTGGTCATTCCTAATGCATTAGATTATCAAAAAGTATAAATTCCCTGTGAGTGAGTGGTCTTGGCAGTGTTTGTATACCATGATGCATGGAGTGTTTGACGAAGAAACAAAAAACACCAAAAATTCCGAGCCTTTACCCTCCTCTATTTCTTTAATCTGTTGTTTGAAGAACCGCATTTTGAGGGTGTAACCAGTAGTCACCTCTGGGCCAGGTTGGAAAAGAAATCAATTTTTTAAACCACTAATGCTTGCCAAGAAATCGCCTTATGAGAACATGGTGTGTGTCTCTGACAATGCGTGGCACATCTAAATTGATCATTCATAATTTTATCTACCCAGTCATGTACTGGAGAGTGGCAAAAGTCTGACGCACCTGCATATCTCTAGTCCCTGTGTTCTGCACATCCCCACGGTGGGGACGCCACCAAGCCTCAGACTCTTACCATCCCGGTGCATGCAGGTCTCCATGAAGAAGCTGGGACTCATTCACATTTCAAGATCCAAATGCTGTGCAAACAGTGTAAGCTTAAATTTTCTGTAAATGAAGGGTCATTTCTCTTTTTTTTTTTTTTTAAAGAAAATGTGTCTGCAACATGGATTCCAAAGCATTTTCAGCATCAAACATGAAAACATTGATGAATGAGGAACAATCACAAAAGCTGTGTCTCTCTATATAGCTCTACACAACATGTATCTGGATACACTCATTATTTAAACCACATGCCAGGGAAAAACACCAAATTTTGAGGTCTTTTACATACAGTGATATGCTACTAAGGAGAATTAAACTCCTACTGCTTCCTCTGAATATTAAGAAACAATTTAAATTGTTATAACTTCATAAAACTCATGACTGAGTCTGGCAAACATGTGCAACTCTTGTATTGCTCCATTTTCTTGTCAATGGAAGAAACCCTTCCACGTGTATGCAAGTCGGAGATGAAAACCTGCATTTTTAAAGGACAAACACTGAATTTAAGCATGAGTGGCCTTAATAAATATAGTTGTCTTTCTTTGCTGCTGTGGAAACGATTCTAAACAGATGTCCCTGAAGTCTTGCATTGAATTTAGTCATTATTATTACTTTTTAAAATGTTGGTCCAATTAACTCTGGACCTCTCTTGTCACCCATAGAGATATTTAATAGACAAACACCTTATTTGTCGGGGAAGATGAAACCGTCCCTGAGTTCCACCATTCTTTCTTGCTGCATTCCCGGTTAACATACTCAAGCAGGTTTCTTGCTTCTGGCTTTGTTCTTGTCATCAGTAACTATAACAAACTATGTAATGCTTATGTGTTGCATAAACAATCCAAATGCATTCATGTTTTAAAACTTTGTCCTTTAACTATCAGACGGATCTAGGTCTTGGTTAGAGAAGTAAGCAGAGTTCTTTGCAAGCTTATTTAGCACATTTTGACACAATGTTGCACTGAAAACCCAGACCACAAATGTGTCCCAGTGAACAGTTTGGATGTCCTCAAAGAAGTGGTTCTCACTCCCTCCTACAACCAGCTCTTGACCTGAACTCTGCAACTGAATACTTGAAGTAGGAACTAGGAAATCCAGTAGCGAAAATAGGGTCCTTGAAACAGAAAAAAAAAACCAACCCATGTATACCTAGCTATTTCTATGTATGTGCCAATTTTGTCACAGCTCTTGTTTGGAGGGATCATTTTCTGCCCAACTTTCATTGGTTAAAATATTACTGATCTTACCTTTATGAGGTCGTATAATTTAGTCCCTTAAAAATTAAATTCTCTCTAACATAACAACCTTTCCCATTTCGTGTAATATTCTCTGATCTTTGGGGGTTACCAAAAATATCCCTTTTTCACATATTAAAAATAGTCTCTCGGTTTACAACAAACACTGTGATGTTGGGAACCTATTTCCTTTGCGCAAACTTTAACACGTTTTCTTCTAATCATAACATAGTTGAAAAAAGAAGTTTGGGCTAACATTTAGGAGAAGTTGGTCTTATTTTGTGCAAAAGCACGCTTGTGCTTTATACCCCATTTGATTTCGATGTACAGTCTCAATTTTGTATTTAATGATTTTTGTCTATCCAGTATGCACGTTAACAGCGTGTCAACTTTCATTTGAAAGTGGGTTTCAATTTACTTTTTAAACAGTCTTTATGACGAGACCTCAGATGTGTTGACGTAAGCTCTATCTGCAATGTTTTTGTGTAGAGTGGCGATTGAATGCTGCCCAGGGTCAGTGTATCTAATTCCCCGAGACCCTCGTTTGATAGTGCTTCTTGTAATATTTCTTCAAGTGAGTGGCATGTGGGTTGTGATATTGACCATGTGATTATGGACATCGATATGAAAAATAAATAAATAAAACTAAGGAACCCTGGAAACTACCAGTCGGCATGTATTAGCCAGTCATTGTAACCTCGTGTCTAGTAGAACAATGTACAAGGTATGTACAGTTCATAAATTTGTTGTCATGTCTATGAGAAGTACTTTGTGCTGATCGCCTTATTTATATTCATCAAATAAACCTTGTTTCTTTCTGAAAAAAAAAAAAAAAAAORF Start: ATG at 233 ORF Stop: TAG at 3104957 aa MW at 110552.4DaSEQ ID NO: 26NOV11a,MYGSARTITNLECSPSRSPRLPRSPRLGHRRTSSCGGGGTGKTLSMENIQSLNAAYATCG111464-01Protein SequenceSGPMYLSDHEGVASPTYPKCTMTLGRATNRAVYGCRVTAMCSSPNIASAGLSHTDVLSYTDQHGGLTCSSHHHHHQVPSMLRQVRDSTMLDLQAQLKELQRENDLLRKELDIKDSKLGSSMNSIKTFWSPELKKERVLRKEEAARMSVLKEQMRVSHEENQHLQLTIQALQDELRTQRDLNHLLQQESGNRGAEHFTIELTEENFRRLQAEHDRQAKELFLLRKTLEEMELRIETQKQTLNARDESIKKLLEMLQSKGLPSKSLEDDNERTRRMAEAESQVSHLEVILDQKEKENIHLREELHRRSQLQPEPAKTKALQTVIEMKDTKIASLERNIRDLEDEIQMLKANGVLNTEDREEEIKQIEVYKSHSKFMKTKIDQLKQELSKKESELLALQTKLETLSNQNSDCKQHIEVLKESLTAKEQRAAILQTEVDALRLRLEEKESFLNKKTKQLQDLTEEKGTLAGEIRDMKDMLEVKERKINVLQKKIENLQEQLRDKDKQLTNLKDRVKSLQTDSSNTDTALATLEEALSEKERIIERLKEQRERDDRERLEEIESFRKENKDLKEKVNALQAELTEKESSLIDLKEHASSLASAGLKRDSKLKSLEIAIEQKKEECSKLEAQLKKAHNIEDDSRMNPEFADQIKQLDKEASYYRDECGKAQAEVDRLLEILKEVENEKNDKDKKIAELESLTLRHMKDQNRKVANLKHNQQLEKKKNAQLLEEVRRREDSMADNSQHLQIEELMNALEKTRQELDATKARLASTQQSLAEKEAHLANLRIERRKQLEEILEMKQEALLAAISEKDANIALLELSASKKKKTQEEVMALKREKDRLVHQLKQQTQNRMKLMADNYDDDHHHYHHHHHHHHHRSPCRSQHSNHRPSPDQDDEEGIWA

[0373] Further analysis of the NOV11a protein yielded the following properties shown in Table 11B.

51TABLE 11BProtein Sequence Properties NOV11aPSort0.9400 probability located in nucleus; 0.3000 probabilityanalysis:located in microbody (peroxisome); 0.1000 probability locatedin mitochondrial matrix space: 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0374] A search of the NOV11a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 11C.

52TABLE 11CGeneseq Results for NOV11aNOV11aIdentities/Protein/Residues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueABG05140Novel human150 . . . 957808/8080.0diagnostic protein(100%)#5131—Homo 1 . . . 808808/808sapiens, 808 aa.(100%)[WO200175067-A2, 11 OCT.2001]ABG05140Novel human150 . . . 957808/8080.0diagnostic protein(100%)#5131—Homo 1 . . . 808808/808sapiens, 808 aa.(100%)[WO200175067-A2, 11 OCT.2001]AAU83013Human homo- 1 . . . 957662/9670.0logue of SRB4 (68%)protein target for 1 . . . 888779/967antifungal (80%)compound—Homo sapiens,888 aa.[WO200202055-A2, 10 JAN.2002]AAM79969Human protein460 . . . 957372/5420.0SEQ ID NO (68%)3615—Homo 5 . . . 533439/542sapiens, 533 aa. (80%)[WO200157190-A2, 09 AUG.2001]AAM78985Human protein506 . . . 957331/496e−180SEQ ID NO (66%)1647—Homo 2 . . . 484396/496sapiens, 484 aa. (79%)[WO200157190-A2, 09 AUG.2001]

[0375] In a BLAST search of public sequence datbases, the NOV11a protein was found to have homology to the proteins shown in the BLASTP data in Table 11D.

53TABLE 11DPublic BLASTP Results for NOV11aIdentities/NOV11aSimilaritiesProteinResidues/for theAccessionProtein/MatchMatchedExpectNumberOrganism/LengthResiduesPortionValueBAA20832KIAA0378 1 . . . 957956/9570.0protein—Homo (99%)sapiens (Human),14 . . . 970956/957970 aa (99%)(fragment).O15083KIAA0378150 . . . 957 808/8080.0protein—Homo(100%)sapiens (Human), 1 . . . 808808/808808 aa(100%)(fragment).Q9U1K7ELKS—Homo 1 . . . 957700/9670.0sapiens (Human), (72%)948 aa. 1 . . . 948829/967 (85%)Q99M12Rab6-interacting 1 . . . 957697/9950.0protein 2 isoform (70%)A—Mus 1 . . . 976831/995musculus (83%)(Mouse), 976 aa.BAA83033KIAA1081 1 . . . 957 700/10110.0protein—Homo (69%)sapiens (Human), 12 . . . 1003 829/10111003 aa(81%)(fragment).

Example 12

[0376] The NOV12 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 12A.

54TABLE 12ANOV12 Sequence Analysis3450 bpSEQ ID NO: 27NOV12a,ATGGAAGTCATGCTACGGTTTCCCGGCCACATCGACGTACGGCTTGGGTACCCACAGGCG111512-01DNA SequenceCCTCAGATGCCTCTTGGGCTTTGGAAAGTTGAATGCTGCAACCCCAAGCCCACTTTCAGGTAGGGATGAGCCCATTGCCCAATGCTGGGGTCCGAGTGGGCCTGAAGGCTCCCAGAGGACCACGTTCTCAGCCCTGCATCGGCAGGGACCCTCCAGACCTGGCCTGTGTGGACACAGGGGAAAAGTTCCAGAGCTGGTGGCTGCAGGAATCCTTCAATCGAGGCGATGTTTGCAAGCAGCACCAACCTAGTTGGTTGGTCGTCGAGTCCGTGGCATCCAGAAGCTTTTCCAAAAACTCCGCCCAGGAGCTATATAGGCGGCGTGAGGCAGGCGAGCGGGGCAGCGCAGCCGAGCGGACCCCACGAGAGCAGAGAGCGAGCCTGACCGAGAGACGGGCAAGCACGGAGGAGGAAGCCGCCGGTGCGTCGGGACGGGAGCGCAGGTGCTCGGGCACCCGACCTGGAGCTCCCCAGCCGCCGGTCATGTACCGCTCCACCAAGGGCGCCTCCAAGGCGCGCCGGGACCAGATCAACGCCGACATCCGGAACCTCAACCAGCTGCTGCCCCTGGCCGAAGCGCACAAGGTCCGGCTGTCCTACCTGCACATCATGAGCCTCGCCTGCATCTACACTCGCAAGGGCGTCTTCTTCGCTGGTGGCACTCCTCTGCCCGCCCCCACGGGGCTTCTCTCACCTCAAGAGCTTGAGGACATCGTAGCGGCACTACCCCGCTTTCTCCTTGTGTTCACAGCCGAGGGGAAATTGCTCTACCTGTCTGAGAGTGTGAGCGAGCATCTGGGCCACTCCATCGTGGACCTGGTTGCCCAGGGTGACAGCATCTACGACATCATTGACCCAGCTGACCACCTCACTCTGCGCCAGCAACTCACCCTGCCCTCTCCCCTGGACACTGATCGCCTCTTCCGCTGCCGCTTCAACACCTCCAAGTCCCTCAGGCGCCAGAGTCCAGGCAACAAACTCGTGCTTATTCGAGGCCGATTCCATGCTCACCCACCTGGACCCTACTGGGCAGCAAATCCCGTCTTCACAGCTTTCTGTGCCCCTCTCGAGCCCAGACCCCCCCCAGGTCCTGCCCCTGGCCCTGGCCCTGCCTCGCTCTTCCTGGCCATGTTCCAGAGCCGCCATGCTAAAGACCTGGCTCTACTCGACATCTCCGACAGTGTCCTAATCTACCTCCCCTTTCACCCCAGTGAACTGCTTTGTAAATCATGGTATCGACTGCTGCACCCCGAGGACCTGGCCCACCCTTCTGCTCAACACTACCGCCTCTTCCCTCAGAGTGGAGATATTCAGGCACACATCCTGCTCACGCTACAGGCCAAGACTCGACGCTGCGCATGGATTTACTCCCTGTTATACTCAGAAGGTCCAGAGGGACCCATTACTGCCAATAACTACCCAATCAGTGACATGGAAGCCTGGAGCCTCCGCCACCACTTGAACTCTCAACACACCCACCCAGCTTATGTCCTGGGCACTCCCACCATGCTGCCCTCATTCCCTGAAAACATTCTTTCCCACGAACAGTCCTCCAGCACTAACCCACTCTTCACCCCAGCACTGGGGGCTCCCACTTGCACCACCTTCCCCAGTGCTCCTGAACTGAGTGTTGTCTCTCCATCAGACACCTTCCCCGACCCTCCAAAGAACTGGAACTTCAGTTACCTCACATTCCCTTCTCCCCCTCACCCTTCTCTCCAAGCAGAACTAAGCAAGCATCTTGTGTCCACTCCACCTTACACCCCCCATCAGCCACCACGCTGTGCCTTCCTCTTCAGCCTCCATCAGCCCTTCCAGACCCATTTGCCCACCCCATCCAGCACTCTTCAAGAACAGCTGACTCCAAGCACTGCCACCTTCTCTCATCAGTTGACGCCCACCAGTGCAACCTTCCCAGATCCACTAACTAGCCCACTGCAAGCCCACTTCACTGAAACCTCGGTCACAAGCTATGAAGACCAGTTCACTCCCTCCACCTCCACCTTCCCACACCAGCTGCTTCCCAGCACAGCCACCTTCCCACACCCTCTCCCCACCCCTGCCCATCAACACCTCACTCCTCCCAGCACACCATTCCAAGCACACCTGGACACCCCCAGCCAAACCTTCCCACAGCAACTCACCCCCAACCCTACCAAGACTTACTTTGCCCACGACCGATCCAGTTTTCTCTATCACAAGTTGCCCCCAACTCCTACCACCCCTGGTAATGGGGACTCCACGCTCTTCGCCCTACCCCAGCTCCGGGCCCCCCTCTCTCTCCATGTCCCCCTGGTCCCCCAACCCCTCCTCACACCTGAGGCCTCTCCAGTCAACCAGAGTTTCTTCCACTACTCTGAAAACCACCAGAATCAGATAGACCCTCTCATCCAGCAGATTAGCCAATTGGCTCAGGCCATCGACAGACCCTTCTCAGCTGACCCTGGCACTGGCGGACTAGACCCACTTGCACCACTCGACCCCCTGCACTCCAACCTGTCCCTCTCAGCCGCACGCCCCCCTCTGCTCAGCCTCCACCTGAAACCCTGGAAATGCCAGGAGCTGCACTTCCTGGCTCACCCTCATAACATGTTCCTCCAACACACCCCCGTGGAAGACATCTTCATGGATCTCTCTACCCCACATCCCACTGAGGAATGGGGCTCAGGGGATCCTCAGGCACAGCCCCCACGACGGCCCCCATCCCCTTCCAACAACCTGTCCCCAGAACACCACACCTTCCTGCAGGACCTGGCCACATATGAAACCGCCTTTCAGACAGGTGTCTCAGCATTCCCCTATGATCGCTTTACTGATGAGTTGCATCAACTCCAGAGCCAAGTTCAAGACAGCTTCCATGAAGCGAAGCAACTTCCTTCTCGGGCCCTGGATCCACTCACTGGAAATTATAACCACGTCTGTTATCCTTCCACAGCGCTTTCACCTGACACACACTTTTACCTCTCTTATTTGCTCCAACAATTCTTCTGGGCAGCCATATTACCCCATCTCACTGATGAACAAACTCACCACCACAGGGTCCTCTTCCCGCCCTTCCTGGACCCCTCTGGAGGCATGTGCACTGAGCCCATCATCCAGGATGCCCTCTGGCCAGCTGCCTCGCGGATTAACCCATGCACACCCGCTGCACTCTTAGCACAACTTAGAAACAGTGTGGGGAGCCCACATCCAGTCTCTCACCAATCCTCTTGGCTTCACTTTCAAAACCAGATCCAGAATCTGACCACTCCTGCACACCTTCTTTCCCACCCACCCCCGGCCCACCTCCCTACCAACGCCAATCTAGATTTCCCCAACAGCCTCTCCCCTCGTGTCTCTCTTGCCCTCTCCATCCTCCCAGAGGGATCCTTTCAAAATCCAAGTCACATCTGAORF Start: ATG at 1 ORF Stop: TGA at 34481149 aa MW at 124718.3DaSEQ ID NO: 28NOV12a,MEVMLRFACDIDVGLGYPQASDASWALEVECCNFRPQFQVGMSPLPNACVRVGLKAPRCG111512-01Protein SequenceGPRSQPWMGRDPGDLACVDTGEKFQSWWLQESFNGCDVCKQQQPSWLVVESVASRSFSKKSAQELYRREEAGEGGSAAERSPGEQRASLEERRGSTEEEAAGASGRERRCSGTRAGAPQRPVMYRSTKGASKARRDQINAEIRNLKELLPLAEADRVRLSYLHIMSLACTYTRKGVFFAGGTPLAGPTGLLSAQELEDIVAALPGELLVFTAEGKLLYLSESVSEHLGHSMVDLVAQGDSTYDTIDPADHLTVRQQLTLPSALDTDRLFRCRFNTSKSLRRQSAGNKLVLIRGRFRAHPPGAYWACNPVFTAFCAPLEPRPRPGPGPGPGPASLFLAMFQSRHAKDLALLDISESVLTYLCFERSELLCKSWYGLLHPEDLAHASAQHYRLLAESCDIQAEMVVRLQAKTGGWAWIYCLLYSECPEGPITANNYPISDMEAWSLRQQLNSEDTQAAYVLGTPTMLPSFPENILSQEECSSTNPLFTAALGAPRSTSFPSAPELSVVSASEELPRPSKELDFSYLTFPSGPEPSLQAELSKGLVCTPPYTPHQPGGCAFLFSLHEPFQTHLPTPSSTLQEQLTPSTATFSDQLTPSSATFPDPLTSPLQGQLTETSVRSYEDQLTPCTSTRPDQLLPSTATFPEPLGSPAHEQLTPPSTAFQAHLDSPSQTFPEQLSPNPTKTYFAQEGCSFLYEKLPPSFSSPGNGDCTLLALAQLRGPLSVDVPLVPEGLLTFEASPVKQSFFHYSEKEQNEIDRLIQQISQLAQGMDRFFSAEAGTGGLEPLGGLEPLDSNLSLSCAGPPVLSLDLKPWKCQELDFLADPDNMFLEETPVEDIFMDLSTFDPSEEWCSGDFEAEGPGGAPSPCNNLSPEDHSFLEDLATYETAFETGVSAFPYDGFTDELHQLQSQVQDSFHEGKQLPCGALDRLTGNYNHVCYPCTGLSADTHFYLSYLLQQFFWAGILAHLTDEETEDHRVLFPPFLEASGGMCTEPTIQDCLWGACWRTNPCTPAALLAEVRNSVGSPHPVSQQILLASLSKEIQNLTTPGHLLCHPPPAQVASNANLDFPNSLSRGVSLALSILREGSFQNPSQI

[0377] Further analysis of the NOV12a protein yielded the following properties shown in Table 12B.

55TABLE 12BProtein Sequence Properties NOV12aPSort0.4500 probability located in cytoplasm; 0.3654 probabilityanalysis:located in microbody (peroxisome); 0.1000 probability locatedin mitochondrial matrix space; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0378] SignalP No Known Signal Sequence Predicted analysis:

[0379] A search of the NOV12a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 12C.

56TABLE 12CGeneseq Results for NOV12aNOV12aIdentities/Protein/Residues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAE18906Human PAS181 . . . 560334/414 (80%)0.0domain protein 1 . . . 412343/414 (82%)(PASDP-1)—Homo sapiens,643 aa.[WO200210200-A2, 07 FEB.2002]AAY84169A variant of157 . . . 595125/504 (24%)1e−19human hypoxia 2 . . . 481201/504 (39%)inducible factor-1alpha protein—Synthetic, 789 aa.[WO200010578-A1, 02 MAR.2000]AAY84172A variant of157 . . . 744135/615 (21%)3e−19human hypoxia 2 . . . 581231/615 (36%)inducible factor-1alpha protein—Synthetic, 710 aa.[WO200010578-A1, 02 MAR.2000]ABB15397Human nervous450 . . . 494 43/45 (95%)9e−19system related20 . . . 64 44/45 (97%)polypeptide SEQID NO 4054—Homo sapiens,65 aa.[WO200159063-A2, 16 AUG.2001]AAY84168A variant of157 . . . 591117/492 (23%)9e−19human hypoxia 2 . . . 461199/492 (39%)inducible factor-1alpha protein—Synthetic, 642 aa.[WO200010578-A1, 02 MAR.2000]

[0380] In a BLAST search of public sequence datbases, the NOV12a protein was found to have homology to the proteins shown in the BLASTP data in Table 12D.

57TABLE 12DPublic BLASTP Results for NOV12aNOV12aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ18018C15C8.2 protein183 . . . 657160/522 (30%)8e−47(Putative tran- 79 . . . 575237/522 (44%)scription factorC15C8.2)—Caenorhabditiselegans, 636 aa.T19307hypothetical protein183 . . . 657153/516 (29%)7e−42C15C8.2— 79 . . . 546229/516 (43%)Caenorhabditiselegans, 647 aa.Q8UVV3Single-minded181 . . . 620117/463 (25%)7e−22protein— 1 . . . 429186/463 (39%)Brachydanio rerio(Zebrafish) (Zebradanio), 585 aa.Q98SW2Hypoxia-inducible185 . . . 839173/701 (24%)4e−21factor 1 alpha— 22 . . . 680263/701 (36%)Oncorhynchusmykiss (Rainbowtrout) (Salmogairdneri), 766 aa.Q8QGM4Hypoxia-inducible185 . . . 654130/510 (25%)1e−20factor 2 alpha— 19 . . . 501210/510 (40%)Fundulusheteroclitus(Killifish)(Mummichog),873 aa.

[0381] PFam analysis predicts that the NOV12a protein contains the domains shown in the Table 12F.

58TABLE 12EDomain Analysis of NOV12aPfamNOV12aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValuePAS252 . . . 31817/70 (24%)0.0001946/70 (66%)

Example 13

[0382] The NOV13 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 13A.

59TABLE 13ANOV13 Sequence Analysis2572 bpSEQ ID NO: 29NOV13a,CGGGGCGGCGCGGCCGGAGCCCGGGGCGCGCACTCGGCTCGGCCCGGCCCGGGCCGCACG111646-01DNA SequenceGCATGGCCGAGCCGCTACTCAGGAAAACCTTCTCCCGCCTGCGGGGCCGGGAGAAACTTCCCCGGAAAAAGTCGGACGCCAAGGAGCGCGGCCACCCAGCCCAGCGCCCACAGCCCAGCCCTCCACAGCCAGAGCCCCAGGCTCCCGAAGGGTCCCAGGCCGGAGCAGAGGGGCGCCCAGTACCCGCCGATGGGTGCTGGGTGGGGCCAAGCCAGCTGAGGACACCTCTTTAGGGCCTGCGGTACCTGCCACTGGGGAGCCCCCCCGCGACATCTCGTACAACCCCATCCCTGAGGAAGACCCCAGACCTCCAGCACCTCAGCCCCCCCGCCCACAGCCTCGCTCAGCTGAGTCAGAGGGCCTGCCCCCCCAAGGTCCACCCCCCGCCAGCCCCCCAACCAAAGCCTCCCGCACCAAGTCCCCGGCCCCCCCCAGCCCCCTCTCCATAAAGATGAAGAACCTGCCGGAACTCCGGCGCCGCCTGAGCCTGCGAGGCCCCCGGGCTGGCAGGGAGCGCCAGAGGGCTGCCCCTGCCGGCTCCGTCATCAGCCGCTACCACCTGGACAGCAGCGTGGGGGGCCCCCGGCCCCCAGCAGCGCCTCCCGGCACCCCCACCCCGACCCCCGCTTACCTCAGCGACGCGGACTCACCGGACCCCCCAGCTGGGCCCCCATCACCCACCTCCTTCCGGCCCTACGAGCTGGGTCCCGCACCCCGGGCACCCCCGGCCGCACTCTGCGCCCCCCTCACCCTGCACCTGTACGGTCTCCGCGGGCTCCGCCCACCGCCGCGCGCCACCCCCAGCGACCTCTGCTGCCTACTGCAAGTGCATGGGGAGGCCAGCCCCCCAACAGGGCCACTGCGAGGGGGCCCGGACTTCCTGCCCCTGGACCACACCTTCCACCTGCAGCTGGAGGCCGCCAGGCTCCTGCGCGCCCTCGTGCTTGCCTGCGACCCTGGCGTCAGAACCCACCCGCCCTCTGCCCAGGCCACCGTCCTGCTCCCCACGGTCTTCCGAGGGTGCCACCCCCAACACCTCCCCGTGCGCCTCGACCCTCAGCGCCTCCTCTATCCQAAGCTCACCCTGTCGGAGCAGCACGAAGCCCCTCCCACAGCTGACCCCCCCCTCTTTGCCCTGCCCCTGCCACTGCTGGTGGAGCGGGAGCCCCCCCCCCGCCAGCTCCCCCTCATCATCCACAACTGCGTTCGCCACATCGAGCGCCGAGGCCTGCCCGTAGTGGCACTGTACCGTCTTTCTCCCTCAGCCCCAGTGAAGAAAGAGCTTCCCCATGCCTTTGAGCGGCACAGTCCAGCCCTCTCCCTATCTGAGGACCTGTACCCCGATATCAATGTCATCACTCGCATCCTCAAGGATTATCTTCCAGAGTTGCCCACCCCACTCATCACCCACCCCCTGTATAAGCTCGTACTGGAGGCCATCGCCCGCGACCCCCCAAACAGAGTTCCCCCCACCACTGACGCCACCCGAGCCCTCCTCAGCTGCCTGCCAGATGTCGAAAGGGCCACGCTGACGCTTCTCCTGGACCACCTGCGCCTCGTCTCCTCCTTCCATCCCTACAACCCCATGACCCCACAGAACTTCGCCGTGTCCTTCGCGCCTGTGCTGCTGCCCGCACCCCAGGCGCCCACAACGCCTCGTGCCCGCAGCTCCGGCCCAGGCCTTGCCAGTGCACTGGACTTCAAGCACCACATCCACGTCCTCCACTACCTGCTGCAGTCTTGGCCAGATCCCCGCCTGCCCCCACAATCTCCAGATGTCGCCCCTTACTTGCGACCCAAACCACACCCACCTCTCCACCTCCCGCTGGCAGACCCCCAAGTGGTCACTCCGCCCCGCGGTCGACCAGGCCCCGAAAGCCCCCCGAGCAACCGCTACGCCCCCGACTGGAGCGTTTGCGGGCGGCACTTCCTCCCCTGTGGGCGGGATTTCCTGTCCGGGCCAGACTACGACCACGTGACGGCCAGTGACAGCGAGGACGAGGACGACGAGCATCGCGAGCCGAGGGTCACCGGTGACTTCCAAGACCACTTCGATGCGCCCTTCAACCCCCACCTGAATCTCAAAGACTTCGACGCCCTCATCCTGCATCTCGAGAGAGAGCTCTCCAAGCPAATCAACGTCTGCCTCTGAGCCAGATCACGGGCTCGGACCCCGGTTACTAAGCACCGGGCGCCCAGTCGCTAAGCCCGTGCCCTGGTGACCAACCACACCCACACCTCTTGCTCAGGCCGAGCTCCTGGTTGCCACCGACTTACCACCGCACCAGTCGCGTGTATGGCTGAGACTCATTCCCAGTTTCCAGCCCCCCCTATTTGCACACTAGTTCCCAAGTCTCGCCCCTCGGGATTTTACGGACCAGCGGTTCTCACCATCTTTCCTGACCACCAAGCCCTTCCCCTTTTGTTGCCAAAAAGGTAGTTCTCGCGCTTGCTAGORF Start: ATG at 61 ORF Stop: TGA at 2266735 aa MW at 79791.6DaSEQ ID NO: 30NOV13a,MAEPLLRKTFSRLRCREKLPRKKSDAKERGHPAQRPEPSPPEPEPQAPECSQAGAEGPCG111646-01Protein SequenceSSPEASRSPARGAYLQSLEPSSRRWVLGGAKPAEDTSLGPGVPGTCEPACETWYNPIPEEDPRPPAPEPPCPQPGSAESEGLAPQGAAPASPPTKASRTKSFGPARRLSIKMKKLPELRRRLSLRCPRAGRERERAAPAGSVISRYHLDSSVGGPGPAAGPGGTRSPRAGYLSDGDSPERPAGPPSPTSFRRYEVGPAARAPPAALWGRLSLHLYGLCGLRPAPCATPRDLCCLLQVDGEARARTCPLRGCPDFLRLDHTFPLELEAARLLRALVLAWDPGVRRHRPCAQGTVLLPTVFRCCQAQQLAVRLEPQGLLYAKLTLSEQQRAPATARPRVFGLPLPLLVERERPPCQVPLTIQKCVCQIERRCLRVVCLYRLCGSAAVKKELRDAFERDSAAVCLSEDLYPDINVITCILKDYLRELPTPLTTQPLYKVVLEAMARDPPNRVPPTTECTRCLLSCLPDVERATLTLLLDHLRLVSSFHAYNRMTPQNLAVCFGPVLLPARQAPTRPRARSSGPGLASAVDFKHHIEVLHYLLQSWPDPRLPRQSPDVAPYLRPKRQPPLHLPLADPEVVTRPRGRGCPESPPSNRYAGDWSVCGRDFLPCGRDFLSGPDYDHVTCSDSEDEDEEVGEPRVTGDFEDDGDAPFNPHLNLKDFDALILDLERELSKQINVCL

[0383] Further analysis of the NOV13a protein yielded the following properties shown in Table 13B.

60TABLE 13BProtein Sequence Properties NOV13aPSort0.9800 probability located in nucleus; 0.4436 probabilityanalysis:located in (peroxisome); 0.2110 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0384] A search of the NOV13a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 13C.

61TABLE 13CGeneseq Results for NOV13aNOV13aIdentitiesResidues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, DateResiduesRegionValueAAB94679Human protein sequence SEQ ID499 . . . 735237/237 (100%) e−142NO:15631 - Homo sapiens, 237 aa. 1 . . . 237237/237 (100%)[EP1074617-A2, 7 FEB. 2001]AAU25458Human mddt protein from clone393 . . . 660237/269 (88%) e−135LI:895427.1:2000MAY01 - Homo 2 . . . 270240/269 (89%)sapiens, 288 aa. [WO200162922-A2, 30 AUG. 2001]AAU17430Novel signal transduction pathway314 . . . 445130/132 (98%)4e−69protein, Seq ID 995 - Homo 1 . . . 132131/132 (98%)sapiens, 138 aa. [WO200154733-A1, 2 AUG. 2001]ABB58723Drosophila melanogaster194 . . . 608172/459 (37%)4e−63polypeptide SEQ ID NO 2961 -687 . . . 1127240/459 (51%)Drosophila melanogaster, 1844 aa.[WO200171042-A2, 27 SEP. 2001]AAU17463Novel signal transduction pathway454 . . . 551 96/98 (97%)2e−49protein, Seq ID 1028 - Homo 1 . . . 98 96/98 (97%)sapiens, 109 aa. [WO200154733-A1, 2 AUG. 2001]

[0385] In a BLAST search of public sequence datbases, the NOV13a protein was found to have homology to the proteins shown in the BLASTP data in Table 13D.

62TABLE 13DPublic BLASTP Results for NOV13aNOV13aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueAAH29926Similar to hypothetical protein89 . . . 735640/647 (98%)0.0FLJ13511 - Homo sapiens22 . . . 668642/647 (98%)(Human), 668 aa.Q9DBZ91200008N06Rik protein - Mus 1 . . . 735640/737 (86%)0.0musculus (Mouse), 737 aa. 1 . . . 737669/737 (89%)Q9H8K4CDNA FLJ13511 fis, clone499 . . . 735 237/237 (100%)e−142PLACE1005331, highly similar to 1 . . . 237237/237 (100%)Homo sapiens 7h3 protein mRNA(Hypothetical 26.4 kDa protein) - Homo sapiens (Human), 237 aa.O60432F02569_2 - Homo sapiens113 . . . 607 309/516 (59%)e−140(Human), 512 aa.31 . . . 469328/516 (62%) Q9UH667h3 protein - Homo sapiens521 . . . 735 187/228 (82%)e−101(Human), 450 aa (fragment). 7 . . . 234191/228 (83%)

[0386] PFam analysis predicts that the NOV13a protein contains the domains shown in the Table 13E.

63TABLE 13EDomain Analysis of NOV13aPfamNOV13aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValueRhoGAP414 . . . 569 69/174 (40%)1.8e−44122/174 (70%)

Example 14

[0387] The NOV14 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 14A.

64TABLE 14ANOV14 Sequence Analysis4524 bpSEQ ID NO: 31NOV14a,GGCCCGCTACTCGCCCACTCTGAGCGCCGTGGCGCCTGGTGTTCGGCGCGACCCCGGCCG111744-01DNA SequenceGGGGCTCCAGGTTCCGCCCTGCTCCCCCGCGCCCCGCCCGGGCTGGGCTAAAGGCCGCGGCCGGGCCATGCAGTGTCCTCCTCAGGGAGGGCAGGAGAGCCTGAGGACTGGCGGGGCCGCCACACAGCGAAATGTCATCAGTCCAGTCACAACAGGAGCAGTTGTCCCAGTCAGATCCATCTCCGTCACCAAACTCATCTAGTTCCTTTGAGCTAATAGACATGCATGCTGGCAGCTTCTATGAACCAGTTTCTCCCCATTGGTTTTATTCTAAGAATATAGATTCTAAGGAGACATGGATTCCTTTCAACTCTGAGGATTCACAGCAGCTGGAAGAGCCATATAGCTCTGGAAAAGGTTGTAATCGGAGAGTTGTTCCTACTGATGGGGGCAGATATGATGTTCATTTGGGGGAGAGGATGCGGTATGCTGTATACTGGGATGATATGCCATCGGAAGTGAGACGATGTACGTGGTTTTACAGGGGGACAAAGACAAATAACTATGTTCCCTACTCGGAGAGCTTCAGCCAAGTTTTAGAGGAAACTTACATGCTTGCTGTAACTTTGGATGAATGGAAAAAGAACTGGAATCTCCCAACAGAGAAATTATTATTTTAACACAATCCAAAGCTTATGGTGCATTACCAGCCAGTTGCACGGTCTCATGATTGGGGTTCAACACCCACGGAGCAGGGTCGACCAAGAACTGTCAAGAGAGCAGTTGAGAACATCTCTGTTGACATTCATTGTGGAGAACCTTTACAAATAGATCACTTGGTTTTTGTAGTCCATGGGATTGGACCAGCTTGTGATCTCCGCTTTCGAAGCATTGTACAGTGTGTTAATGATTTTCGCAGTCTTTCCTTGAACTTGCTACAGACACATTTTAAGAAAGCCCAAGAAAATCAGCAGATTGGGAGGGTAGAATTTCTTCCAGTCAACTGGCACAGTCCTTTGCATTCTACTGGTGTGGATGTAGATCTGCAGCGAATAACCCTGCCCAGCATTAACCGCCTCAGGCACTTCACCAATGACACAATTCTGGATGTCTTCTTCTACAATAGTCCCACCTACTGTCAGACTATTGTGGACACAGTTGCTTCTGAATGAACCGAATATACACACTTTTTCTACAGAGGAATCCCTGATTTCAAAGGGGGTGTATCCATTGCTGGTCATAGTTTACGTTCCCTTATATTGTTTCATATCCTAACAAATCAGAAAGATTCTTTGGGGGATATTGACAGTGAAAAGGCTTCGCTAAATATTGTAATGGATCAAGGAGATACACCTACACTAGAGGAAGATTTCAACAAACTTCAGCTCTCTGAATTCTTTGATATCTTTGAGAAGGAGAAAGTAGATAAGGAACCTCTGCCTTTATGTACAGACCGAGATCTTCAGGAAATAGGAATTCCTTTAGGACCAAGAAAGAAGATATTAAACTATTTCACCACCAGAAAAAACTCAATCGGTATTAAGAGACCACCCCCGCAGCCTGCTTCAGGGGCAAACATCCCCAACAATCTGACTTCTGCAGGTAGCAGTAATACTAGAAATGGTGACTATCTGGATGTTGGCATTGGGCAGGTCTCTGTGAAATACCCCCCGCTCATCTATAAACCAGAGATATTCTTTCCCTTTGGATCTCCCATTGGAATGTTCCTTACTGTCCGAGGACTAAAAAGAATTGATCCCAACTACAGATTTCCAACGTGCAAAGGTTTCTTCAATATTTATCACCCTTTTGATCCTGTGGCCTATAGGATTGAACCAATGGTGGTCCCAGGAGTGGAATTTGAGAGCCAACTGATCCCACATCATAAAGGCAGGAAGCGGATGCACTTAGAACTGAGAGAGGGCTTGACCACGATCAGTATGGACCTTAAGAACAACTTGCTAGGTTCGCTGCGGATGGCCTGGAAGTCTTTTACCAGAGCTCCATACCCTGCCTTACAAGCTTCAGAAACACCAGAAGAAACTGAAGCAGAACCTGAATCAACTTCAGAGAAGCCTAGTGATGTTAACACAGAAGAGACCTCTGTGGCAGTTAAAGAAGAAGTCCTGCCTATCAATGTGGCGATGCTGATGGAGGCCAACGCATTGACTATGTGCTACAGGAGAAGCCTATTTGAAAGTTTTAATGAGTATTTATTTGCTTTACAAAGCCATCTATGCTACTGGGAGTCTGAAGATACAGTATTGCTCGTCCTCAAAGAGATCTACCAAACCCAGGGTATCTTCCTTGATCAGCCTTTACAGTAAAAATGACCATCTATGGCTGCTTAATACGCACATTCAAGGGATCCTTCCCCAGAAAATCCACCTGTTTGTTGCTGCAATTTTCCTCTCCTCAGCTGCGTCATTTCCTGCATGTTGCCTGCCACTTACTCACCACTGGGGTCTTTGGAAGATAATCTTCCTCTTTGGAAATGAATGGAAAAGCAAAAGGCCCTATTACTTTTAACCACTGGCTTCATATAAACACTTGCCATTTTTTTCTGCATAGCTGGGCCTCGTTTGTGTCTTTAATTCTTTGATGATAGTTTATAGTTGCCACACTTTATTGATTAGTACTTGACAGGGTGTAAAGCCTATTTTCGGTTTGATTTGTTTTGGGTGGGGTAGACATGTTTTTAAGCAACTTATTGCTTATCTTTAGAAAATGTTCTACTTTCCAAACACATTCTTGAGATTCAGAAGGCATTTTGGAGTACACTTATCTCTTGTTTGTGTTGAACTCAAGGCTAAGTCTCAGTGGACATGGAAAAGACTTTTGGGTGATTTATTTTTGAACCTGCATTTCTTTCTTATCTGTAGTGTATGAAGAAAGACTAGAATGTAGCTTTAAAAAAGTGTTGTTTACTCTCTTAGAACTGACAGACTTATTGCCAGAAATCACTGATGTTCATTGTTTTTGCAACTGTTTGAGCTGCTGTAAGAGTCTAAAGTTGACAAGTTAGTTCATCTTAGGTGCATCTTTATAAAGCAAACATGTTGTATATCCTAGGCCTCCCTTTTATATTTGATAGAAGTTATTTGCTAATACCTTCTATTCTTACGTTGAAAATAGTTGTAAAAGCTGATGAACCTGAAATTGTGTAGCCTCTACAGCCTGACTGAGTTCTAAATAAAACCTTTTAGTGGTGCCTTTATGGTGPAACAGAATTTGTCACCTGCCATTTCTACTTCAGCTAAGGTAGTATTGTGTATCCTCTTTCCTTCTTAGGTATCCATAATCCACAAAGCATATTTAAAAGGCTCTTGCCACGGGCAGCATTGGTTGAGCAGGTAGGTTTGGCTAGGGGGAAATGTTTAACTTGTTCTGAAAGAAAAACTTATGTCTGTAGGGTCCAAGAAACAGCTATTCCAGAGTCAGTGTCAGCTGAGTCTGGAACATATCAAGTGAGGTTTACTTCTAAGAACACAAGTGACTGCACACTAATTTTGTCAAGGCATCTTTTCACTACTTTGCTGTAGATTTTTCTTCTTCATTCGTCAGTTTGTCATTGTCTTTCTAGTTCTCTTTATGATAATCCTTTATACTTCCTCTCAGATTCCACAGGCCTCTGTTTATAGAGTGCCAAAGGCAGGCGAGCTGTGGTTTATTGTTTATAAATTTTTTTATAAATGTTATGGTATTCAAAGCCACTGACATTTAATATTTACTGAAGCCATTCCTTAGACAGCAGTGGTCTTTATCCCTTTCTCGAAAGAAAAGGAAAATGAAGGGTAATTACTGTCACCATGGAGATTGTAGAGGTAAGGTTGGGGTATAGGTCAGGCCTGGCCTTTCTTTGTCATCTGCTTATAGTCTAGTGCTAAGTATGCCACTAAGTTTCAGATATATGGAATACTTTATTTTTTTAAAGGTATATAAACTCTGAGTTATTGAGIATTAAGTATTCACTGTATATTAAGGGGAAGCTTTTGCCAAGTTGTGGTCTTCAAATTTATGTTTACTCTTCCTATTCGCAGAATAGGTGCTATTTAAGAGTAAACCAAACGATAAGCAGAGGCACATCCCTATAACCAAGATCCACAGCATAGCCCTGGATAGCCAGATAAACCACTCTTTGTATTAAGAAATTGTTCTTTCCTAGTGGTGAGGGGTGGGTAACTGTQAAAGAGCTTTATATCTTGTCTATTCATGGTATTATAGCTGTATATTCCCAGGATGATAAGCTTGATTGAAATCCTGTATTTAGTCATATATTATTTGCGCTGCTTCATTTGTATCATGTGCAATCTCTACACCAACCCTATTTTTAAACTCTGGTACAGCATCATTTTGTACATATTCCCAGCTGCAGAACTAGTATCACTTATCTCAGCAAAAGAGATTGTTTGCATGGAAAGATTAATAGCACTGATTAGATTTCTAATATTTTGCATTTTTCAAATGTTTGTTTTCTACGTGATTATATTTAAAACTTTAGTAAATACTAAAATGAAAAAATAAAAORF Start: ATG at 190 ORF Stop: TAA at 2323711 aa MW at 80972.9DaSEQ ID NO: 32NOV14a,MSSVQSQQEQLSQSDPSPSPNSCSSPELTDMDAGSLYEPXTSPHWPYCLTDSKETWIPCG111744-01Protein SequenceFNSEDSQQLEEAYSSGKGCNGRVVPTDGGRYDVHLGERMRYAVYWDELASEVRRCTWFYKGDKDNKYVPYSESFSQVLEETYMLAVTLDEWKKKLESPNREITILHNPKLMVHYQPVAGSDDWCSTPTEQGRPRTVKRGVENTSVDIHCGEFLQIDHLVPVVHAIGPACDLRFRSIVQCVNDFRSVSLNLLQTHFKKAQENQQIGRVEFLPVNWHSPLHSTGVDVDLQRITLPSTNRLRHFTNDTTLDVPFYNSPTYCQTTVDTVASEMNRIYTLFLQRNPDFKGGVSIAGHSLGSLILFDTLTNQKDSLGDIDSEKCSLNIVMDQGDTPTLEEDLKKLQLSEFFDIFEKEKVDKEALALCTDRDLQEIGIPLGPRKKILNYFSTRKNSMGTKRPAPQFASGANIPKESEFCSSSNTRNGDYLDVGIGQVSVKYPRLIYKPEIFFAFGSPIGMELTVRGLKRIDPNYRFPTCKGFFNIYHPFDPVAYRIEPMVVPGVEFEPMLIPHHKGRKRMHLELREGLTRMSMDLKNNLLGSLRMAWKSFTRAPYPALQASETFEETEAEPESTSEKPSDVNTEETSVAVKEEVLPINVGMLNGGQRIDYVLQEKPIESFNEYLFALQSHLCYWESEDTVLLVLKEIYQTQGIFLDQPLQ

[0388] Further analysis of the NOV14a protein yielded the following properties shown in Table 14B.

65TABLE 14BProtein Sequence Properties NOV14aPSort0.3667 probability located in microbody (peroxisome); 0.3000analysis:probability located in nucleus; 0.1000 probability located inmitochondrial matrix space; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0389] A search of the NOV14a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 14C.

66TABLE 14CGeneseq Results for NOV14aNOV14aIdentities/Protein/Residues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAM41595Human poly- 44 . . . 711663/668 (99%)0.0peptide SEQ ID 10 . . . 677664/668 (99%)NO 6526—Homo sapiens,677 aa.[WO200153312-A1, 26 JUL.2001]AAM39809Human poly- 97 . . . 711614/615 (99%)0.0peptide SEQ ID 1 . . . 615614/615 (99%)NO 2954—Homo sapiens,615 aa.[WO200153312-A1, 26 JUL.2001]AAB94501Human protein327 . . . 711384/385 (99%)0.0sequence SEQ ID 1 . . . 385384/385 (99%)NO: 15202—Homo sapiens,385 aa.[EP1074617-A2,07 FEB. 2001]AAB92643Human protein 2 . . . 709403/772 (52%)0.0sequence SEQ ID235 . . . 998520/772 (67%)NO: 10972—Homo sapiens,1000 aa.[EP1074617-A2,07 FEB. 2001]ABB89332Human poly- 97 . . . 467359/372 (96%)0.0peptide SEQ ID 1 . . . 172359/372 (96%)NO 1708—Homo sapiens,372 aa.[WO200190304-A2, 29 NOV.2001]

[0390] In a BLAST search of public sequence datbases, the NOV14a protein was found to have homology to the proteins shown in the BLASTP data in Table 14D.

67TABLE 14DPublic BLASTP Results for NOV14.NOV14aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueO94830KIAA0725139 . . . 711572/573 (99%)0.0protein—Homo 1 . . . 573572/573 (99%)sapiens (Human),573 aa(fragment).Q9H8X7CDNA FLJ13156327 . . . 711384/385 (99%)0.0fis, clone 1 . . . 385384/385 (99%)NT2RP3003490,weakly similar toHomo sapiensputative phospho-lipase (Unknown)(Protein forMGC: 16854)—Homo sapiens(Human), 385 aa.Q9Y6Y8Phospholipase— 2 . . . 709403/172 (52%)0.0Homo sapiens235 . . . 998520/772 (67%)(Human),1000 aa.Q9VLS7CG8552 37 . . . 707283/696 (40%) e−145protein—1373 . . . 1989399/696 (56%)Drosophilamelanogaster(Fruit fly),2016 aa.Q9CVE92010305K11Rik 1 . . . 149134/149 (89%)3e−78 protein—Mus 1 . . . 149140/149 (93%)musculus(Mouse), 149 aa(fragment).

[0391] PFam analysis predicts that the NOV14a protein contains the domains shown in the Table 14E.

68TABLE 14EDomain Analysis of NOV14aPfamNOV14aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValueWWE 35 . . . 112 21/88 (24%)0.00041 52/88 (59%)SAM383 . . . 445 24/68 (35%)2.3e−07 49/68 (72%)DDHD495 . . . 700104/266 (39%)9.8e−107201/266 (76%)

Example 15

[0392] The NOV15 clone was analyzed, and then nucleotide and encoded polypeptide sequences are shown in Table 15A.

69TABLE 15ANOV15 Sequence AnalysisSEQ ID NO:331843 bpNOV15a.ATGGGAGCATCTGAAACACCCTTCACCATCTAGATGCACAAGGAAGCAGAGATGCTAACG111815-01DNA SequenceTTGGTCCCCAGCTGGATGAGAAGCGCTGGGGGTGGAGGTTGGGAGATGGGAGTGCTGCCCCTCCCTTCCTCCCCCAAGCCCTGTCTTTCCTTCTCCTCCTGCCACTGGCCAGCGCCCTACAGCCCACTCCACTGCCCTTTACAGAGCTGAGGCTGGTGGGGGGCCCCAGCCGCTGCCGGGGCCGCCTGGAAGTCATGCACGGTGGCTCCTGGGGCAGCGTCTGTGATGACGACTGGGACGTGGTGGACGCCAACGTAGTGTGTCGCCAGCTGGGCTGTGGCCTGGCACTGCCCGTGCCACGGCCCCTTGCCTTTGGCCAAGGCCGAGGCCCCATCCTGCTGGACAACGTGGAGTGCCGCGGGCAGGAAGCTGCGCTGAGCGAGTGCGGCAGCCGCGGCTGGGGCGTCCACAATTGCTTTCACTACGAGGATGTGGCTGTCCTGTGTGATGAATTCTTGCCAACGCAGCCCCCAACAAGGAAGATGTTAACCAGTAGAGCACCTCCTACGACACTGCCGAATGGAAAAAGTGAGGGCAGCGTACGCCTGGTAGGGGGCGCGAACCTGTGTCAGGGCCGAGTGGAGATCCTGCACAGTGGCCTGTGGGGCACCGTGTGTGACGACGACTGGGGGCTGCCGGATGCCGCTGTGGTCTGTCGTCAGCTGGGCTGCGGGGCGGCCATGGCCGCCACCACCAACGCCTTCTTCGGCTATGGCACCGGACACATCCTGCTGGACAACGTGCACTGCGAAGGCGGCGAGCCCCGCCTGGCAGCCTGCCAGAGCCTGGGCTGGGGTGTGCACAACTGCGGCCACCACGAGGACGCGGGCGCGCTCTGCGCAGGCCTGGGTCCCCCAACGCTCACAGCACTGCCATCCTCAGCCACAAGAGAGGACTGGGCTTGGCAGACAGATCCGTCCGCTACAGGAGTTGGCCCCCAGCCTTCCCGGGAGACAGCACTGCTCACCACCGCCGCCTGGGCCGCGGGGAAGAAAAGTGGGCGGCTGCGACTGGTGGGCGGCCCGGGTCCGTGCCGCGGCCGCGTGGAGGTGTTGCACGCCGGGGGCTGGGGCACCGTGTGCGACGATGACTGGGACTTTGCGGACGCGCGCGTGGCCTGCCGCGAAGCGGGCTGCGGGCCTGCGCTGGGCGCTACGGGACTGGGCCACTTCGGCTACGGCCGCGGCCCCGTGCTGCTGGACAACGTGGGCTGCGCCGGCACCGAGGCTCGCCTGAGCGACTGCTTCCACCTGGGCTGGGGCCAGCACAACTGCGGCCACCACGAGGACGCGGGAGCGCTCTGCGCAGGCCCAGAGGAGCTGGGACTGCAAGTCCAGCAGGATGGTTCTGAGACCACGCGGGTGCCCACTCCTCGGCCCAGGGACGGGCATCTACGTCTGGTCAATGGAGCCCACCGATGCGAGGGACGTGTAGAGCTCTACCTAGGGCAACGGTGGGGCACTGTCTGTGATGATGCTTGGGACCTGCGGGCAGCCGGTGTCCTGTGCCGCCAGCTGGGCTGTGGCCAGGCCCTCGCAGCCCCTGGCGAGGCTCACTTTGGCCCAGGCCGAGGCCCCATTCTCCTGGACAATGTCAAGTGCCGTGGGGAAGAAAGTGCTCTGCTGCTCTGCTCTCATATCCGCTGGGATGCCCACAACTGTGACCACAGCGAGGATGCCAGTGTCCTGTGCCAGCCTTCATGACCCAGCCCGCTCTGCAGACACTCTCTCTGGACTGTGACTCCTCTCTCAGAGCTCTTGTATATAGTATGCTCTCTGCTGAAACORF Start: ATG at 34ORF Stop: TGA at 1759SEQ ID NO: 34575 aaMW at 60790.9DaNOV15a.MHKEAEMLIGPQLDEKRWGWRLGDGSAAPPFLPQALSFLLLLPLASALQPTPLPFTELCG111815-01Protein SequenceRLVGGPSRCRGRLEVMHGGSWGSVCDDDWDVVDANVVCRQLGCGLALPVPRPLAFGQGRGPILLDNVECRGQEAALSECGSRGWGVHNCFHYEDVAVLCDEFLPTQPPTRKMLTSRAPPTTLPNGKSEGSVRLVGGANLCQGRVEILHSGLWGTVCDDDWGLPDAAVVCRQLGCGAAMAATTNAFFGYGTGHILLDNVHCEGGEPRLAACQSLGWGVHNCGHHEDAGALCAGLGPPTLTALPSSATREDWAWQTDPSATGVGPQPSRETALLTTAAWAAGKKSGRLRLVGGPGPCRGRVEVLHAGGWGTVCDDDWDFADARVACREAGCGPALGATGLGHFGYGRGPVLLDNVGCAGTEARLSDCFHLGWGQHNCGHHEDAGALCAGPEELGLQVQQDGSETTRVPTPRPRDGHLRLVNGAHRCEGRVELYLGQRWGTVCDDAWDLRAAGVLCRQLGCGQALAAPGEAHFGPGRGPILLDNVKCRGEESALLLCSHIRWDAHNCDHSEDASVLCQPS

[0393] Further analysis of the NOV15a protein yielded the following properties shown in Table 15B.

70TABLE 15BProtein Sequence Properties NOV15aPSort0.4500 probability located in cytoplasm; 0.4378 probabilityanalysis:located in microbody (peroxisome); 0.2327 probability locatedin lysosome (lumen); 0.1000 probability located inmitochondrial matrix spaceCleavage site between residues 48 and 49analysis:

[0394] A search of the NOV15a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 15C.

71TABLE 15CGeneseq Results for NOV15aNOV15aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAE09447Human sbg14862SPERCTa57 . . . 575519/525 (98%)0.0protein #2 - Homo sapiens, 552 aa.28 . . . 552519/525 (98%)[WO200160850-A1,23-AUG-2001]AAE09446Human sbg14862SPERCTa74 . . . 575406/502 (80%)0.0protein #1 - Homo sapiens, 422 aa. 1 . . . 422408/502 (80%)[WO200160850-A1,23-AUG-2001]AAW64591Human SRCR protein - Homo45 . . . 572266/546 (48%) e−146sapiens, 1785 aa. [WO9830687-595 . . . 1111319/546 (57%)A2, 16-JUL-1998]AAW07609Rat von Ebner's gland protein82 . . . 444189/402 (47%)5e−97Ebnerin - Rattus rattus, 1290 aa. 1 . . . 392224/402 (55%)[WO9639513-A2, 12-DEC-1996]AAM39494Human polypeptide SEQ ID NO57 . . . 572199/523 (38%)5e−942639 - Homo sapiens, 1154 aa.372 . . . 851 248/523 (47%)[WO200153312-A1,26-JUL-2001]

[0395] In a BLAST search of public sequence datbases, the NOV15a protein was found to have homology to the proteins shown in the BLASTP data in Table 15D.

72TABLE 15DPublic BLASTP Results for NOV15aNOV15aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ8WTU2Scavenger 1 . . . 575574/575 (99%)0.0receptor cysteine- 1 . . . 575574/575 (99%)rich protein,SRCRB-S4Dprecursor(SRCRB-S4Dproteinprecursor)—Homo sapiens(Human), 575 aa.Q60997CrP-ductin58 . . . 572264/536 (49%)e−147precursor (CrP)—462 . . . 978 323/536 (60%)Mus musculus(Mouse), 2083 aa.Q9JMJ9Vomeroglandin58 . . . 575269/550 (48%)e−147precursor—Mus48 . . . 576325/550 (58%)musculus(Mouse), 1957 aa.Q9UJ57DMBT1/8kb.243 . . . 575262/534 (49%)e−146protein847 . . . 1353314/534 (58%)precursor—Homo sapiens(Human),2412 aa.Q9UGM3DMBT1 proto-46 . . . 575265/546 (48%)e−146type precursor—848 . . . 1366317/546 (57%)Homo sapiens(Human),2426 aa.

[0396] PFam analysis predicts that the NOV15a protein contains the domains shown in the Table 15E.

73TABLE 15EDomain Analysis of NOV15aPfamNOV15aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValueSRCR 61 . . . 15851/114 (45%) 6e−3178/114 (68%)SRCR192 . . . 28949/114 (43%)5.2e−3174/114 (65%)SRCR347 . . . 44447/114 (41%)4.6e−2978/114 (68%)SRCR476 . . . 57349/114 (43%)9.9e−3883/114 (73%)

Example 16

[0397] The NOV16 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 16A.

74TABLE 16ANOV16 Sequence Analysis549 bpSEQ ID NO: 35NOV16a,ACTCACTATACGGCTCGACCGGCCGCTCAAATTCTAGCGGCCGCTGAATTCTAGGCGCCG112464-01DNA SequenceCTTATACCCTCTCAACTTCTTGCTTGGGATCTCCAACCTCACCGCGGCTCGAAATGGACCCCAACTGCTCCTGCGCCACTGGTGCCTCCTGCACCTGCACTGGCTCCTGCAAATGCAAGAGTGCAAATGCAACTCCTGCAAGAAGAGTGAGTGCGGGCGCCATCTCCAGGAATCTGGGGCTGAGCCAAGTCAGAGGCAGCAAACCAGAGCTGGCCATGGAGGAGTAGGCCAATGATCCATTTCCCACATCCCCTTCCCCAGCAACTCATTCAGGATCAGAGCCAGATCTTTAGACGTGATGGATTCCCAAGTTTCGTTCTTAAATTAGACAAACTGAGGCCAAGAGAGTGCACCAGCCTGCCAAGCACAGACATCACACCTAAGGACTTTCGTCCCCTAAGTGTGTCGTTCTGGGGACCCAGCCTTCCTTTGTCCTTCATAACCCCAGTCACTGCCTTTCCAGCCTTCTGCCAGGTCTGGGGCTCAGATGGORF Start: ATG at 112 ORF Stop: TAG at 28357 aa MW at 5980.8DaSEQ ID NO: 36NOV16a,MDPNCSCATGGSCTCTGSCKCKECKCNSCKKSECGATSRNLGLSQVRGRKPELGMEECG112464-01Protein Sequence

[0398] Further analysis of the NOV16a protein yielded the following properties shown in Table 16B.

75TABLE 16BProtein Sequence Properties NOV16aPSort0.6500 probability located in cytoplasm; 0.1000 probabilityanalysis:located in mitochondrial matrix space; 0.1000 probabilitylocated in lysosome (lumen); 0.0000 probability located inendoplasmic reticulum (membrane)SignalPNo Known Signal Sequence Predictedanalysis:

[0399] A search of the NOV16a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 16C.

76TABLE 16CGenseq Results for NOV16aNOV16aIdentities/Protein/Residues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAM79472Human protein 1 . . . 5757/57 (100%)6e−31SEQ ID NO19 . . . 7557/57 (100%)3118—Homosapiens, 75 aa.[WO200157190-A2, 09 AUG.2001]AAM39981Human poly- 1 . . . 4232/42 (76%) 2e−15peptide SEQ ID 1 . . . 4233/42 (78%) NO 3126—Homosapiens, 46 aa.[WO200153312-A1, 26 JUL.2001]ABG25977Novel human 6 . . . 5234/47 (72%) 2e−14diagnostic protein 90 . . . 13636/47 (76%) #25968—Homosapiens, 159 aa.[WO200175067-A2, 11 OCT.2001]ABG25977Novel human 6 . . . 5234/47 (72%) 2e−14diagnostic protein 90 . . . 13636/47 (76%) #25968—Homosapiens, 159 aa.[WO200175067-A2, 11 OCT.2001]ABG25975Novel human 8 . . . 4331/36 (86%) 4e−14diagnostic protein619 . . . 65432/36 (88%) #25966—Homosapiens, 960 aa.[WO200175067-A2, 11 OCT.2001]

[0400] In a BLAST search of public sequence datbases, the NOV16a protein was found to have homology to the proteins shown in the BLASTP data in Table 16D.

77TABLE 16DPublic BLASTP Results for NOV16aNOV16aIdentities/ProteinResidue/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ8TD51Hypothetical 13.9 1 . . . 4341/43 (95%)6e−21kDa protein—Homo 1 . . . 4341/43 (95%)sapiens (Human),127 aa.Q9NKE1BG:DS00180.7 3 . . . 4918/51 (35%)4.4protein—Drosophila265 . . . 31226/51 (50%)melanogaster (Fruitfly), 421 aa.Q9VJU8BG:DS00180.8 3 . . . 4918/51 (35%)4.4protein—Drosophila879 . . . 92626/51 (50%)melanogaster (Fruitfly), 1035 aa.Q9Y415Tesmin11 . . . 5215/43 (34%)9.9(Metallothionein- 97 . . . 13918/43 (40%)like 5, testis-specific) (Testis-specificmetallothionein-likeprotein)—Homosapiens (Human),299 aa.

[0401] PFam analysis predicts that the NOV16a protein contains the domains shown in the Table 16E.

78TABLE 16EDomain Analysis of NOV16aPfamNOV16aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValuemetalthio1 . . . 5730/67 (45%)8.3e−0538/67 (57%)

Example 17

[0402] The NOV17 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 17A.

79TABLE 17ANOV17 Sequence Analysis1598 bpSEQ ID NO: 37NOV17a,GTGCTGATGCTCCTGGCCCTGCCCCTGGCGGCCCCCAGCTGCCCCATGCTCTCCACCTCG112475-01DNA SequenceGCTACTCATCCCCGCCCACCGTGAGCTGCCAGGCCAACAACTTCTCCTCTGTGCCGCTGTCCCTGCCACCCAGCACTCAGCGACTCTTCCTGCAGAACAACCTCATCCGCACGCTGCGGCCAGGCACCTTTGGGTCCAACCTCCTCACCCTGTGGCTCTTCTCCAACAACCTCTCCACCATCTACCCGGGCACTTTCCGCCACTTGCAAGCCCTGGAGGAGCTGGACCTCGGTGACAACCGGCACCTGCGCTCGCTGGAGCCCGACACCTTCCAGGGCCTGGAGCGGCTGCAGTCGCTGCATTTGTACCGCTGCCAGCTCAGCACCCTGCCCGACAACATCTTCCGAGGCCTCGTCAGCCTGCAGTACCTCTACCTCCAGGAGAACAGCCTGCTCCACCCCACCCAGGATGACTTCTTCGCGGACCTGGCCAACCTGAGCCACCTCTTCCTCCACGGGAACCGCCTGCGCCTGCTCACAGAGCACGTGTTTCGCGCCCTGGGCAGCCTGGACCGGCTGCTGCTGCACGGGAACCGGCTGCAGGGCCTGCACCGCGCGCCCTTCCCCGGCCTCAGCCGCCTCACCATCCTCTACCTGTTCAACAACAGCCTGGCCTCGCTGCCCGGCGAGGCGCTCGCCGACCTGCCCTCGCTCGAGTTCCTGCGGCTCAACACTAACCCCTGGGCCTGCCACTGCCGCGCCCGCCCGCTCTGGGCCTGGTTCCAGCCCGCGCGCGTGTCCAGCTCCCACGTGACCTGCCCCACCCCCCCGGACCGCCAGGGCCGAGACCTGCGCGCGCTCCGCGAGGCCGACTTCCAGGCGTGTCCGCCCGCGGCACCCACGCGGCCGGGCAGCCGCGCCCGCGGCAACAGCTCCTCCAACCACCTGTACCCGGTGCCCGAGGCCGGGGCGCCCCCAGCCGATCCCTCCACCCTCTACCGAGATCTGCCTGCCGAAGACTCGCGGGGGCGCCAGCGCGGGGACGCGCCTTGTAACTTACCCTGTAAGTTGCATGGGGCAGGTGATGATTTGGAAAGCACAAAGAATGTGGTCCTCCGATGTAATCAGGATGGGCCACAAAAGCTCATGCCAAGCCCAGCTCCTGATGCTCCAGGATCCAGGACGCAAGGACCTCTTTCTAAACAGAACGCACCAAACCCTGAGGCGAGCCCAGTGCCTTTTTTCCCCCAACGACAGCAAAGGCCTTTTGTTCAAAGAAAATTTTACACAAAAATTCATAGCCTTGAGGAAGGTGGACTCGGCGGAGGCGGCGGGCAAGATCGCTCTGCGTCAGGGACCATCCCAAATGTCACCACCTCAAGGAAGCCTTTGGGTACTGCTCACCCAGAAGCAATCTCTCCCCCTCCCCCAGGCTCAACAGTCTTTTGTACCTCCTCGACAGCACAGCCCACTTCAAGCACCCCTGTCTGTCACCACCATCCTAGACTGGGAACTCCTCTGGGGCACCAGGCCATGCCACCTTTCTAGCACCCACTGGGTGTGGCACCCAGGGACCAACTGTAAATGCCAGCAGAATGACAORF Start: ATG at 7 ORF Stop: TAG at 1543512 aa MW at 55611.3DaSEQ ID NO: 38NOV17a,MLLALPLAAPSCPMLCTCYSSFFTVSCQANNFSSVPLSLPPSTQRLFLQNNLIRTLRPCG112475-01Protein SequenceGTFGSNLLTLWLFSNNLSTIYPGTFRHLQALEELDLGDNRHLRSLEPDTFQGLERLQSLHLYRCQLSSLPGNIFRGLVSLQYLYLQENSLLHPTQDDLFADLANLSHLFLHGNRLPLLTEHVFRGLGSLDRLLLHGNRLQGVHRAAPRGLSRLTTLYLFNNSLASLPGEALADLPSLEFLRLNANPWACDCRARPLWAWFQRARVSSSDVTCATPPERQGRDLRALREADFQACPFAAPTRPGSRARGNSSSNHLYGVAEAGAPPADPSTLYRDLFAEDSRGRQGGDAPCNLPCKLHCAGDDLESTKNVVLGCNQDGFEKLMPSPAPDAPGSRTQGPLSKQNAANPEGSPVPFFPQRQQRPFVQRKFYTKIHRLEEGGLGGGGGQDRSASGTIPNVTTSRKPLGTAHPEATSPPPPGSTVFCTSWTAQATSSTPVCHHHPRLGTPLGAGAMPPL

[0403] Further analysis of the NOV17a protein yielded the following properties shown in Table 17B.

80TABLE 17BProtein Sequence Properties NOV17aPSort0.5500 probability located in endoplasmic reticulumanalysis:(membrane); 0.3506 probability located in lysosome (lumen);0.1000 probability located in endoplasmic reticulum (lumen);0.1000 probability located in outsideSignalPCleavage site between residues 17 and 18analysis:

[0404] A search of the NOV17a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 17C.

81TABLE 17CGeneseq Results for NOV17aNOV17aIdentities/Protein/Residues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueABG15173Novel human 1 . . . 347318/355 (89%) e−178diagnostic protein406 . . .752321/355 (89%)#15164—Homosapiens, 807 aa.[WO200175067-A2, 11 OCT.2001]ABG15173Novel human 1 . . . 347318/355 (89%) e−178diagnostic protein406 . . . 752321/355 (89%)#15164—Homosapiens, 807 aa.[WO200175067-A2, 11 OCT.2001]AAU83655Human PRO 2 . . . 464213/472 (45%)4e−94protein, Seq ID 18 . . . 463261/472 (55%)No 128—Homosapiens, 473 aa.[WO200208288-A2, 31 JAN.2002]AAB49891Human PR0526 2 . . . 464213/472 (45%)4e−94 protein 18 . . . 463263/472 (55%)sequence—Homosapiens, 473 aa.[WO200070050-A1, 23 NOV.2000]AAB50908Human PR0526 2 . . . 464213/472 (45%)4e−94 protein—Homo 18 . . . 463263/472 (55%)sapiens, 473 aa.[WO200073452-A2, 07 DEC.2000]

[0405] In a BLAST search of public sequence datbases, the NOV17a protein was found to have homology to the proteins shown in the BLASTP data in Table 17D.

82TABLE 17DPublic BLASTP Results for NOV17aNOV17aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ9N0E3Unnamed protein 2 . . . 464214/472 (45%)1e−94product—Macaca18 . . . 463262/472 (55%)fascicularis (Crabeating macaque)(Cynomolgusmonkey), 473 aa.Q9BZR6Nogo receptor— 2 . . . 464213/472 (45%)9e−94Homo sapiens18 . . . 463263/472 (55%)(Human), 473 aa.AAH30471Similar to Nogo 1 . . . 297174/300 (58%)8e−93receptor—Mus13 . . . 310215/300 (71%)musculus(Mouse), 445 aa.AAM46772NOGO-66 9 . . . 464202/465 (43%)3e−88receptor—Rattus24 . . . 463248/465 (52%)norvegicus (Rat),473 aa.Q99P18Nogo receptor— 9 . . . 464198/465 (42%)3e−85Mus musculus24 . . . 463245/465 (52%)(Mouse), 473 aa.

[0406] PFam analysis predicts that the NOV17a protein contains the domains shown in the Table 17E.

83TABLE 17EDomain Analysis of NOV17aPfamNOV17aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValueLRRNT11 . . . 4011/31 (35%)0.46 17/31 (55%)LRR64 . . . 8711/25 (44%)0.057 20/25 (80%)LRR 88 . . . 11213/26 (50%)0.009522/26 (85%)LRR113 . . . 13610/25 (40%)0.003720/25 (80%)LRR162 . . . 185 9/25 (36%)0.97 19/25 (76%)LRR186 . . . 209 7/25 (28%)0.62 20/25 (80%)LRR210 . . . 23312/25 (48%)0.006620/25 (80%)LRRCT243 . . . 29318/55 (33%)1.2e−0733/55 (60%)

Example 18

[0407] The NOV18 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 18A.

84TABLE 18ANOV18 Sequence Analysis3117 bpSEQ ID NO: 39NOV18a,TATAGAACTCTACTTCATTTTAAAAACTGATATTATTTTTAAAACTCCTACATTGTATCG112713-01DNA SequenceTCCTAATATGGTTGTGTCATAGTGTATCATCTAGGAGGCTTTCAGAAGCAAGTACCAGACAATCCAACTCAAACTAGCTTAAACAATAAAGAATGGGCCGGGCACGGTCGGTCACATCTGTAATCCCAGCACTTTGGGAGGCCAAGTGTGCGCCTCATTCTAAGTCTGACTTCCCTAATGCTCAGAAGATGGCTATGTTGAGTCCACAAACTTTTGAATTCAGAAACAAGATTGAGTTGATTTCAGAAGCTCTCCCAGAAGATCAAGAAACAACTTTCCAGGATCTCCAGGAACCTGAATTGAGTCATACCCCAAACGTGACTATGAGTGCCCAGACTTCCCCAGCAGAGAAGGGCCTGAATCCGGCGCTGATGTGCCAGGAAAGTTACCCTTGCAGCGGGACTGATGAACCTATCTTTGAGTGTGATGAGTGCTGCAGTCTGCAGTCTCTCCCCTGCCAGGAGGAGCTCCATCGGCAGGAGCCCCTGAGAAACCATGAGCGGATAAGACTCAAACCTCGCCATGTCCCTTACTGTGACCTCTGCAAGGGTCTCAGTGGGCATTTACCAGGTGTTAGGCAGAGGGCAATAGTGAGGTGCCAGACCTGCAAAATTAACTTGTGCCTGGAGTGCCAGAAGAGGACTCATTCTGCGGGTAACAAAAGGAGACACCCTCTTACTGTGTACAATGTCAGTAATCTCCAGCAGTCACTGGAGGCAGAAGAGATGGATGAGCAGACCAACAGGAAGAAGATGACTGAGAACGTTGTGAGTTTCCTCCTAGTAGACGAAAATCAAGAAATTCAGGTAACAAATCAAGAAGACTTTATTAGAAAATTGCACTCCAAACCTGATCAGCATCTGAAACTGGTTTCCATTTTTGGAAATACTGGTGATGGAAAGTCTCATACTCTCAACCACACTTTCTTTTATGGTCGTGAAGTCTTTAAAACCTCCCCGACCCAGGAGTCCTGCACTGTGGGAGTGTGGGCAGCCTATGACCCAGTTCACAACTAGCAGTGATCGATACGGAAACCCCTCCTGGGGGCCACCGTGAATCTAAGCCAGAGAACACGGCTGCTGCTTAAGGTCCTGGCCATCTCAGACCTCGTCATCTATCGAACTCATGCAGACCGGCTGCATAACGACCTCTTCAAATTCCTTGGGGATGCCTCAGAAGCTTATCTGAAGCACTTCACCAAGGAGCTCAAGGCCACCACTGCTCGCTGTQGCCTGGATGTCCCTTTATCCACACTGGGCCCTGCAGTTATCATCTTCCATGAGACCGTGCACACCCAGCTACTGGGCTCTGATCATCCCTCAGAGGTGCCAGAGAAGCTCATCCAGGACCCGTTCCGGAACCTGGGCCGTTTCCCTGGTGCCTTTAGTTCCATTCACTACAAGGGAACGAGGACTTACAACCCTCCCACGGACTTTTCTGGGCTTCGGCGTGCTTTGGAGCAGCTACTAGACATAAACACCACCCGTTCTCCCCGGCACCCGGGAGTCATCTTCAAAGCCCTGAAGGCACTAAGTCACCGCTTCAGCGGTCAGATCCCCGATGACCAGATGGCGCACAGCTCCTTTTTTCCAGATGACTATTTCACCTGCTCCTCCTTCTGCCTCAGCTCTGGCCTTGCATGTAACAAAGCATCAATCATCGCAAGGAAGCCAGTCCCTCATGAAGCCAAGACCCGCTGCAGATACTCCCACCAGTATGACAACCGAATGTATACCTGCAAGGCCTGCTATGAGAGAGGCGAGGAAGGTCAGTGTAGTGCCAAAACATCTGCTTCCACTGACTCCCCCTCGATCCGTCTCGCAAAATATGCCTGGTCTGGTATGTCATCCGAATGTCCTAACTGTGGCGTGGTCTATCGTAGTCGGCAGTACTGGTTTGGAAACCAAGATCCTGTGCATACGCTCGTCCCGACAGACATTGTCCATGTGTCCCCTGCACGACTTACTGGTTCTGAGTTGGCCACGACTGATGGGTTTCTGAAGGACAACAACAATGCTGCCCAGCGCCTGTTCCACGCGATCAACTTCATGCCTCACTCGCTGTCCGAGCTTACCCTTGCACCCACCAAGGCTGTCACTTCCTGGCTGACAGACCACATCCCCCCTGCCTACTGGACCCCCAACTCCCAGATTCTGAGCTGCAACACTGTGCGACGTCCTTTAAAGATTAACGACACTAAGCATCACTGCCGAGCCTGTGCCCAGGCCTTCTGTCACACCTGTTCATCAAAGACTCGGCCAGTGCCTGACCCCGGCTGGCGCCCTGCGCCAGTGCGGGTCTCTGACACTCTGCTACGAGCCAGGACCTCCAGTTAGCTGTTACCGAGGCACAAGTGGACGATGAAGGTTGGAACCCTCATTGCTCGCAAGGTGGGCCAGGCCCTGCAGAACACTCTGCGACCCGTGGTGACAGCCATTGACATACCACTAGGTCTGGTAAAGGACGCGGCCACCCCTCCGTACTGGGTGCCTGACCACGAAATCCTCCACTGCCACAACTGCCGGAAGGAGTTCAGCATCAAGCTCTCCAAGCACCACTGCCGAGCCTCCGGACAGGCCTTCTCTGATGAGTGCTCCCATGACCCCCGGGCTGTTCCTTCTCCTGGCTCGGACCATCCCGTCCGACTCTGCTTCAACTGCAATAAAAAGCCCGCTGTGATGAGCCTCCCTATGTCGCTGAAGACCCTTCGTCCTGAACACCCCATCACCCTAATTACAGTTGATGACAAGAAACTAGGGGAAAGGGAGGGGCCAGAAATTCTGGGCTTCGCACACCTTGCCTTTCTCCCACGACAATCAGAAAAAATCTCACCCTTGTCTCTGACCCATGTGGAAAAAATGGATGAGATCAAGATCAATTGGACCAAATGGTACAAAGGATCATGTGAGTAGAGGAGTGCCCCAGGATGGTCGAGTTGCCCTGCCAGGAGCCTTTACCCTGTTAGAAAAGTATCTCTCAACTCTTTCCCATTGTTGTTAACCTGGGCCTGGAAAATGAGCAGGACACAGCAGTGAGGGGAACAGGGGCTTCAGAGTTGGORF Start: ATG at 151 ORF Stop: TAG at 2968939 aa MW at 105547.9DaSEQ ID NO: 40NOV18a,MGRARWVTSVIFALWEAKCGPHSKSDPFNAQKMAMLSPQTFEFRNKIELISEALPEDQCG112713-01Protein SequenceERTFQDLQEPELSHTPNVSMSAQTSPAEKGLNPGLMCQESYACSCTDEAIFECDECCSLQCLRCEEELHRQERLRNHERTRLKPGHVPYCDLCKGLSGHLPGVRQRAIVRCQTCKINLCLECQKRTHSGGNKRRHPVTVYNVSNLQESLEAEEMDEETKRKKMTEKVVSELLVDENEEIQVTNEEDFIRKLDCKPDQHLKVVSIFGNTGDCKSNTLNHTRFYCREVFKTSPTQESCTVGVWAAYDPVHKVAVIDTECLLGATVNLSQRTRLLLKVLATSDLVIYRTHADRLHNDLFKFLGDASEAYLKHFTKELKATTARCCLDVPLSTLGPAVIIFHETVHTQLLGSDHPSEVPEKLIQDRFRKLGRFPEAFSSTHYKGTRTYNPPTDFSGLRRALEQLLENNTTRSPRHPGVIFKALKALSDRFSGEIFDDQMAHSSFFPDEYFTCSSLCLSCGVGCKKSMNHGKECVPHEAKSRCRYSHQYDNRVYTCKACYERGEEVSVVFKTSASTDSPWMGLAKYAWSCYVTECPNCGVVYRSRQYWFGNQDPVDTVVRTEIVHVWPGGVSGSELATTDGFLKDNNNAAQRLLDGMNFMAQSVSELSLCPTKAVTSWLTDQIAPAYWRPNSQILSCNKCATSFKDNDTKHHCRACGEGFCDSCSSKTRPVPERGWGPAPVRVCDNCYEARNVQLAVTEAQVDDEGGTLIARKVCEAVONTLGAVVTAIDIPLGLVKDAARPAYWVPDHEILHCHNCRKEFSIKLSKHHCRACGQGFCDECSHDRRAVPSRGWDHPVRVCFNCNKKPAVMSLPMWLKTLGAEHRITLITVDDKKLGEREGPEILGLAELAFLPREMRKISPLSLTHVEKMDEIKINWTKWYEGSCE

[0408] Further analysis of the NOV18a protein yielded the following properties shown in Table 18B.

85TABLE 18BProtein Sequence Properties NOV18aPSort0.6000 probability located in nucleus; 0.4811 probabilityanalysis:located in mitochondrial matrix space; 0.1892 probabilitylocated in mitochondrial inner membrane; 0.1892 probabilitylocated in mitochondrial intermembrane spaceSignalPCleavage site between residues 20 and 21analysis:

[0409] A search of the NOV18a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 18C.

86TABLE 18CGenseq Results for NOV18aIdentities/NOV18aSimilaritiesProtein/Residues/for theGeneseqOrganism/LengthMatchMatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAB95874Human protein 78 . . . 845759/7680.0sequence SEQ ID (98%)NO: 18961—Homo 1 . . . 759759/768sapiens, 759 aa. (98%)[EP1074617-A2,07 FEB. 2001]AAM42017Human polypeptide497 . . . 744239/248e−147SEQ ID NO 6948—(96%)Homo sapiens, 6 . . . 244239/248268 aa. (96%)[WO200153312-A1,26 JUL. 2001]AAM40231Human polypeptide630 . . . 860228/231e−140SEQ ID NO 3376— (98%)Homo sapiens, 22 . . . 252229/231255 aa. (98%)[WO200153312-A1,26 JUL. 2001]ABG27188Novel human 1 . . . 188188/188e−112diagnostic protein(100%)#27179—Homo 1 . . . 188188/188sapiens, 188 aa.(100%)[WO200175067-A2,11 OCT. 2001]ABG27188Novel human 1 . . . 188188/1881e−112diagnostic protein(100%)#27179—Homo 1 . . . 188188/188sapiens, 188 aa.(100%)[WO200175067-A2,11 OCT. 2001]

[0410] In a BLAST search of public sequence datbases, the NOV18a protein was found to have homology to the proteins shown in the BLASTP data in Table 18D.

87TABLE 18DPublic BLASTP Results for NOV18aIdentities/NOV18aSimilaritiesProteinResidues/for theAccessionProtein/MatchMatchedExpectNumberOrganism/LengthResiduesPortionValueQ9HCI3KIAA1589 protein— 75 . . . 860776/7860.0Homo sapiens(98%)(Human), 816 aa 37 . . . 813777/786(fragment).(98%)Q9HBF4Double FYVE- 78 . . . 860774/7830.0containing protein 1(98%)(Phosphoinositide- 1 . . . 774774/783binding protein)—(98%)Homo sapiens(Human), 777 aa.Q96K57CDNA FLJ14493 78 . . . 845759/7680.0fis, clone(98%)MAMMA1002972— 1 . . . 759759/768Homo sapiens(98%)(Human), 759 aa.Q9BXP9Tandem FYVE493 . . . 860359/3680.0fingers-1 protein—(97%)Homo sapiens 1 . . . 359359/368(Human), 362 aa.(97%)Q8WYX7Hypothetical 36.6 kDa558 . . . 860294/3030.0protein—Homo(97%)sapiens (Human), 36 . . . 329294/303332 aa.(97%)

[0411] PFam analysis predicts that the NOV18a protein contains the domains shown in the Table 18E.

88TABLE 18EDomain Analysis of NOV18aPfamNOV18aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValuezf-B_box143 . . . 19810/58 (17%)0.6235/58 (60%)FYVE679 . . . 74631/72 (43%)2.1e−1446/72 (64%)zf-AN1807 . . . 84212/44 (27%)0.6821/44 (48%)FYVE796 . . . 85728/67 (42%)1.8e−1447/67 (70%)

Example 19

[0412] The NOV19 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 19A.

89TABLE 19ANOV19 Sequence Analysis1262 bpSEQ ID NO: 41NOV19a,TTTTTGGTTAATGTCCCTGTTTCTGTGTTTTGATGCAGGACCTCCGGGAGCCGGCGGGCG112731-01DNA SequenceTTGCCAGGACACAACGGATTGGATGGACAGCCTGGTCCTCAGGGCCCAAAAGGAGAAAAAGGAGCAAATGGAAAAAGAGGAAAAATGGGGATACCTGGAGCTGCAGGAAATCCAGGGGAAGGGGAGAAAAGGGAGACCATGGTGAACTGGGCCTGCAGGGGAAATGAGGGCCCACCAGGGCAGAACGCAGAAAAGGCTGACAAAGGAGATGTGTCCAACGACGTGCTCCTGGCAGGTCCCAAAGGTGACCATCGCCCACCCGGTCCACCTGGCCCCCCAGGCCCTCCAGGTCCTCCAGGGCCCCCTGGAAGCAGAAGAGCCAAACGCCCTCGGCAGCGAAGCATGTTCAACGGCCAGTGCCCAGGTGAGACTTGTGCCATACCAAATGATGATACCTTGGTTGGAAAAGCTGATGAGAAAGCCAGTGAACACCATTCCCCACTTCCAGAATCCATGATCACTTCCATTGGAAACCCAGTGCAAGTACTGAAAGTGACAGAGACATTTGGGACTTGGATAAGAGAGTCTGCTAACAAGAGTGATGACCGGATTTGGGTGACAGAGCATTTTTCAGGCATCATGGTTAAGGAATTCAAGGATCAGCCCTCACTTCTGAATGGCAGTTACACGTTCATCCACCTTCCATACTATTTCCATGGCTGTGGCCACGTTGTTTACAACAACTCTCTCTACTACCACAAAGGGGGTTCTAATACCCTAGTGAGATTTGATTTGGCCCAGGAAACATCCCAAACTCTGAAGCTTGAATGCCTTGTAATTTTGGATCGAAAATACCTTTTTGCAAATTCCAAAACTTACTTCAATCTAGCTGTAGATGAACCCCCTTTGGATTATCTATGCGCGTCAAGTGTGGACGGCTCGACCATTCETGTAGCACAACTGGATGAGAGGACATTCTCACTGGTGCAACACGTCAATACCACGEACCCTAAATCCAAGGCTGGCPACGCCTTCATTGCCCCAGGAATCCTCTATGTCACACACACCAAAGATATCAGGGTCACATTTGCCTTTGATTTCTTAGGAGGGAAACAGATCAATGCAAACTTTCATTTAAGAACTTCCCAGTCTGTTCTTCCCATGTTAGCATACAACATGAGAGATCAGCATTTATATTCATGGCAAGATGGCCATTTAATGCTTTATCCTGTCCACTTTTTGTCAACTACCTTAAATCAGTGATORF Start: ATG at 11 ORF Stop: TGA at 1259416 aa MW at 44878.0DaSEQ ID NO: 42NOV19a,MSLFLCFDAGPPGAGGLPGHNCLDGQPCFQGPKGEKGANGKRGKMGIPGAAGNPGERGCG112731-01Protein SequenceEKGDHGELGLQGNaGPPGQKGEKGDKGDVSNDVLLAGAKGDQGPPGPPGPPGPPGPPGPPGSRRAKGPRQPSMFNGQCPGETCATPNDDTLVGKADEKASEHHSPQAESMITSIGNPVQVLKVTETFGTWIRESANKSDDRIWVTEHFSGTMVKEFKDQPSLLNCSYTFIHLPYYFHCCGHVVYNNSLYYHKGGSNTLVRFEFCQETSQTLKLENALYFERKYLFANSKTYFNLAVDEKGLWIIYASSVDGSSTLVAQLDERTFSVVQHVNTTYPKSKAGNAFIARGILYVTDTKDMRVTFAFDLLGGKQINANFDLRTSQSVLAMLAYNMRDQHLYSWEDGHLMLYPVQFLSTTLNQ

[0413] Further analysis of the NOV19a protein yielded the following properties shown in Table 19B.

90TABLE 19BProtein Sequence Properties NOV19aPSort0.4158 probability located in microbody (peroxisome); 0.3000analysis:probability located in nucleus; 0.2177 probability located inlysosome (lumen); 0.1000 probability located in mitochondrialmatrix spaceSignalPCleavage site between residues 17 and 18analysis:

[0414] A search of the NOV19a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 19C.

91TABLE 19CGeneseq Results for NOV19aIdentities/NOV19aSimilaritiesProtein/Residues/for theGeneseqOrganism/LengthMatchMatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAU81220Human lung169 . . . 407 82/2454e−33cancer protein,(33%)Seq ID No 39— 3 . . . 247138/245Homo sapiens,(55%)258 aa.[WO200192525-A2, Dec. 6,2001]ABB53281Human poly-169 . . . 407 82/2454e−33peptide #21—(33%)Homo sapiens,216 . . . 460138/245471 aa.(55%)[WO200181363-A1, Nov. 1,2001]ABB53282Human poly-169 . . . 407 83/2452e−32peptide #22—(33%)Homo sapiens,230 . . . 473139/245484 aa.(55%)[WO200181363-A1, Nov. 1,2001]AAE02532Bovine alpha1(1) 8 . . . 134 68/1399e−28collagen—Bos(48%)sp, 1463 aa.746 . . . 877 76/139[WO200134647-(53%)A2, May 17,2001]AAR53257Human collagen 10 . . . 135 67/1323e−27(Type V)—Homo(50%)sapiens, 1838 aa.1426 . . . 1556 80/132[JP06105687-A,(59%)Apr. 19, 1994]

[0415] In a BLAST search of public sequence datbases, the NOV19a protein was found to have homology to the proteins shown in the BLASTP data in Table 19D.

92TABLE 19DPublic BLASTP Results for NOV19aNOV19aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ8UVR1Noelin-1—Xenopus169 . . . 407 79/245 (32%)4e−33laevis (African230 . . . 474139/245 (56%)clawed frog), 485aa.Q8UVR2Noelin-2—Xenopus169 . . . 407 79/245 (32%)4e−33laevis (African203 . . . 447139/245 (56%)clawed frog), 458aa.173636neronal olfacto-169 . . . 407 81/245 (33%)9e−33medin-related ER202 . . . 446138/245 (56%)localized protein—rat, 457 aa.Q8R357Olfactomedin 1—169 . . . 407 81/245 (33%)9e−33Mus musculus230 . . . 474138/245 (56%)(Mouse), 485 aa.Q99784Noelin precursor169 . . . 407 82/245 (33%)9e−33(Neuronal olfacto-230 . . . 474138/245 (55%)medin-related ERlocalized protein)(Olfactomedin 1)—Homo sapiens(Human), 485 aa.

[0416] PFam analysis predicts that the NOV19a protein contains the domains shown in the Table 19E.

93TABLE 19EDomain Analysis of NOV19aPfamNOV19aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValueCollagen 8 . . . 66 26/60 (43%)2.3e−08 45/60 (75%)Collagen 67 . . . 127 32/61 (52%)0.0017 45/61 (74%)OLF167 . . . 411 78/293 (27%)8.2e−41144/293 (49%)

Example 20

[0417] The NOV20 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 20A.

94TABLE 20ANOV20 Sequence Analysis1068 bpSEQ ID NO: 43NOV20aGCCCCACGTTCTGCAGCCTTAAGGTTGAACATGAGTGCACGTCCATGTCAGTGCTGTGCG112749-01DNA SequenceGGACTCCTGTGCGTGCCTCGCACTGCGTCTGTCGGCCGGACGCAGGCACACGTGGCTGCAAGGGTCGCTCCTTCCCCTCGCCCCCAACACCCTCCTCGAGCATCCTCAGTCTCGCTGCCTCCCTCGACGCAGAGCCTTCAAGCGCCGCAGTCCCCGACGCCTTCCCCGCGGGCCCCACTGTCTCCCCAAGACCCCTGGCGAGGCCGCCGGGGCTGGAGGACGCGCTCACCGCGCTGGGGCTGCAGGGAGAACGCGAGTACCCCGGGGACATCTTCGCCGAAGTCATGGTGTGCCGCGIGCTGCCCCTGAGAGCCCTCCCCCGCCCTGTGACCCCGGACATGCGCGCCCTGGTGGTAGACTGGCTCCTCCACGTGCACGAGTACCTCGGTCTCGCTGGTGACACACTTTATCTGGCGGTTCACCTGCTTGATTCCTACCTGAGCGCTGGCCCCGTGCGTCTACATCGCCTGCAGCTCCTGCGCCTGGCTTGCCTGTTTGTCGCCTGCAAAATCGAAGAGTGCGTGCTTCCCGAGCCCGCCTTCCTCTGCCTCCTGAGCGCGGACTCCTTCTCACGGGCGGAGCTCCTGCGCGCCGAGCGTCGCATCCTGAGCCCCCTGCATTTCCGGCTGCACCACCCCGGCCCGCTGCTGTGCCTCGGGCTGCTGGCCGCCCTGGCAGGGAGCAGCCCCCAGGTCATGTTACTTGCCACCTACTTCCTGGAGCTGTCTTTGCTGGAGGCCGACGCGCCCGCATGGGACCCGGGTCGTCGTCCCGCTCCGGCTCTCACCCTGCCCCACCGCTTGCTCCACGGGGCGCGCTCCAGGCTCCACCCAGAACTTTACACCCCCGAGGAACTGGCCACCCTCCAGCCGTGCATGCCCCCCGCTCCGCTCCGACGTCCCCCCCCCGGTCCCGCCGCAGTCTTCCTCAAGTATGCGCGGCCCCACCGCCAGGGGACCACCCTTCCCGCCGCCTCCCTGCTCCGCCGCCTCCAGTCTGAGCCTCCCTGAORF Start: ATG at 31 ORF Stop: TGA at 1066345 aa MW at 37077.6DaSEQ ID NO: 44NOV20a,MSARPCQCCGTPVRASDCVCRRDAGTRCCKCRCLASPATPSWRMLSLAASLDAEPSSACG112749-01Protein SequenceAVPDGFPAGPTVSPRRLARPPGLEEALSALGLQGEREYAGDIFAEVMVCRVLPLRALPRAVTPEMRALVVDWLVQVHEYLGLACDTLYLAVHLLDSYLSACRVRLHRLQLLCVACLFVACKMEECVLPEPAFLCLLSADSFSRAELLRAERRTLSRLDFRLHHPCPLLCLGLLAALAGSSPQVMLLATYFLELSLLEAEAACWEPCRRAAAALSLAHRLLDGAGSRLQPELYSPEELCTLEPCMARAALRGPAPGRAAVFLKYARPQRQGTSLAAACLLRRLQSEPP820 bpSEQ ID NO: 45NOV20b.CCTTAACCTTCAACATCAGTCCACGTCCATGTCAGTGCTGTGGGACTCCTGTGCGTGCCG112749-02DNA SequenceCTCGGACTGCGTCTGTCCGCCCGACCCACGCACACCTGCGTGTGCCGCGTCCTGCCCCTGAGACCCCTGCCCCCCGCTGTGACCCCGGAGATGCGCCCCCTGGTCCTACACTCGCTGGTCCAGGTGCACCACTACCTGGGTCTGCCTGGTGACACACTTTATCTCCCCGTTCACCTGCTTCATTCCTACCTGAGCGCTCCCCCCCTCCCTCTACATCGCCTGCACCTCCTGGGCGTGCCTTGCCTCTTTGTGCCGTGCAAAATCCAACAGTGCCTGCTTCCCGACCCCGCCTTCCTCTGCCTCCTGAGCGCGGACTCCTTCTCACGGGCGGACCTGCTCCCCCCCGAGCGTCGCATCCTGAGCCGCCTGGATTTCCGCCTGCACCACCCCCGCCCGCTGCTGTGCCTCGGGCTGCTCCCCGCGCTGCCGCGGAGCAGCCCCCACGTCATCTTACTTGCCACCTACTTCCTGGAGCTGTCTTTCCTCCACGCCGACCCGCCCCGATCGCACCCGCGTCGTCGTGCGGCTGCCCCTCTGAGCCTGCCCCACCGCTTCCTCCACCCCCCCCCCTCCACCCTCCAGCCACAACTTTACACCCCCCACCAACTGGGCACCCTCCAGCCGTCCATGGCCCGCGCTGCGCTCCGACCTCCCCCCCCCGGTCGCCCCGCAGTCTTCCTCAACTATCCGCCGCCCCAGCGCCACGCGACCACCCTTGCCGCCCCCTGCCTCCTCCGCCCCCTCCAGTCTCAGCCTCCCTGAORF Start: ATG at 99 ORF Stop: TGA at 818263 aa MW at 28774.4DaSEQ ID NO: 46NOV20b,MSVLWDSCACLGLRVSACRRHTWVCRVLPLRALPRAVTPEMRALVVDWLVQVHEYLGLCG112749-02Protein SequenceAGDTLYLAVHLLDSYLSAGRVRLHRLQLLCVACLFVACKMEECVLPEPAFLCLLSADSFSRAELLRAERRILSPLDERLHHPCPLLCLGLLAALAGSSPQVMLLATYELELSLLEAEAACWEPCRRAAAALSLAHRLLDCACSRLQPELYSPEELCTLEPCMARAALRGPAPGRAAVFLKYARPQRQCTSLAAACLLRRLQSEPP

[0418] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 20B.

95TABLE 20BComparison of NOV20a against NOV20b.ProteinNOV20a Residues/Identities/SimilaritiesSequenceMatch Residuesfor the Matched RegionNOV20b106 . . . 345164/240 (68%) 24 . . . 263164/240 (68%)

[0419] Further analysis of the NOV20a protein yielded the following properties shown in Table 20C.

96TABLE 20CProtein Sequence Properties NOV20aPSort0.4651 probability located in mitochondrial matrix space;analysis:0.3000 probability located in microbody (peroxisome); 0.2231probability located in lysosome (lumen); 0.1642 probabilitylocated in mitochondrial inner membraneSignalPNo Known Signal Sequence Predictedanalysis:

[0420] A search of the NOV20a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 20D.

97TABLE 20DGeneseq Results for NOV20aIdentities/NOV20aSimilaritiesProtein/Residues/for theGeneseqOrganism/LengthMatchMatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueABG20300Novel human 1 . . . 345345/3450.0diagnostic protein(100%)#20291—Homo516 . . . 860345/345sapiens, 860 aa.(100%)[WO200175067-A2, Oct. 11,2001]ABG20300Novel human 1 . . . 345345/3450.0diagnostic protein(100%)#20291—Homo516 . . . 860345/345sapiens, 860 aa.(100%)[WO200175067-A2, Oct. 11,2001]AAB95393Human protein 22 . . . 187117/1661e−53sequence SEQ ID (70%)NO: 17745— 6 . . . 141120/166Homo sapiens, (71%)155 aa.[EP1074617-A2,Feb. 7, 2001]AAB35800Protein involved112 . . . 323 73/2223e−24in cell cycle (32%)regulation SEQ263 . . . 484107/222ID 26—Zea (47%)mays, 509 aa.[WO200065040-A2, Nov. 2,2000]AAU72490Arabidopsis 96 . . . 325 81/2467e−24partial cell cycle (32%)protein CCP9—172 . . . 417119/246Arabidopsis (47%)thaliana, 436 aa.[WO200185946-A2, Nov. 15,2001]

[0421] In a BLAST search of public sequence datbases, the NOV20a protein was found to have homology to the proteins shown in the BLASTP data in Table 20E.

98TABLE 20EPublic BLASTP Results for NOV20aNOV20aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ9H8S5OVARC1000937 22 . . . 187117/166 (70%)3e−53protein—Homo 6 . . . 141120/166 (71%)sapiens (Human),155 aa.Q9DG96G2/mitotic-specific119 . . . 306 77/188 (40%)2e−29cyclin B2—Oryzias150 . . . 337106/188 (55%)luzonensis (Luzonricefish), 386 aa.Q91BG0G2/mitotic-specific119 . . . 306 76/188 (40%)5e−29cyclin B2—Oryzias151 . . . 338105/188 (55%)latipes (Medakafish) (Japanesericefish), 387 aa.Q9DGA3G2/mitotic-specific 30 . . . 306 98/290 (33%)9e−29cyclin B2—Oryzias 59 . . . 339142/290 (48%)curvinotus (Hynannricefish), 388 aa.Q9DG99G2/mitotic-specific118 . . . 302 75/185 (40%)2e−28cyclin B2—Oryzias145 . . . 329105/185 (56%)javanicus (Javanesericefish), 382 aa.

[0422] PFam analysis predicts that the NOV20a protein contains the domains shown in the Table 20F.

99TABLE 20FDomain Analysis of NOV20aPfamNOV20aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValuecyclin 99 . . . 22051/147 (35%)1.8e−3090/147 (61%)cyclin_C222 . . . 33732/137 (23%)0.0570/137 (51%)

Example 21

[0423] The NOV21 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 21A.

100TABLE 21ANOV21 Sequence AnalysisSEQ ID NO:471017 bpNOV21a,GAGCATGGGGGAAGTCTCGAGGGGTTTCCCTAGACCCATAGGGGGCAGCCGGAGTCGGCG112758-01DNA SequenceCTGCCGGAGGTGAGGGGGCGGAGAAAGGGTGGGGACCAGCCCCGCGGGGGGCGATGCGGTAGCTGCAGCGGCGGCGGCAGGAGTTTCCCACAATGCAGCGCGGCGCGCTGTCCCCGGTGCTGATGCTCAGCGCTGCCCCGGAGCCTCCGCCGCGCCCGCCTCCCGCCCTCTCCCCACCGGGCTCGGGCCCAGGCTCGGGCTCCCGCCATGGCTCGGCTCGTCCCGGTCCTACCCCAGAGCCGTCGGGGAGCCTGGGCGCGGCGCTCGACAGCAGCCTGCGTGCCGCCGTGGCGTTCAAGGCAGAGGGCCAGCGCTGCTATCGAGAGAAGAAGTTCCGGGAGGCCATCGGCAAGTACCACCGAGCGCTGCTGCAGCTGAAGGCGGCGCAGGGGGCCCGCCCTAGCGGCCTGCCCGCCCCCGCCCCCGGGCCCACCAGCAGCCCCGGGCCGGCGCGCCTCAGCGAGGAGCAGCGGCGCCTGGTGGAGAGCACGGAGGTGGAGTGTTACGACTCCCTCACGATGTGCCTGCTGCAGTCGGAGCTGGTAAACTACGAGCGCGTGCGCGAGTACTGTCTCAAGGTACTGGAGAAGCAGCAGGGCAACTTCAAGGCCACCTACCGTGCCGGCATTGCCTTCTACCACCTGGGCGACTACGCACGCGCGCTGCGCTACCTGCAGGAGGCCCGCAGCCGGGAACCCACAGACACCAATGTGCTCCGCTACATCCAGCTGACTCAGCTGAAGATGAATCGTTGCAGCCTCCAGCGGGAAGACAGTGGGGCTGGGTCCCAGACTCGGGATGTAATTGGCTGAGGCCAATCCAGGGGGACCTCTCTATCCCTCGCCCTCCCACCTCACCATGTAACTTCCCCCGACTCATGTGTTTGTTGGTAAAACACTTGTCACTGGTGATCATAACTTGTGTGGTGTTCTTGGGGGGACCAGGGAGGGCCTCATCCCORF Start: ATG at 151ORF Stop: TGA at 868SEQ ID NO:48239 aaMW at 25992.2DaNOV21a,MQRGALSPVLMLSAAPEPPPRPPPALSPPGSGPGSGSRHGSARPGPTPEPSGSLGAALCG112758-01Protein SequenceDSSLRAAVAFKAEGQRCYREKKFREAIGKYHRALLQLKAAQGARPSGLPAPAPGPTSSPGPARLSEEQRRLVESTEVECYDSLTMCLLQSELVNYERVREYCLKVLEKQQGNFKATYRAGIAFYHLGDYARALRYLQEARSREPTDTNVLRYIQLTQLKMNRCSLQREDSGAGSQTRDVIGSEQ ID NO:491017 bpNOV21b,GAGCATGGGGGAAGTCTCGAGGGGTTTCCCTAGACCCATAGGGGGCAGCCGGAGTCGGCG112758-02DNA SequenceCTGCCGGAGGTGAGGGGGCGGAGAAAGGGTGGGGACCAGCCCCGCGGGGGGCGATGCGGTAGCTGCAGCGGCGGCGGCAGGAGTTTCCCACAATGCAGCGCGGCGCGCTGTCCCCGGTGCTGATGCTCAGCGCTGCCCCGGAGCCTCCGCCGCGCCCGCCTCCCGCCCTCTCCCCACCGGGCTCGGGCCCAGGCTCGGGCTCCCGCCATGGCTCGGCTCGTCCCGGTCCTACCCCAGAGCCGTCGGGGAGCCTGGGCGCGGCGCTCGACAGCAGCCTGCGTGCCGCCGTGGCGTTCAAGGCAGAGGGCCAGCGCTGCTATCGAGAGAAGAAGTTCCGGGAGGCCATCGGCAAGTACCACCGAGCGCTGCTGCAGCTGAAGGCGGCGCAGGGGGCCCGCCCTAGCGGCCTGCCCGCCCCCGCCCCCGGGCCCACCAGCAGCCCCGGGCCGGCGCGCCTCAGCGAGGAGCAGCGGCGCCTGGTGGAGAGCACGGAGGTGGAGTGTTACGACTCCCTCACGGCTTGCCTGCTGCAGTCGGAGCTGGTAAACTACGAGCGCGTGCGCGAGTACTGTCTCAAGGTACTGGAGAAGCAGCAGGGCAACTTCAAGGCCACCTACCGTGCCGGCATTGCCTTCTACCACCTGGGCGACTACGCACGCGCGCTGCGCTACCTGCAGGAGGCCCGCAGCCGGGAACCCACAGACACCAATGTGCTCCGCTACATCCAGCTGACTCAGCTGAAGATGAATCGTTGCAGCCTCCAGCGGGAAGACAGTGGGGCTGGGTCCCAGACTCGGGATGTAATTGGCTGAGGCCAATCCAGGGGGACCTCTCTATCCCTCGCCCTCCCACCTCACCATGTAACTTCCCCCGACTCATGTGTTTGTTGGTAAAACACTTGTCACTGGTGATCATAACTTGTGTGGTGTTCTTGGGGGGACCAGGGAGGGCCTCATCCCORF Start: ATG at 151ORF Stop: TGA at 868SEQ ID NO:50239 aaMW at 25932.0DaNOV21b,MQRGALSPVLMLSAAPEPPPRPPPALSPPGSGPGSGSRHGSARPGPTPEPSGSLGAALCG112758-02Protein SequenceDSSLRAAVAFKAEGQRCYREKKFREAIGKYHRALLQLKAAQGARPSGLPAPAPGPTSSPGPARLSEEQRRLVESTEVECYDSLTACLLQSELVNYERVREYCLKVLEKQQGNFKATYRAGIAFYHLGDYARALRYLQEARSREPTDTNVLRYIQLTQLKMNRCSLQREDSGAGSQTRDVIG

[0424] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 21B.

101TABLE 21BComparison of NOV21a against NOV21b.ProteinNOV21a Residues/Identities/SimilaritiesSequenceMatch Residuesfor the Matched RegionNOV21b1.239168/239 (70%)1.239168/239 (70%)

[0425] Further analysis of the NOV21a protein yielded the following properties shown in Table 21C.

102TABLE 21CProtein Sequence Properties NOV21aPSort0.5500 probability located in endoplasmic reticulumanalysis:(membrane); 0.2372 probability located in lysosome (lumen);0.1000 probability located in endoplasinic reticulum (lumen);0.1000 probability located in outsideSignalPCleavage site between residues 17 and 18analysis:

[0426] A search of the NOV21a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 21D.

103TABLE 21DGeneseq Results for NOV21aNOV21aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueABG07676Novel human diagnostic protein 1 . . . 239219/240 (91%) e−122#7667 - Homo sapiens, 240 aa. 1 . . . 240221/240 (91%)[WO200175067-A2, 11 OCT. 2001]ABG07676Novel human diagnostic protein 1 . . . 239219/240 (91%) e−122#7667 - Homo sapiens, 240 aa. 1 . . . 240221/240 (91%)[WO200175067-A2, 11 OCT. 2001]AAU23696Novel human enzyme polypeptide105 . . . 226 78/122 (63%)7e−41#782 - Homo sapiens, 126 aa. 2 . . . 122101/122 (81%)[WO200155301-A2, 02 AUG. 2001]AAM42005Human polypeptide SEQ ID NO 50 . . . 219 82/170 (48%)1e−386936 - Homo sapiens, 259 aa. 81 . . . 244111/170 (65%)[WO200153312-A1, 26 JUL. 2001]AAB64390Amino acid sequence of human 58 . . . 219 81/162 (50%)2e−38intracellular signalling molecule 1 . . . 156110/162 (67%)INTRA22 - Homo sapiens, 171 aa.[WO200077040-A2, 21 DEC. 2000]

[0427] In a BLAST search of public sequence datbases, the NOV21a protein was found to have homology to the proteins shown in the BLASTP data in Table 21E.

104TABLE 21EPublic BLASTP Results for NOV21aNOV21aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueAAH29539Similar to RIKEN cDNA 1 . . . 239238/239 (99%) e−1362900074C18 gene - Homo sapiens 1 . . . 239238/239 (99%)(Human), 239 aa.Q9D6E42900074C18Rik protein - Mus 1 . . . 239219/241 (90%) e−123musculus (Mouse), 239 aa. 1 . . . 239224/241 (92%)Q96NP9CDNA FLJ30373 fis, clone 1 . . . 142142/142 (100%)6e−78BRACE2007882, weakly similar to 1 . . . 142142/142 (100%)actin-depolymerizing protein N-wasp - Homo sapiens (Human),192 aa.Q92623KIAA0227 protein - Homo sapiens 16 . . . 226121/221 (54%)1e−58(Human), 336 aa (fragment).128 . . . 332155/221 (69%)Q9BGT1Hypothetical 20.0 kDa protein - 58 . . . 219 81/162 (50%)5e−38Macaca fascicularis (Crab eating 1 . . . 156110/162 (67%)macaque) (Cynomolgus monkey),171 aa.

[0428] PFam analysis predicts that the NOV21a protein contains the domains shown in the Table 21F.

105TABLE 21FDomain Analysis of NOV21aIdentities/NOV21aSimilaritiesExpectPfam DomainMatch Regionfor the Matched RegionValueTPR171 . . . 20410/34 (29%)0.004425/34 (74%)

Example 22

[0429] The NOV22 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 22A.

106TABLE 22ANOV22 Sequence AnalysisSEQ ID NO:51696 bpNOV22a,GCTTGGCGACGCCATGTTTCAAGGGCAGCGCGGTTGGTTTTGCGGCAGCGTTAGCCAGCG112892-01DNA SequenceGATCTGAGGCAATTCTGGGGTAGGGAAGGGGGAACGATCAGTGACCCGCGAGCCGCCGACTTCTTGTTCAGCTGTGATGCCTCGCACCCAGACACGCTGAGGAGAATATATCAGAGCCTTGATTACATAGAAGATAATGCTACAGTTTTTCATGCCTACTATCTCTCTGCGGTAGCTAATGCCAAAATAAAAAACTCGGTGGCTTTGGGTCATTTCATTCTTCCTCCTGCGTGCCTGCAAAAAGAAATAAGAAGAAAAATTGGTAGTTTTATTTGGGAACAAGACCAACATTTTCTGATAGAAAAGCAGCATGATGAAGTAACACCAAATGAAATAAAGACCCTTAGGGAAAACAGTGAACTAGCAACAGAGCACAAAAAAGAATTATCCAAAAGCCCAGAAAAGCATTTTATAAGAACTCCAGTTGTAGAAAAGCAGATGTACTTCCCTCTACAGAATTACCCAGTTAACAACATGGTAACAGGTGGTTATATATCAATTGATGCCATGAAGAAATTCCTTGGGGAGCTACATGACTTCATTCCTGGAACCTCAGGATATTTGGCATATCATGTTCAAAATGAAATTAATATGTCTGCTATAAAAAACAAATTGAAGAGGAAATAGTAAATTAAATTORF Start: ATG at 14ORF Stop: TAG at 683SEQ ID NO:52223 aaMW at 25700.0DaNOV22a,MFQGQRGWFCGSVSQDLRQFWGREGGTISDPRAADFLFSCDASHPDTLRRIYQSLDYICG112892-01Protein SequenceEDNATVFHAYYLSAVANAKIKNSVALGHFILPPACLQKEIRRKIGSFIWEQDQHFLIEKQHDEVTPNEIKTLRENSELATEHKKELSKSPEKHFIRTPVVEKQMYFPLQNYPVNNMVTGGYISIDAMKKFLGELHDFIPGTSGYLAYHVQNEINMSAIKNKLKRK

[0430] Further analysis of the NOV22a protein yielded the following properties shown in

107TABLE 22BProtein Sequence Properties NOV22aPSort0.4567 probability located in microbody (peroxisome); 0.4500analysis:probability located in cytoplasm; 0.1000 probability locatedin mitochondrial matrix spacc; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0431] A search of the NOV22a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 22C.

108TABLE 22CGeneseq Results for NOV22aNOV22aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAM95390Human reproductive system related 10 . . . 187171/178 (96%)4e−93antigen SEQ ID NO: 4048 - Homo 1 . . . 175172/178 (96%)sapiens, 181 aa. [WO200155320-A2, 02 AUG. 2001]AAY77575Human cytoskeletal protein 94 . . . 189 26/99 (26%)0.046(HCYT) (clone 1655208) - Homo1046 . . . 1142 49/99 (49%)sapiens, 2442 aa. [WO200006730-A2, 10 FEB. 2000]AAB18324Plasmodium falciparum 94 . . . 160 17/69 (24%)2.6chromosome 2 related protein SEQ 906 . . . 974 41/69 (58%)ID NO: 182 - Plasmodiumfalciparum, 1558 aa.[WO200025728-A2, 11 MAY 2000]AAW24790P. falciparum liver stage antigen-3- 94 . . . 160 17/69 (24%)2.6Plasmodium falciparum, 1786 aa.1138 . . . 1206 41/69 (58%)[WO9641877-A2, 27 DEC. 1996]AAB87479B thuringiensis 14 kDa toxin 180 . . . 214 12/35 (34%)3.5protein SEQ ID NO: 60 - Bacillus 38 . . . 72 21/35 (59%)thuringiensis, 113 aa.[WO200114417-A2, 01 MAR. 2001]

[0432] In a BLAST search of public sequence datbases, the NOV22a protein was found to have homology to the proteins shown in the BLASTP data in Table 22D.

109TABLE 22DPublic BLASTP Results for NOV22aNOV22aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueAAH29537Similar to RIKEN cDNA 1 . . . 223218/223 (97%) e−12244933406J08 gene - Homo sapiens 1 . . . 220218/223 (97%)(Human), 220 aa.Q9D49444933406J08Rik protein - Mus 1 . . . 223171/223 (76%)1e−95musculus (Mouse), 218 aa. 1 . . . 216193/223 (85%)Q9C7Z6Hypothetical 456.6 kDa protein - 104 . . . 173 24/71 (33%)0.11Arabidopsis thaliana (Mouse-ear 271 . . . 335 35/71 (48%)cress), 4099 aa.Q9LNG1F21D18.20 - Arabidopsis thaliana 104 . . . 173 24/71 (33%)0.11(Mouse-ear cress), 488 aa. 266 . . . 330 35/71 (48%)Q9H450DJ47704.6 (Cdc42 effector protein 94 . . . 189 26/99 (26%)0.112 (centrosomal protein 2,1046 . . . 1142 49/99 (49%)centrosomal NEK2-associatedprotein 1, C-NAP1, CEP250))-Homo sapiens (Human), 2442 aa.

Example 23

[0433] The NOV23 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 23A.

110TABLE 23ANOV23 Sequence AnalysisSEQ ID NO:53573 bpNOV23a,GAGATGGTCCCCGGCGCCGCGGGCTGGTGTTGTCTCGTGCTCTGGCTTCCCACGGCTCCG113794-01DNA SequenceTGGCTTCCCACGGCTTCCGTATCCATGATTATTTGTACTTTCAAGTGCTGAGTCCTGGGGACATTCGATACATCTTCACAGCCACACCTGCCAAGGACTTCGGTGGTATCTTTCACACAAGGTATGAGCAGATTCACCTTGTCCCTGCTGAACCTCCAGAGGCCTGCGGGGAACTCAGCGCAGGTTTCTTCATCCAGGACCAGATCGCTCTGGTGGAGAGTGGGGGCTGCTCCCTCCTCTCCAAGACTCGGGTGGTCCAAGAGCATGGCGGGCGGGCCGTGATCATCTCTGACAATGCGGTTGACAATGACAGCTTCTATGTGGCGATGATCCAGGACAGTACCCAGCGCACAGCTGACATCTCCGCCCTCTTTCTTCTCAGCCGAGAGGGCTACATGATCCGCCGCTCCCTGGAACAGCCTGGGCTGCCATGGGCCATCATTTCCATCCCAGTCAATGTCACCAGTATCCCCACCTTTGAGCTGCAGCAACCGTCCTGGTCCTTCTGGTAGAAGORF Start: ATG at 4ORF Stop: TAG at 568SEQ ID NO:54188 aaMW at 20850.6DaNOV23a,MVPGAAGWCCLVLWLPTALASHGFRIHDYLYFQVLSPGDIRYIFTATPAKDFGGIFHTCG113794-01Protein SequenceRYEQIHLVPAEPPEACGELSAGFFIQDQIALVESGGCSLLSKTRVVQEHGGRAVIISDNAVDNDSFYVAMIQDSTQRTADISALFLLSREGYMIRRSLEQPGLPWAIISIPVNVTSIPTFELQQPSWSFW

[0434] Further analysis of the NOV23a protein yielded the following properties shown in Table 23B.

111TABLE 23BProtein Sequence Properties NOV23aPSort0.5500 probability located in lysosome (lumen); 0.3700analysis:probability located in outside; 0.2417 probability located inmicrobody (peroxisome); 0.1000 probability located inendoplasmic reticulum (membrane)SignalPCleavage site between residues 21 and 22analysis:

[0435] A search of the NOV23a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 23C.

112TABLE 23CGeneseq Results for NOV23aNOV23aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueABB84944Human PRO1760 protein sequence 1 . . . 188173/188 (92%)e−100SEQ ID NO: 256 - Homo sapiens, 1 . . . 188177/188 (94%)188 aa. [WO200200690-A2,03 JAN. 2002]AAU83694Human PRO protein, Seq ID No 206 - 1 . . . 188173/188 (92%)e−100Homo sapiens, 188 aa. 1 . . . 188177/188 (94%)[WO200208288-A2, 31 JAN. 2002]AAB66198Protein of the invention #110 - 1 . . . 188173/188 (92%)e−100Unidentified, 188 aa. 1 . . . 188177/188 (94%)[WO200078961-A1, 28 DEC. 2000]AAB87427Human gene 9 encoded secreted, 1 . . . 188173/188 (92%)e−100protein fragment, SEQ ID NO: 168 -44 . . . 231177/188 (94%)Homo sapiens, 231 aa.[WO200118022-A1, 15 MAR. 2001]AAB87350Human gene 9 encoded secreted 1 . . . 188173/188 (92%)e−100protein HOEEK12, SEQ ID NO: 91 - 1 . . . 188177/188 (94%)Homo sapiens, 188 aa.[WO200118022-A1, 15 MAR. 2001]

[0436] In a BLAST search of public sequence datbases, the NOV23a protein was found to have homology to the proteins shown in the BLASTP data in Table 23D.

113TABLE 23DPublic BLASTP Results for NOV23aResidues/Similarities forAccessionMatchthe MatchedNumberProtein/Organism/LengthResiduesPortionValueQ9BSG0Similar to RIKEN cDNA 1 . . . 188173/188 (92%) e−1001700040103 gene - Homo sapiens 1 . . . 188177/188 (94%)(Human), 188 aa.Q9D9N81700040103Rik protein- Mus 1 . . . 188171/188 (90%)3e−98musculus (Mouse), 188 aa. 1 . . . 188175/188 (92%)Q9W1W9CG9849 protein (RE13814p) - 30 . . . 188 60/161 (37%)1e−25Drosophila melanogaster (Fruit 36 . . . 196 94/161 (58%)fly), 196 aa.Q9UFV7Hypothetical 41.8 kDa protein - 41 . . . 158 32/122 (26%)0.003Homo sapiens (Human), 380 aa108 . . . 229 57/122 (46%)(fragment).Q9BZQ6Putative alpha-mannosidase 41 . . . 158 32/122 (26%)0.003Clorf22 (EC 3.2.1.-) - Homo617 . . . 738 57/122 (46%)sapiens (Human), 889 aa.

[0437] PFam analysis predicts that the NOV23a protein contains the domains shown in the Table 23E.

114TABLE 23EDomain Analysis of NOV23aIdentities/NOV23aSimilaritiesExpectPfam DomainMatch Regionfor the Matched RegionValuePA56 . . . 15623/114 (20%)0.002761/114 (54%)

Example 24

[0438] The NOV24 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 24A.

115TABLE 24ANOV24 Sequence AnalysisSEQ ID NO:551592 bpNOV24a,CTACAACAAAATGGGGAGAAGAAATGAGAACTGTGCTAACAGCCTACGTGTGTCAAACCG114814-01DNA SequenceATCTCTCAGGAGAACTTATCTCACTGGAATTTGGATTCAGAAGTACCTGTTTCTGAAAATAAAAACCTCCCAGCTGGAAGGGATGGAGCAGCAGGTGGTAAGTTGGAAATTCCAGTGGAGCAACTGATGCTAGAACCTAATTTGTCGGTGCATAGTCAAAAAAGTACACAGCAGAATAGTAAACAAGGGATCTTTCAATTATGGAATTGTCCTCTTAATGAAGGAAGTACCATAGAGAAGAGGAACAGCAGTGTGGAAGAAAATTTCACAGATGAAAGTGATTTATCAGAAAATGAGAAGACAAATGATACTTTACTCAGCTATTTTAAAAAGGTGGACCTGAACTTGAAGCCAGAAACAATAAAAAATGTTGAGGAACCTTTCACCGAGGAGCCAAATGAAGTATTTCCATATCCTGATTTTCTCCCTCCTCCTTTCAGTGCTCTAGACTTGCACAATTTAGCCCTCTCCAAATCTGACAATTGGAAAGTGACAGTGGACCCTGCAGAAACCTCTGTTGAACACTTGATAACTCGTTTACTGGAACTAGAACGATTACAACATATGACTATTCAAAAACAGAGGCCAAGACTACAAACGACTTTCTGTACTCCAGCAGTTACTGAACGACCCTCTTCCTCCAAAGCTACACCAAAAGTGAGACAGCCAAAACTTTGCGACTCTTTGAGTCTTCAGATACCTTGTGTAGATAAAAGTCAAGAAAAAAGTAAAAACAACTCTGGTTCTTGTAAGCTTGAACAAAATGCTTTAAAACGGAATTGGAGCAATGCTGGCAAATATAGATGGAATTCTAGACCACTGTCTCTAAAAAGTTCTTCCACCCCAAAACAATTGATTGAAACTTATGATAAGAATCCCAAAAGTTCTATTTTAAGTCCATGCCAAGAACTCTCATTCAAACCTACTATTGGCCATACAAATCAATCAATGGTTAAAATGGTCTCCACAAGATGTCTGCCATGGAGGTCTCCAATGCCAGTTTCACCTATACCTCTGACTTTTCCCGAAAATCAGAAGGAAGAAATTAAGGCACCGAAGAGAAACTTTGGGACCAAAAAGAAACTTTACCGACAAAATATAGTGTTGAATAGACCATTCTCTATTCAGAAGCTAAACTGTTTGTCGCCTTCCCTTATTGCTAAGGATAAGTGCTGCTCACCCATTGAACAAAAATAACTCTTTTCTTTCATACATCTCAATGTGAACACATCTACTCTAAGAAGCCCAACTAAGATATGGTTAATTATTCCAAGACACAGGTACTATTAACAGTCCCCCAAAATCACCAAACAGTTGCTTGATGTGATATGGAGTAGAACTTGTGAAAAGCACTGCTGAGATGTCTATATATAAACCCACAGGCTTCTATACTGACATATTTCACAATCTGTTGCATGTTGTGTTTCAAGTAAATGGTTCACTTGGTAGACTATTCTATTCAAAAGGCTACTCTTTTTTCAGTGATTGTTTTCCAGTATAATTCCATCAATAAATGGTATAATTGACTTATAAAORF Start: ATG at 11ORF Stop: TAA at 1253SEQ ID NO:56414 aaMW at 46912.8DaNOV24a,MGRRNENCANSLRVSNISQENLSHWNLDSEVPVSENKNLPAGRDGAAGGKLEIPVEQLCG114814-01Protein SequenceMLEPNLSVHSQKSTQQNSKQGIFQLWNCPLNEGSTIEKRNSSVEENFTDESDLSENEKTNDTLLSYFKKVDLNLKPETIKNVEEPFTEEPNEVFPYPDFLPPPFSALDLHNLALSKSDNWKVTVDPAETSVEHLITRLLELERLQHMTIQKERPRLQTTFCTPAVTERPSSSKATPKVRQPKLCDSLSLQIPCVDKSQEKSKNNSGSCKLEQNALKRNWSNAGKYRWNSRPLSLKSSSTPKQLIETYDKNPKSSILSPCQELSFKPTIGHTNQSMVKMVSTRCLPWRSPMPVSPIPLTFPENQKEEIKAPKRNFGTKKKLYRQNIVLNRPFSIQKLNCLSPSLIAKDKCCSPIEQK

[0439] Further analysis of the NOV24a protein yielded the following properties shown in Table 24B.

116TABLE 24BProtein Sequence Properties NOV24aPSort0.4500 probability located in cytoplasm; 0.3600 probabilityanalysis:located in mitochondrial matrix space; 0.1000 probabilitylocated in lysosome (lumen); 0.0000 probability located inendoplasmic reticulum (membrane)SignalPNo Known Signal Sequence Predictedanalysis:

[0440] A search of the NOV24a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 24C.

117TABLE 24CGeneseq Results for NOV24aNOV24aIdentitiesProteinResidues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAM03928Peptide #2610101 . . . 21340/119 (33%)8e−05encoded by probe 72 . . . 18961/119 (50%)for measuringbreast geneexpression—Homo sapiens,370 aa.[WO200157270-A2, Aug. 9,2001]AAM16198Peptide #2632101 . . . 21340/119 (33%)8e−05encoded by probe 72 . . . 18961/119 (50%)for measuringcervical geneexpression—Homo sapiens,370 aa.[WO200157278-A2, Aug. 9,2001]AAM68380Human bone101 . . . 21340/119 (33%)8e−05marrow expressed 72 . . . 18961/119 (50%)probe encodedprotein SEQ IDNO: 28686—Homo sapiens,370 aa.[WO200157276-A2, Aug. 9,2001]AAM56010Human brain101 . . . 21340/119 (33%)8e−05expressed single 72 . . . 18961/119 (50%)exon probeencoded proteinSEQ ID NO:28115—Homosapiens, 370 aa.[WO200157275-A2, Aug. 9,2001]ABB20615Protein #2614101 . . . 21340/119 (33%)8e−05encoded by probe 72 . . . 18961/119 (50%)for measuringheart cell geneexpression—Homo sapiens,370 aa.[WO200157274-A2, Aug. 9,2001]

[0441] In a BLAST search of public sequence datbases, the NOV24a protein was found to have homology to the proteins shown in the BLASTP data in Table 24D.

118TABLE 24DPublic BLASTP Results for NOV24aNOV24aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ9D9W61700026J04Rik 1 . . . 414254/426 (59%) e−129protein—Mus 1 . . . 419314/426 (73%)musculus (Mouse),419 aa.Q9NTX9DJ551D2.5 (novel101 . . . 213 40/119 (33%)2e−04 protein)—Homo 85 . . . 202 61/119 (50%)sapiens (Human),383 aa.Q9NTA3Hypothetical 34.5101 . . . 213 39/119 (32%)0.001kDa protein—Homo 18 . . . 135 60/119 (49%)sapiens (Human),316 aa (fragment).Q9X6U0Surface protein C 19 . . . 365 71/365 (19%)0.10 PspC—139 . . . 475134/365 (36%)Streptococcuspneumoniae, 730 aa(fragment).Q9VRV1CG10289 protein— 89 . . . 153 25/66 (37%)0.23 Drosophila12 . . . 70 37/66 (55%)melanogaster(Fruit fly), 962 aa.

Example 25

[0442] The NOV25 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 25A.

119TABLE 25ANOV25 Sequence AnalysisSEQ ID NO:571427 bpNOV25a,GGGCAGCCTGGTAGTAAAACACTGTTGAATGGGCCACAGTTTCAGCAGACCATCAGGTCG116840-01DNA SequenceGAATGGGACCAGTCTCTCTTCTTCCAAAATATCAGAAGTTAAACACTTGGAACGGAGATTTGGCCAAGATGACCCATTTACAGGCTGGACTCAGTCCAGAGACTATAGAGAAAGCTCGCCTGGAACTGAATGAAAACCCCGATGTTTTACATCAGGATATTCAGCAAGTCAGGGACATGATCATCACCAGGCCTGACATTGGATTTTTACGTACAGATGATGCCTTCATCCTGAGATTTCTCCGAGCCAGGAAGTTTCACCAAGCGGATGCCTTTAGACTCCTGGCTCAGTATTTCCAGTACCGCCAGCTAAACCTGGACATGTTCAAAAACTTCAAGGCAGATGATCCCGGCATTAAGAGGGCTCTGATCGATGGGTTCCCCGGGGTGCTGGAAAACCGAGACCATTACGGCAGGAAGATTCTTTTGCTGTTTGCAGCCAATTGGGATCAGAGTAGGAACTCCTTCACAGACATCCTTCGTGCCATCCTGCTGTCATTGGAAGTCCTAATCGAAGATCCGGAGCTTCAGATAAATGGCTTCATTTTAATTATAGACTGGAGTAATTTTTCCTTCAAACAAGCCTCCAAACTGACACCTTCAATCCTTAAACTGGCCATTGAAGGGTTGCAGGACAGCTTTCCTGCCCGCTTTGGAGGAGTCCACTTTGTCAACCAGCCCTGGTACATTCATGCCCTCTACACACTCATCAAGCCATTTCTTAAAGACAAGACCAGGAAACGGATTTTCCTGCATGGAAACAATTTAAACAGCCTTCACCAGCTAATACACCCTGAATTTTTGCCCTCTGAATTTGGAGGAACTCTTCCTCCTTATGACATGGGAACTTGGGCCCGGACGTTACTCGGTCCCGACTACAGCGATGAAAATGACTATACTCACACATCCTATAATGCAATGCACGTGAAGCATACGTCCTCGAATCTGGAGAGAGAATGCTCACCCAAGCTGATGAAAAGATGTCAGTCTGTGGTAGAAGCTGGGACCCTGAAACATGAGGAGAAGGGAGAGAATGAGAACACCCAGCCACTCCTGGCTCTGGACTGAACCCTGAGTCACCCCAATGCTCCTGCACACTGGCCTTCAGTGGTATCAGCCACCCAGGAAGCACATGCACAACTGACCCATGCAGACACGTGTGTTCTGCTTGACACAAGGTCCTCCACTCCTGAACCCCTGCAGTGACTGTCACCAGCCATCGGTCTGAGCAGCCAAAGTTGGACAAAGACTTGAGAGATGCTTTTTTTTTCCCCCAGTGAGGGGACTGGAGGATGATGCAAGGCATTTATGTAAAAAAGATTCTCCCTCCTTTCATATTTATTGTAGTAAATTGAAAAAATAAAGACTAAORF Start: ATG at 61ORF Stop: TGA at 1123SEQ ID NO:58354 aaMW at 40803.2DaNOV25a,MGPVSLLPKYQKLNTWNGDLAKMTHLQAGLSPETIEKARLELNENPDVLHQDIQQVRDCG116840-01Protein SequenceMIITRPDIGFLRTDDAFILRFLRARKFHQADAFRLLAQYFQYRQLNLDMFKNFKADDPGIKRALIDGFPGVLENRDHYGRKILLLFAANWDQSRNSFTDILRAILLSLEVLIEDPELQINGFILIIDWSNFSFKQASKLTPSILKLAIEGLQDSFPARFGGVHFVNQPWYIHALYTLIKPFLKDKTRKRIFLHGNNLNSLHQLIHPEFLPSEFGGTLPPYDMGTWARTLLGPDYSDENDYTHTSYNAMHVKHTSSNLERECSPKLMKRCQSVVEAGTLKHEEKGENENTQPLLALDSEQ ID NO:591143 bpNOV25b,GTAGTAAAACACTGTTGAATGGGCCACAGTTTCAGCAGACCATCAGGTGAATGGGACCCG116840-02DNA SequenceAGTCTCTCTTCTTCCAAAATATCAGAAGTTAAACACTTGGAACGGAGATTTGGCCAAGATGACCCATTTACAGGCTGGACTCAGTCCAGAGACTATAGAGAAAGCTCGCCTGGAACTGAATGAAAACCCCGATGTTTTACATCAGGATATTCAGCAAGTCAGGGACATGATCATCACCAGGCCTGACATTGGATTTTTACGTACAGATGATGCCTTCATCCTGAGATTTCTCCGAGCCAGGAAGTTTCACCAAGCGGATGCCTCTAGACTCCTGGCTCAGTATTTCCAGTACCGCCAGCTAAACCTGGACATGTTCAAAAACTTCAAGGCAGATGATCCCGGCATTAAGAGGGCTCTGATCGATGGGTTCCCCGGGGTGCTGGAAAACCGAGACCATTACGGCAGGAAGATTCTTTTGCTGTTTGCAGCCAATTGGGATCAGAGTAGGAACTCCTTCACAGACATCCTTCGTGCCATCCTGCTGTCATTGGAAGTCCTAATCGAAGATCCGGAGCTTCAGATAAATGGCTTCATTTTAATTATAGACTGGAGTAATTTTTCCTTCAAACAAGCCTCCAAACTGACACCTTCAATCCTTAAACTGGCCATTGAAGGGTTGCAGGACAGCTTTCCTGCCCGCTTTGGAGGAGTCCACTTTGTCAACCAGCCCTGGTACATTCATGCCCTCTACACACTCATCAAGCCATTTCTTAAAGACAAGACCAGGAAACGGATTTTCCTGCATGGAAACAATTTAAACAGCCTTCACCAGCTAATACACCCTGAATTTTTGCCCTCTGAATTTGGAGGAACTCTTCCTCCTTATGACATGGGAACTTGGGCCCGGACGTTACTCGGTCCCGACTACAGCGATGAAAATGACTATACTCACACATCCTATAATGCAATGCACGTGAAGCATACGTCCTCGAATCTGGAGAGAGAATGCTCACCCAAGCTGATGAAAAGATCTCAGTCTGTGGTAGAAGCTGGGACCCTGAAACATGAGGAGAAGGGAGAGAATGAGAACACCCAGCCACTCCTGGCTCTGGACTGAACCCTGAGTCACCCCAATGCTCCTGCACORF Start: ATG at 51ORF Stop: TGA at 1113SEQ ID NO:60354 aaMW at 40727.1DaNOV25b,MGPVSLLPKYQKLNTWNGDLAKMTHLQAGLSPETIEKARLELNENPDVLHQDIQQVRDCG116840-02Protein SequenceMIITRPDIGFLRTDDAFILRFLRARKFHQADASRLLAQYFQYRQLNLDMFKNFKADDPGIKRALIDGFPGVLENRDHYGRKILLLFAANWDQSRNSFTDILRAILLSLEVLIEDPELQINGFILIIDWSNFSFKQASKLTPSILKLAIEGLQDSFPARFGGVHFVNQPWYIHALYTLIKPFLKDKTRKRIFLHGNNLNSLHQLIHPEFLPSEFGGTLPPYDMGTWARTLLGPDYSDENDYTHTSYNAMHVKHTSSNLERECSPKLMKRSQSVVEAGTLKHEEKGENENTQPLLALD

[0443] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 25B.

120TABLE 25BComparison of NOV25a against NOV25b.ProteinNOV25a Residues/Identities/SimilaritiesSequenceMatch Residuesfor the Matched RegionNOV25b1 . . . 354352/354 (99%)1 . . . 354352/354 (99%)

[0444] Further analysis of the NOV25a protein yielded the following properties shown in Table 25C.

121TABLE 25CProtein Sequence Properties NOV25aPSort0.6020 probability located in microbody (peroxisome); 0.2269analysis:probability located in lysosome (lumen); 0.1000 probabilitylocated in mitochondrial matrix space; 0.0000 probabilitylocated in endoplasmic reticulum (membrane)SignalPNo Known Signal Sequence Predictedanalysis:

[0445] A search of the NOV25a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 25D.

122TABLE 25DGeneseq Results for NOV25aNOV25aIdentities/ProteinResidues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAG78850Human 1 . . . 354353/354 (99%)0.0retinaldehyde- 1 . . . 354353/354 (99%)binding protein39—Homosapiens, 354 aa.[WO200173004-A1, Oct. 4,2001]AAU74690Human30 . . . 296107/277 (38%)3e−53retinaldehyde-40 . . . 314161/277 (57%)binding protein 1,RLBP1, variant3—Homosapiens, 317 aa.[WO200192278-A2, Dec. 6,2001]AAU74689Human30 . . . 296106/277 (38%)8e−53retinaldehyde-40 . . . 314161/277 (57%)binding protein 1,RLBP1, variant2—Homosapiens, 317 aa.[WO200192278-A2, Dec. 6,2001]AAU74688Human30 . . . 296106/277 (38%)8e−53retinaldehyde-40 . . . 314161/277 (57%)binding protein 1,RLBP1, variant1—Homosapiens, 317 aa.[WO200192278-A2, Dec. 6,2001]AAU74687Human30 . . . 29 106/277 (38%)8e−53retinaldehyde-40 . . . 314161/277 (57%)binding protein 1,RLBP1—Homosapiens, 317 aa.[WO200192278-A2, Dec. 6, 2001]

[0446] In a BLAST search of public sequence datbases, the NOV25a protein was found to have homology to the proteins shown in the BLASTP data in Table 25E.

123TABLE 25EPublic BLASIP Results for NOV25aNOV24aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ9D4C94933402J24Rik 1 . . . 354343/354 (96%)0.0protein—Mus 1 . . . 354347/354 (97%)musculus (Mouse),354 aa.Q95KF7Hypothetical 38.023 . . . 354264/332 (79%) e−153kDa protein— 1 . . . 327293/332 (87%)Macacafascicularis (Crabeating macaque)(Cynomolgusmonkey), 327 aa.Q9BE37Hypothetical 38.023 . . . 354263/332 (79%) e−152kDa protein— 1 . . . 327291/332 (87%)Macaca fascicularis(Crab eatingmacaque)(Cynomolgusmonkey), 327 aa.A31955cellular30 . . . 296109/277 (39%)5e−54 retinaldehyde-40 . . . 314161/277 (57%)binding protein—bovine, 317 aa.P10123Cellular30 . . . 296109/277 (39%)5e−54retinaldehyde-39 . . . 313161/277 (57%)binding protein(CRALBP)—Bostaurus (Bovine),316 aa.

[0447] PFam analysis predicts that the NOV25a protein contains the domains shown in the Table 25F.

124TABLE 25FDomain Analysis of NOV25aPfamNOV25aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValueCRAL_TRIO124 . . . 274 53/154 (34%)4.5e−47124/154 (81%)

Example 26

[0448] The NOV26 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 26A.

125TABLE 26ANOV26 Sequence AnalysisSEQ ID NO:612427 bpNOV26a,TGGCGCCCGCCGCCGCCCGGAGCCCCGCAATATGCCGCCGCGGCCCTCTGGCTCTAGGCG116903-01DNA SequenceCCATGGCGAGGCTCTGCCGGCGTGTCCCCTGCACCCTGCTTCTCGGCCTGGCCGTGGTGCTGCTGAAAGCGCGGCTGGTCCCCGCGGCCGCCAGAGCGGAACTCAGCCGCTCCGACCTCAGCCTCATCCAACAGCAGCAGCAGCAGCAGCAACAACAACAACAACAGCAAAAGCAGCTGGAGGAGGCTGAGGAGGAGAGGACAGAGGTGCCTGGGGCAACCTCCACCTTGACGGTTCCAGTGTCTGTATTTATGTTGAAAGTCCAGGTGAATGACATCATCAGTCGTCAGTACCTGAGCCAAGCAGTTGTAGAAGTGTTTGTAAACTACACGAAGACAAATTCCACAGTAACTAAAAGCAATGGAGCAGTGCTGATAAAAGTACCCTACAAATTAGGACTTAGTTTAACTATTATTGCTTACAAAGATGGCTACGTGTTGACCCCTCTGCCTTGGAAAACCAGAAGAATGCCAATATATTCATCAGTTACACTTTCACTGTTCCCGCAAAGCCAAGCAAATATATGGCTATTTGAAGACACTGTTTTAATTACTGGAAAATTAGCTGATGCCAAGTCTCAACCAAGTGTTCAGTTTTCAAAAGCCTTAATTAAACTTCCTGACAACCATCATATTAGCAACGTTACTGGCTATCTTACAGTTCTACAACAGTTTTTGAAAGTGGACAATTTTCTGCATACAACTGGAATTACTCTCAATAAACCAGGTTTTGAAAACATTGAATTGACTCCTCTTGCTGCAATATGTGTGAAAATATATTCTGGAGGAAAAGAACTAAAGGTCAATGGCTCTATTCAAGTTTCTCTTCCTCTTCTACGTCTGAATGATATAAGTGCAGGGGATCGCATACCTGCTTGGACATTTGATATGAACACAGAAATCAGGGGAACACTTACTTACACTTACCAGCTTGTAATAAAGGATACAGATAAAGAGCAGATGAAGAGGGACAAGTGTGGTACTCCACAGAAAAGAGAAAGAAATATCACTAAACTTGAGGTCCTCAAGAGAGACCAGACAACTTCAACAACACACATAAATCATATCAGTACAGTTAAAGTTGCATTAAAAGCTGAGGACAAGTCGCAGTTATTCAATGCCAAAAACTCCTCATATAGTCCTCAGAAAAAGGAACCATCAAAGGCAGAAACAGAAGAAAGAGTTTCCATGGTAAAAACTCGGGACGATTTTAAAATCTACAATGAAGATGTTTCATTTCTATCAGTCAATCAAAATAATTACTCAAGAAACCCAACACAGTCTTTGGAGCCCAATGTAGGGTCCAAACAACCTAAACATATTAACAACAATCTATCTTCATCTCTAGGTGATGCTCAAGATGAAAAGAGGTATCTCACAGGTAATGAGGAGGCGTATGGGCGTTCCCATATTCCTGAACAGCTTATGCATATTTACAGCCAACCCATTGCCATCCTTCAAACATCTGACCTTTTCTCCACACCGGAACAATTACATACTGCTAAGTCAGCTACTTTGCCAAGAAAGGGACAGTTAGTCTATGGCCAATTGATGGAACCAGTAAATCGAGAGAACTTTACGCAGACCTTGCCCAAAATGCCAATTCATTCTCATGCACAGCCCCCAGATGCCAGGGAAGAGGATATCATACTTGAAGGTCAACAGAGCCTGCCATCCCAGGCTTCAGATTGGAGCCGATACTCAAGCAGCTTACTGGAATCCGTCTCTGTTCCTGGAACACTAAATGAGGCTGTTGTAATGACTCCATTTTCATCGGAACTTCAAGGAATTTCAGAACAGACCCTCCTGGAGCTGTCCAAAGGAAAGCCCTCCCCGCATCCCAGAGCCTGGTTTGTGTCTCTTGATGGAAAGCCAGTTGCACAAGTGAGGCACTCCTTTATAGACCTGAAAAAGGGCAAGAGAACCCAGAGCAATGACACCAGTCTGGACTCTGGGGTGGACATGAATGAGCTTCACTCAAGTAGAAAGCTCGAGAGGGAGAAAACATTCATCAAAAGCATGCATCAGCCCAAGATCCTTTACTTAGAAGATTTAGACCTAAGCAGCAGTGAGAGTGGAACCACCGTCTGTTCCCCTGAGGACCCAGCTTTAAGGCACATCCTAGATGGAGGGAGTGGAGTGATCATGGAGCACCCTGGAGAAGAGTCGCCAGGAAGGAAAAGCACTGTTGAAGATTTTGAAGCTAATACATCCCCCACTAAAAGAAGGGGCAGACCACCACTAGCCAAAAGAGATAGCAAGACTAACATCTGGAAGAAGCGAGAGGAACGCCCACTGATTCCCATAAATTAACTCCAATGGGGATTGTGTGTCTGCTGTCTCGTGCTGTTTATTCTTGCTTCTTGTTGTORF Start: ATG at 61ORF Stop: TAA at 2368SEQ ID NO:62769 aaMW at 86199.1DaNOV26a,MARLCRRVPCTLLLGLAVVLLKARLVPAAARAELSRSDLSLIQQQQQQQQQQQQQQKQCG116903-01Protein SequenceLEEAEEERTEVPGATSTLTVPVSVFMLKVQVNDIISRQYLSQAVVEVFVNYTKTNSTVTKSNGAVLIKVPYKLGLSLTIIAYKDGYVLTPLPWKTRRMPIYSSVTLSLFPQSQANIWLFEDTVLITGKLADAKSQPSVQFSKALIKLPDNHHISNVTGYLTVLQQFLKVDNFLHTTGITLNKPGFENIELTPLAAICVKIYSGGKELKVNGSIQVSLPLLRLNDISAGDRIPAWTFDMNTEIRGTLTYTYQLVIKDTDKEQMKRDKCGTPQKRERNITKLEVLKRDQTTSTTHINHISTVKVALKAEDKSQLFNAKNSSYSPQKKEPSKAETEERVSMVKTRDDFKIYNEDVSFLSVNQNNYSRNPTQSLEPNVGSKQPKHINNNLSSSLGDAQDEKRYLTGNEEAYGRSHIPEQLMHIYSQPIAILQTSDLFSTPEQLHTAKSATLPRKGQLVYGQLMEPVNRENFTQTLPKMPIHSHAQPPDAREEDIILEGQQSLPSQASDWSRYSSSLLESVSVPGTLNEAVVMTPFSSELQGISEQTLLELSKGKPSPHPRAWFVSLDGKPVAQVRHSFIDLKKGKRTQSNDTSLDSGVDMNELHSSRKLEREKTFIKSMHQPKILYLEDLDLSSSESGTTVCSPEDPALRHILDGGSGVIMEHPGEESPGRKSTVEDFEANTSPTKRRGRPPLAKRDSKTNIWKKREERPLIPIN

[0449] Further analysis of the NOV26a protein yielded the following properties shown in Table 26B.

126TABLE 26BProtein Sequence Properties NOV26aPSort0.7953 probability located in outside; 0.1900 probabilityanalysis:located in lysosome (lumen); 0.1000 probability located inendoplasmic reticulum (membrane); 0.1000 probabilitylocated in endoplasmic reticulum (lumen)SignalPCleavage site between residues 29 and 30analysis:

[0450] A search of the NOV26a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 26C.

127TABLE 26CGeneseq Results for NOV26aNOV26aProtein/Organism/Residues/Identities/Geneseq Length [Patent #,MatchSimilarities forExpectIdentifierDate]Residuesthe Matched RegionValueAAG73464Human gene 7-encoded secreted322 . . . 767440/447 (98%)0.0protein fragment, SEQ ID NO: 239- 12 . . . 458441/447 (98%)Homo sapiens, 476 aa.[WO200134628-A1, 17 May 2001]AAG73462Human gene 7-encoded secreted396 . . . 761366/366 (100%)0.0protein fragment, SEQ ID NO: 237- 1 . . . 366366/366 (100%)Homo sapiens, 370 aa.[WO200134628-A1, 17 May 2001]AAG73463Human gene 7-encoded secreted396 . . . 767366/373 (98%)0.0protein fragment, SEQ ID NO: 238- 1 . . . 373367/373 (98%)Homo sapiens, 391 aa.[WO200134628-A1, 17 May 2001]AAG78197Human octamer-binding protein 28-517 . . . 769252/253 (99%) e−145Homo sapiens, 253 aa. 1 . . . 253253/253 (99%)[WO200173007-A1, 4 Oct. 2001]AAB94357Human protein sequence SEQ ID441 . . . 769131/407 (32%)6e−42NO: 14881-Homo sapiens, 419 aa. 19 . . . 417194/407 (47%)[EP1074617-A2, 7 Feb. 2001]

[0451] In a BLAST search of public sequence datbases, the NOV26a protein was found to have homology to the proteins shown in the BLASTP data in Table 26D.

128TABLE 26DPublic BLASTP Results for NOV26aNOV26aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ8TF55KIAA1946148 . . . 769600/679 (88%)0.0protein—Homo 1 . . . 679604/679 (88%)sapiens (Human),679 aa(fragment).Q8WYR8NPD019—Homo 1 . . . 235235/237 (99%) e−126sapiens (Human), 1 . . . 237235/237 (99%)241 aa.AAH30327Hypothetical 35.9498 . . . 769113/302 (37%)2e−41 kDa protein— 32 . . . 326160/302 (52%)Mus musculus(Mouse), 328 aa(fragment).Q9Y438Hypothetical 97.8498 . . . 769118/344 (34%)5e−40 kDa protein—549 . . . 890172/344 (49%)Homo sapiens(Human), 892 aa(fragment).Q8T1J6Hypothetical43 . . . 79 21/37 (56%)0.008174.9 kDa303 . . . 339 28/37 (74%)protein—Dietyosteliumdiscoideum(Slime mold),1518 aa.

Example 27

[0452] The NOV27 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 27A.

129TABLE 27ANOV27 Sequence AnalysisSEQ ID NO:63752 bpNOV27a,GTGCTGACACCTGGCCTATGCAGGGTGGCGGGTATGATCTCAACCTCTTCGCCAGCCCCG118634-01DNA SequenceTCCTGACAGCAACTTCGTGTGCTCCGTCTGCCATGGGGTTCTCAAGAGGCCAGCAAGGTTGCCATGCAGCCACATCTTCTGCAAAAAGTGCATCCAAAAGACCTGTCCGTGCTGTAGGAAAGAGGTGAAAAGGAAAAAGGTTGTCCACATGAATAAACTCCGGAAAACCATTGGCCGCCTGGAAGTCAAGTGCAAGAACGCCGACGCTGGCTGCATAGTGACATGCCCCCTGGCCCATCGCAAGGGGCACCAGGACTCATGCCCCTTTGAGCTAACGGCCTGCCCCAACGAGGGCTGCACCTCGCAGGTGCCGCGTGGGACCCTGGCAGAGCACCGGCAGCATTGCCAGCAAGGGTCCCAGCAGCGCTGCCCCCTGGGCTGCGGGGCCACCCTGGACCCGGCCGAGCGTGCTCGCCACAACTGCTACCGGGAGCTGCACAACGCCTGGAGCGTGCGCCAGGAGCGCCGTCGGCCCCTGCTGCTGTCCCTCCTGCGGCGTGTGCGCTGGCTGGACCAAGCCACCAGTGTCGTTCGTAGAGAGCTGGCGGAGCTCAGCAACTTCCTGGAGGAAGACACCGCTCTGCTGGAGGGTGCCCCACAGGAGGAGGCCGAGGCTGCCCCAGAAGGCAACGTTGGGGCTGAGGTGGTGGGGGAGCCCAGGGCCAACATACCTTGTAAATAGGTAAATAAAAGCORF Start: ATG at 18ORF Stop: TAG at 738SEQ ID NO:64240 aaMW at 26743.5DaNOV27a,MQGGGYDLNLFASPPDSNFVCSVCHGVLKRPARLPCSHIFCKKCIQKTCPCCRKEVKRCG118634-01Protein SequenceKKVVHMNKLRKTIGRLEVKCKNADAGCIVTCPLAHRKGHQDSCPFELTACPNEGCTSQVPRGTLAEHRQHCQQGSQQRCPLGCGATLDPAERARHNCYRELHNAWSVRQERRRPLLLSLLRRVRWLDQATSVVRRELAELSNFLEEDTALLEGAPQEEAEAAPEGNVGAEVVGEPRANIPCKSEQ ID NO:65762 bpNOV27b,TAGACGCAGATCATGGGTGGCGGGTATGATCTCAACCTCTTCGCCAGCCCTCCTGACACC118634-02DNA SequenceGCAACTTCGTGTGCTCCGTCTGCCATGGGGTTCTCAAGAGGCCAGCAAGGTTGCCATGCAGCCACATCTTCTGCAAAAAGTGCATCCTCCGGTGGCTAGCCAGACAAAAGACCTGTCCGTGCTGTAGGAAAGAGGTGAAAAGGAAAAAGATTGTCCACATGAATAAACTCCGGAAAACCATTGGCCGCCTGGAAGTCAAGTGCAAGAACGCCGACGCTGGCTGCATAGTGACATGCCCCCTGGCCCATCGCAAGGGGCACCAGGACTCATGCCCCTTTGAGCTAACGGCCTGCCCCAACGAGGGCTGCACCTCGCAGGTGCCGCGTGGGACCCTGGCAGAGCACCGGCAGCATTGCCAGCAAGGGTCCCAGCAGCGCTGCCCCCTGGGCTGCGGGGCCACCCTGGACCCGGCCGAGCGTGCTCGCCACAACTGCTACCGGGAGCTGCACAACGCCTGGAGCGTGCGCCAGGAGCGCCGTCGGCCCCTGCTGCTGTCCCTCCTGCGGCGTGTGCGCTGGCTGGACCAAGCCACCAGTGTCGTTCGTAGAGAGCTGGCGGAGCTCAGCAACTTCCTGGAGGAAGACACCGCTCTGCTGGAGGGTGCCCCACAGGAGGAGGCCGAGGCTGCCCCAGAAGGCAACGTTGGGGCTGAGGTGGTGGGGGAGCCCAGGGCCAACATACCTTGTAAATAGGTAAATAAAAGCORF Start: ATG at 13ORF Stop: TAG at 748SEQ ID NO:66245 aaMW at 27425.4DaNOV27b,MGGGYDLNLFASPPDSNFVCSVCHGVLKRPARLPCSHIFCKKCILRWLARQKTCPCCRCG118634-02Protein SequenceKEVKRKKIVHMNKLRKTIGRLEVKCKNADAGCIVTCPLAHRKGHQDSCPFELTACPNEGCTSQVPRGTLAEHRQHCQQGSQQRCPLGCGATLDPAERARHNCYRELHNAWSVRQERRRPLLLSLLRRVRWLDQATSVVRRELAELSNFLEEDTALLEGAPQEEAEAAPEGNVGAEVVGEPRANIPCK

[0453] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 27B.

130TABLE 27BComparison of NOV27a against NOV27b.Identities/NOV27a Residues/Similarities forProtein SequenceMatch Residuesthe Matched RegionNOV27b3 . . . 240204/244 (83%)2 . . . 245205/244 (83%)

[0454] Further analysis of the NOV27a protein yielded the following properties shown in Table 27C.

131TABLE 27CProtein Sequence Properties NOV27aPSort0.9800 probability located in nucleus; 0.3000 probabilityanalysis:located in microbody (peroxisome); 0.1000 probability locatedin mitochondrial matrix space; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0455] A search of the NOV27a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 27D.

132TABLE 27DGeneseq Results for NOV27aResidues/Similarities forMatchthe MatchedIdentifier#, Date]ResiduesRegionValueAAM25720Human protein sequence SEQ ID 5 . . . 16154/169 (31%)3e−18NO: 1235-Homo sapiens, 1098 aa.34 . . . 20279/169 (45%)[WO200153455-A2, 26 Jul. 2001]ABB11704Human semaphorin domain- 5 . . . 16154/169 (31%)3e−18associated protein homologue, SEQ34 . . . 20279/169 (45%)ID NO: 2074-Homo sapiens, 1098aa. [WO200157188-A2, 9 Aug. 2001]ABB72326Rat protein isolated from skin cells16 . . . 16151/158 (32%)2e−16SEQ ID NO: 650-Rattus sp, 290 aa. 3 . . . 16074/158 (46%)[WO200190357-A1, 29 Nov. 2001]AAW29257Murine TRAF5, a novel TNF11 . . . 13739/135 (28%)2e−13receptor associated factor family35 . . . 16862/135 (45%)protein-Murine sp, 558 aa.[WO9731110-A1, 28 Aug. 1997]AAW27609Murine TRAF5-Mus sp, 558 aa.11 . . . 13739/135 (28%)2e−13[WO9738099-A1, 16 Oct. 1997]35 . . . 16862/135 (45%)

[0456] In a BLAST search of public sequence datbases, the NOV27a protein was found to have homology to the proteins shown in the BLASTP data in Table 27E.

133TABLE 27EPublic BLASTP Results for NOV27aNOV27aProteinResidues/Identities/AccessionMatchSimilarities forExpectNumberProtein/Organism/LengthResiduesthe Matched PortionValueAAH29501Similar to RIKEN cDNA64 . . . 240177/177 (100%) e−1031700010O16-Homo sapiens 1 . . . 177177/177 (100%)(Human), 177 aa.Q9CQ291700010O16Rik protein-Mus 4 . . . 225158/228 (69%)6e−91musculus (Mouse), 239 aa. 3 . . . 230175/228 (76%)Q9QY55Semaphorin cytoplasmic domain- 5 . . . 161 54/169 (31%)5e−18associated protein 3A-Mus 2 . . . 170 80/169 (46%)musculus (Mouse), 1063 aa.Q96CC2Similar to semaF cytoplasmic 5 . . . 161 54/169 (31%)6e−18domain associated protein 3- 2 . . . 170 79/169 (45%)Homo sapiens (Human), 360 aa.Q9UPQ7KIAA1095 protein-Homo 5 . . . 161 54/169 (31%)6e−18sapiens (Human), 1098 aa34 . . . 202 79/169 (45%)fragment).

[0457] PFam analysis predicts that the NOV27a protein contains the domains shown in the Table 27F.

134TABLE 27FDomain Analysis of NOV27aIdentities/PfamSimilarities forExpectDomainNOV27a Match Regionthe Matched RegionValuezf-C3HC421 . . . 5216/54 (30%)0.000624/54 (44%)zf-TRAF97 . . . 15117/69 (25%)0.02636/69 (52%)

Example 28

[0458] The NOV28 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 28A.

135TABLE 28ANOV28 Sequence AnalysisSEQ ID NO:671908 bpNOV28a,TCCTCCCGTAGGAACCGGCGGACTCGGTTGGCGTTGTGGGGCAGGGGGTGGTGGAGCACG119215-01DNA SequenceAGATGGCGGCTCATCTGTCCTACGGCCGAGTGAACCTAAACGTGTTGCGCGAGGCGGTGCGTCGCGAGCTGCGCGAGTTCCTGGACAAGTGCGCAGGAAGCAAGGCAATAGTTTGGGATGAATACCTAACTGGACCCTTTGGCCTGATTGCACAGTATTCACTATTGAAGGAACATGAAGTGGAAAAAATGTTCACACTTAAAGGAAATCGTTTGCCGGCAGCTGATGTGAAGAATATAATTTTTTTTGTCAGACCCAGGCTAGAGTTGATGGATATAATCGCTGAAAACGTGCTCAGTGAAGATAGACGAGGCCCAACGAGAGATTTTCATATTCTGTTTGTGCCACGCCGTAGCCTGTTGTGCGAACAGCGGTTGAAGGATCTGGGTGTCTTGGGATCCTTTATTCACAGGGAGGAGTACAGCTTAGATCTCATTCCATTCGATGGGGATCTCTTATCCATGGAATCAGAGGGTGCATTCAAAGAGTGCTACCTGGAGGGTGACCAGACGAGCCTGTACCACGCAGCCAAGGGGCTGATGACCCTGCAAGCTCTGTATGGAACGATCCCCCAGATCTTTGGGAAAGGAGAATGCGCTCGGCAAGTGGCCAATATGATGATCAGGATGAAGAGAGAGTTTACAGGAAGCCAGAATTCAATATTTCCTGTTTTTGATAATCTCTTGTTGCTTGATCGGAATGTGGATTTATTAACACCTCTTGCCACTCAGCTGACATATGAAGGACTCATTGATGAAATTTATGGCATTCAGAACAGTTATGTGAAATTACCTCCAGAGAAATTTGCACCTAAGAAACAGGGCGATGGTGGTAAGGACCTCCCCACGGAAGCAAAGAAGCTGCAGCTGAATTCTGCAGAGGAGCTCTATGCTGAGATCCGAGATAAGAACTTCAACGCAGTTGGCTCTGTGCTCAGCAAGAAAGCAAAGATCATCTCTGCAGCATTCGAGGAAAGACACAATGCTAAGACCGTGGGGGAGATCAAGCAGTTTGTTTCCCAGTTGCCCCACATGCAGGCAGCAAGGGGCTCGCTTGCAAACCATACCTCAATTGCAGAATTGATCAAAGATGTCACTACTTCTGAAGACTTTTTTGATAAATTAACCGTGGAACAGGAGTTTATGTCTGGAATAGACACTGATAAGGTCAACAATTACATTGAGGATTGTATCGCCCAAAAGCACTCGTTGATCAAGGTGTTAAGACTAGTTTGCCTCCAATCCGTGTGTAATAGTGGGCTCAAACAAAAAGTTTTGGATTATTACAAAAGAGAGATTCTCCAGACATACGGCTATGAGCACATATTGACCTTACACAACCTGGAGAAGGCCGGCCTGCTGAAACCGCAGACGGGGGGCAGAAACAATTACCCAACTATACGGAAAACATTACGCCTCTGGATGGATGATGTTAATGAGCAAAACCCCACGGACATATCGTATGTGTACAGTGGGTATGCCCCGCTCAGTGTGCGGCTGGCCCAGCTGCTTTCCCGGCCTGGCTGGCGGAGCATCGAGGAGGTCCTCCGCATCCTCCCAGGGCCCCACTTTGAGGAGCGGCAGCCACTGCCCACAGGACTGCAGAAGAAACGTCAACCGGGAGAAAACCGAGTGACTCTGATATTTTTCCTTCGGCGCGTAACCTTCGCTGAAATTGCTGCCCTGCGATTTCTCTCCCAGTTGGAAGATGGAGGTACAGAATATGTCATTGCCACCACTAAACTAATGAATGGAACCAGTTGGATAGAGGCTCTGATGGAAAAACCTTTCTAGGATGTTCAGAGGAGACTTAACAAGTGTACTGCAGAATAAACTACCTCTTTGAAGAAAORF Start: ATG at 61ORF Stop: TAG at 1849SEQ ID NO:68596 aaMW at 67610.1DaNOV28a,MAAHLSYGRVNLNVLREAVRRELREFLDKCAGSKAIVWDEYLTGPFGLIAQYSLLKEHCG119215-01Protein SequenceEVEKMFTLKGNRLPAADVKNIIFFVRPRLELMDIIAENVLSEDRRGPTRDFHILFVPRRSLLCEQRLKDLGVLGSFIHREEYSLDLIPFDGDLLSMESEGAFKECYLEGDQTSLYHAAKGLMTLQALYGTIPQIFGKGECARQVANMMIRMKREFTGSQNSIFPVFDNLLLLDRNVDLLTPLATQLTYEGLIDEIYGIQNSYVKLPPEKFAPKKQGDGGKDLPTEAKKLQLNSAEELYAEIRDKNFNAVGSVLSKKAKIISAAFEERHNAKTVGEIKQFVSQLPHMQAARGSLANHTSIAELIKDVTTSEDFFDKLTVEQEFMSGIDTDKVNNYIEDCIAQKHSLIKVLRLVCLQSVCNSGLKQKVLDYYKREILQTYGYEHILTLHNLEKAGLLKPQTGGRNNYPTIRKTLRLWMDDVNEQNPTDISYVYSGYAPLSVRLAQLLSRPGWRSIEEVLRILPGPHFEERQPLPTGLQKKRQPGENRVTLIFFLGGVTFAEIAALRFLSQLEDGGTEYVIATTKLMNGTSWIEALMEKPF

[0459] Further analysis of the NOV28a protein yielded the following properties shown in Table 28B.

136TABLE 28BProtein Sequence Properties NOV28aPSort0.4589 probability located in mitochondrial inneranalysis:membrane; 0.4400 probability located in plasma membrane;0.3000 probability located in microbody (peroxisome);0.2232 probability located in mitochondrial matrix spaceSignalPNo Known Signal Sequence Predictedanalysis:

[0460] A search of the NOV28a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 28C.

137TABLE 28CGeneseq Results for NOV28aNOV28aIdentities/Protein/Organism/Residues/Similarities forGeneseq Length [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAM41622Human polypeptide SEQ ID NO 1 . . . 596596/596 (100%)0.06553-Homo sapiens, 601 aa. 6 . . . 601596/596 (100%)[WO200153312-A1, 26 Jul. 2001]AAM39836Human polypeptide SEQ ID NO 1 . . . 596596/596 (100%)0.02981-Homo sapiens, 596 aa. 1 . . . 596596/596 (100%)[WO200153312-A1, 26 Jul. 2001]AAU87157Novel central nervous system 1 . . . 362362/362 (100%)0.0protein #67-Homo sapiens, 39018 . . . 379362/362 (100%)aa. [WO200155318-A2,2 Aug. 2001]ABB71264Drosophila melanogaster 9 . . . 592265/607 (43%)e−127polypeptide SEQ ID NO 40584-11 . . . 615372/607 (60%)Drosophila melanogaster, 617 aa.[WO200171042-A2, 27 Sep. 2001]AAB41054Human ORFX ORF8181 . . . 200200/200 (100%)e−112polypeptide sequence SEQ ID1 . . . 200200/200 (100%)NO: 1636-Homo sapiens, 243 aa.[WO200058473-A2, 5-Oct. 2000]

[0461] In a BLAST search of public sequence datbases, the NOV28a protein was found to have homology to the proteins shown in the BLASTP data in Table 28D.

138TABLE 28DPublic BLASTP Results for NOV28aNOV28aProteinResidues/Identities/AccessionMatchSimilarities forExpectNumberProtein/Organism/LengthResiduesthe Matched PortionValueQ96AX1Similar to RIKEN cDNA 1 . . . 596596/596 (100%)0.03830421M04 gene-Homo 1 . . . 596596/596 (100%)sapiens (Human), 596 aa.Q9D2N93830421M04Rik protein-Mus 1 . . . 596582/598 (97%)0.0musculus (Mouse), 598 aa. 1 . . . 598591/598 (98%)Q63615Vacuolar protein sorting homolog 1 . . . 596578/597 (96%)0.0r-vps33a-Rattus norvegicus 1 . . . 597591/597 (98%)(Rat), 597 aa.JC5720vacuolar protein sorting protein 1 . . . 596560/601 (93%)0.033a-rat, 601 aa. 1 . . . 601578/601 (95%)Q9H5Q0CDNA: FLJ23187 fis, clone154 . . . 596443/443 (100%)0.0LNG11989-Homo sapiens 1 . . . 443443/443 (100%)(Human), 443 aa.

[0462] PFam analysis predicts that the NOV28a protein contains the domains shown in the Table 28E.

139TABLE 28EDomain Analysis of NOV28aIdentities/PfamSimilarities forExpectDomainNOV28a Match Regionthe Matched RegionValueSec132 . . . 595190/684 (28%)5.6e−225532/684 (78%)

Example 29

[0463] The NOV29 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown it Table 29A.

140TABLE 29ANOV29 Sequence AnalysisSEQ ID NO:69571 bpNOV29a,ACCTCGGGCGGCGGGTCACGTCGGCCGGGCATGGCTGCATGGAGCCCGGCCGCGGCAGCG121501-01DNA SequenceCGCCTCTCCTCCGCGGGATCCGCGGGCTTCCACTTCACCATCGGATGTTTGCCACTCAGACTGAGGGGGAGCTCAGAGTGACCCAAATTCTCAAAGAAAAGTTTCCACGAGCTACAGCTATAAAAGTCACTGACATTTCAGGAGGTTGTGGGGCGATGTATGAAATTAAAATTGAATCAGAAGAATTTAAGGAGAAGAGAACTGTCCAGCAGCACCAGATGGTTAATCAGGCACTAAAAGAAGAAATCAAAGAGATGCATGGATTGCGGATATTTACCTCTGTCCCCAAACGCTGACCACGCCCTGGCTGCATAGATGCTGCTGCTTAAGACCTTGGATGAACTTCACTGACATCATTCTTCCCTAAGCAGTCACCAAAAAATTTATATATTTTGCTCATATACATTTCCATATTATAATTATAGAAGATGTATAATCTATTTAGATGTTAATTAAAGGAAACAAACAACTGAAGTTTTGAAGGGTCAAAAAAATAAAAAAATAAAAAAATGTORF Start: ATG at 31ORF Stop: TGA at 352SEQ ID NO:70107 aaMW at 12114.1DaNOV29a,MAAWSPAAAAPLLRGIRGLPLHHRMFATQTEGELRVTQILKEKFPRATAIKVTDISGGCG121501-01Protein SequenceCGAMYEIKIESEEFKEKRTVQQHQMVNQALKEEIKEMHGLRIFTSVPKRSEQ ID NO:71571 bpNOV29b,ACCTCGGGCGGCGGGTCACGTCGGCCGGGCATGGCTGCATGGAGCCCGGCCGCGGCAGCG121501-02DNA SequenceCGCCTCTCCTCCGCGGGATCCGCGGGCTTCCACTTCACCATCGGATGTTTGCCACTCAGACTGAGGGGGAGCTCAGAGTGACCCAAATTCTCAAAGAAAAGTTTCCACGAGCTACAGCTATAAAAGTCACTGACATTTCAGGAGGTTGTGGGGCGATGTATGAAATTAAAATTGAATCAGAAGAATTTAAGGAGAAGAGAACTGTCCAGCAGCACCAGATGGTTAATCAGGCACTAAAAGAAGAAATCAAAGAGATGCATGGATTGCGGATATTTACCTCTGTCCCCAAACGCTGACCACGCCCTGGCTGCATAGATGCTGCTGCTTAAGACCTTGGATGAACTTCACTGACATCATTCTTCCCTAAGCAGTCACCAAAAAATTTATATATTTTGCTCATATACATAACAACTGAAGTTTTGAAGGGTCAAAAAAATAAAAAAATAAAAAAATGTORF Start: ATG at 31ORF Stop: TGA at 352SEQ ID NO:72107 aaMW at 12114.1DaNOV29b,MAAWSPAAAAPLLRGIRGLPLHHRMFATQTEGELRVTQILKEKFPRATAIKVTDISGGCG121501-02Protein SequenceCGAMYEIKIESEEFKEKRTVQQHQMVNQALKEEIKEMHGLRIFTSVPKR

[0464] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 29B.

141TABLE 29BComparison of NOV29a against NOV29b.Identities/ProteinNOV29a Residues/Similarities forSequenceMatch Residuesthe Matched RegionNOV29b12 . . . 10784/96 (87%)12 . . . 10784/96 (87%)

[0465] Further analysis of the NOV29a protein yielded the following properties shown in Table 29C.

142TABLE 29CProtein Sequence Properties NOV29aPSort0.4500 probability located in cytoplasm; 0.4299 probabilityanalysis:located in mitochondrial matrix space; 0.1520 probabilitylocated in lysosome (lumen); 0.1092 probability located inmitochondrial inner membraneanalysis:Cleavage site between residues 19 and 20

[0466] A search of the NOV29a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 29D.

143TABLE 29DGeneseq Results for NOV29aNOV29aIdentities/Protein/Organism/Residues/Similarities forGeneseqLength [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAU16281Human novel secreted protein, Seq 1 . . . 107107/107 (100%)2e−56ID 1234-Homo sapiens, 136 aa.30 . . . 136107/107 (100%)[WO200155322-A2, 2 Aug. 2001]ABB10412Human cDNA SEQ ID NO: 720- 1 . . . 107107/107 (100%)2e−56Homo sapiens, 136 aa.30 . . . 136107/107 (100%)[WO200154474-A2, 2 Aug. 2001]ABB10168Human cDNA SEQ ID NO: 476- 1 . . . 107107/107 (100%)2e−56Homo sapiens, 145 aa.39 . . . 145107/107 (100%)[WO200154474-A2, 2 Aug. 2001]AAU31133Novel human secreted protein 1 . . . 107101/108 (93%)3e−51#1624-Homo sapiens, 122 aa.15 . . . 122101/108 (93%)[WO200179449-A2, 25 Oct. 2001]AAG03963Human secreted protein, SEQ ID 1 . . . 57 38/57 (66%)8e−12NO: 8044-Homo sapiens, 101 aa. 1 . . . 57 38/57 (66%)[EP1033401-A2, 6 Sep. 2000]

[0467] In a BLAST search of public sequence datbases, the NOV29a protein was found to have homology to the proteins shown in the BLASTP data in Table 29E.

144TABLE 29EPublic BLASTP Results for NOV29aNOV29aIdentities/ProteinResidues/Similarities forAccessionMatchthe MatchedExpectNumberProtein/Organism/LengthResiduesPortionValueAAH28282Hypothetical 11.4 kDa protein- 2 . . . 5756/56 (100%)3e−25Homo sapiens (Human), 100 aa 1 . . . 5656/56 (100%)(fragment).Q9USK1Hypothetical BolA domain-30 . . . 10437/75 (49%)8e−15containing protein-30 . . . 10354/75 (71%)Schizosaccharomyces pombe(Fission yeast), 116 aa.Q9NEY7Y105E8E.m protein (Y105E8A.p30 . . . 10231/73 (42%)5e−12protein)-Caenorhabditis elegans,31 . . . 10350/73 (68%)106 aa.Q9FIC3Genomic DNA, chromosome 5, P150 . . . 10027/51 (52%)2e−10clone: MYH9-Arabidopsis thaliana20 . . . 7043/51 (83%)(Mouse-ear cress), 93 aa.P39724Hypothetical 13.4 kDa protein in14 . . . 10231/89 (34%)6e−09ACS1-GCV3 intergenic region-20 . . . 10751/89 (56%)Saccharomyces cerevisiae (Baker'syeast), 118 aa.

[0468] PFam analysis predicts that the NOV29a protein contains the domains shown in the Table 29F.

145TABLE 29FDomain Analysis of NOV29aIdentities/PfamSimilarities forExpectDomainNOV29a Match Regionthe Matched RegionValueBo1A30 . . . 10724/87 (28%)2.9e−1062/87 (71%)

Example 30

[0469] The NOV30 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 30A.

146TABLE 30ANOV30 Sequence AnalysisSEQ ID NO:73593 bpNOV30a,AAAAAAACAGGAAAAAAACTCAACATGGAAAATGTCCCCAAGGAAAACAAAGTTGTGGCG121894-01DNA SequenceAGAAGGCCCCAGTGCAGAATGAAGCCCCCGCTTTAGGAGGTGGTGAATACCAGGAGCCTGGAGGAAATGTTAAAGGGGTTTGGGCTCCACCTGCCCCGGGTTTTGGAGAGGATGTGCCCAATAGGCTTGTCGATAACATTGATATGATAGATGGAGATGGAGATGATATGGAACGGTTCATGGAGGAGATGAGAGAGCTAAGGAGGAAAATTAGGGAACTTCAGTTGAGGTACAGTCTGCGCATTCTTATAGGGGACCCTCCTCACCATGATCATCATGATGAGTTTTGCCTTATGCCTTGAATCTTGAGGTTAATAATCATAAAATCCCTGCTTTCTAAATTCGCATTTTTCCTGGTGTACCTTTAATGTGAACCTTTTGGCATTCTTCTGCAATTTTCTGATTGGAGATTGCATTTTGACCTAGTCTGTAAGTTTTTCTGTCAGAAGAGGACTTTCATCAACTTTCATGGAAAGATGTTTATTGCATACTGTAAAGTTAATAAAGCAATTTAAAAGCAAAAAAAAAAAAAAAAORF Start: ATG at 25ORF Stop: TGA at 358SEQ ID NO:74111 aaMW at 12602.1DaNOV30a,MENVPKENKVVEKAPVQNEAPALGGGEYQEPGGNVKGVWAPPAPGFGEDVPNRLVDNICG121894-01Protein SequenceDMIDGDGDDMERFMEEMRELRRKIRELQLRYSLRILIGDPPHHDHHDEFCLMP

[0470] Further analysis of the NOV30a protein yielded the following properties shown in Table 30B.

147TABLE 30BProtein Sequence Properties NOV30aPSort0.6500 probability located in plasma membrane; 0.6500analysis:probability located in cytoplasm; 0.1000 probabilitylocated in mitochondrial matrix space; 0.1000probability located in lysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0471] A search of the NOV30a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 30C.

148TABLE 30CGeneseq Results for NOV30aNOV30aIdentities/Protein/Organism/Residues/Similarities forGeneseqLength [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAB59191Human NADE-Homo sapiens, 1111 . . . 11165/114 (57%)1e−26aa. [WO200075278-A2, 14 Dec.1 . . . 11181/114 (71%)2000]AAB58845Breast and ovarian cancer6 . . . 11163/109 (57%)2e−25associated antigen protein sequence2 . . . 10778/109 (70%)SEQ ID 553-Homo sapiens,107 aa. [WO200055173-A1,21 Sep. 2000]AAO11800Human polypeptide SEQ ID NO1 . . . 6649/66 (74%)4e−2425692-Homo sapiens, 72 aa.7 . . . 7255/66 (83%)[WO200164835-A2, 7 Sep. 2001]AAB59190Mouse NADE-Mus sp, 124 aa.1 . . . 11165/127 (51%)1e−23[WO200075278-A2, 14 Dec. 2000]1 . . . 12481/127 (63%)AAG00999Human secreted protein, SEQ ID1 . . . 10456/107 (52%)5e−20NO: 5080-Homo sapiens, 104 aa.1 . . . 10471/107 (66%)[EP1033401-A2, 6 Sep. 2000]

[0472] In a BLAST search of public sequence datbases, the NOV30a protein was found to have homology to the proteins shown in the BLASTP data in Table 30D.

149TABLE 30DPublic BLASTP Results for NOV30aNOV30aProteinResidues/Identities/AccessionMatchSimilarities forExpectNumberProtein/Organism/LengthResiduesthe Matched PortionValueQ00994p75NTR-associated cell death 1 . . . 11165/114 (57%)3e−26executor (Nerve growth factor 1 . . . 11181/114 (71%)receptor associated protein 1)(Ovarian granulosa cell 13.0 kDaprotein HGR74)-Homo sapiens(Human), 111 aa.Q9WTZ9Brain expressed X-linked protein 3 1 . . . 11164/127 (50%)1e−22(P75NTR-associated cell death 1 . . . 12480/127 (62%)EXECUTOR)-Mus musculus(Mouse), 124 aa.Q9D0S2Brain expressed X-linked 3-Mus 1 . . . 11164/127 (50%)1e−22musculus (Mouse), 147 aa. 1 . . . 12480/127 (62%)Q9CWN9Brain expressed X-linked 3-Mus 1 . . . 11163/127 (49%)5e−22musculus (Mouse), 124 aa. 1 . . . 12480/127 (62%)Q9D1N5Brain expressed X-linked 3-Mus15 . . . 11158/113 (51%)3e−20musculus (Mouse), 114 aa. 4 . . . 11470/113 (61%)

Example 31

[0473] The NOV31 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 31A.

150TABLE 31ANOV31 Sequence AnalysisSEQ ID NO:75641 bpNOV31a,TTCCTTCACTCGGCCATGCTCCCGCGGCCCCTGCGGCTGCTTTTGGACACGAGCCCCCCG121954-01DNA SequenceCCGGGGGAGTCGTACTGAGCAGCTTCCGAAGCCGGGACCCCGAAGAGGGTGGGGGCCCAGGTGGCCTGGTCGTGGGCGGGGGGCAGGAGGAAGAGGAGGAGGAAGAAGAAGAGGCCCCTGTGTCCGTCTGGGATGAGGAGGAGGATGGTGCCGTGTTTACCGTCACAAGCCGCCAATATCGACCTCTTGATCCCTTGGTCCCTATGCCTCCCCCACGTTCCTCCCGACGGCTCCGAGCTGGCACTCTGGAGGCCCTGGTCAGACACCTACTGGATACCCGGACATCAGGGACTGATGTGAGCTTCATGTCAGCCTTCCTGGCTACCCACCGGGCCTTCACCTCCACGCCTGCCTTGCTAGGGCTTATGGCTGACAGGCTGGAAGCCCTTGAATCTCATCCTGCCTCAGGAACTCCTCCGAGTGAGGGAGGAGGGGGCTCCTTTCCCAGGATCAAGGCCACAGGGAGGAAGATTGCACGGGCACTGTTCTGAGGAGGAAGCCCCGTTGGCTTACAGAAGTCATGGTGTTCATACCAGATGTCGGTACCCATCCTGAATGGTGGCAATTATATCACATTGAGACAORF Start: ATG at 16ORF Stop: TGA at 547SEQ ID NO: 76177 aaMW at 18930.0DaNOV31a,MLPRPLRLLLDTSPPGGVVLSSFRSRDPEEGGGPGGLVVGGGQEEEEEEEEEAPVSVWCG121954-01Protein SequenceDEEEDGAVFTVTSRQYRPLDPLVPMPPPRSSRRLRAGTLEALVRHLLDTRTSGTDVSFMSAFLATHRAFTSTPALLGLMADRLEALESHPASGTPPSEGGCGSFPRIKATGRKIARALF

[0474] Further analysis of the NOV31a protein yielded the following properties shown in Table 31B.

151TABLE 31BProtein Sequence Properties NOV31aPSort0.4500 probability located in cytoplasm; 01243analysis:probability located in microbody (peroxisome); 0.1000probability located in mitochondrial matrixspace; 0.1000 probability located in lysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0475] A search of the NOV31a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 31C.

152TABLE 31CGeneseq Results for NOV31aNOV31aIdentities/Protein/Organism/Residues/Similarities forGeneseqLength [Patent #,Matchthe MatchedExpectIdentifierDate]ResiduesRegionValueAAB54354Human pancreatic cancer antigen149 . . . 17729/29 (100%)2e−09protein sequence SEQ ID NO: 806-500 . . . 52829/29 (100%)Homo sapiens, 528 aa.WO200055320-A1, 21 Sep. 2000]AAW37494Human GDP dissociation149 . . . 17729/29 (100%)2e−09stimulating protein-Homo sapiens, 94 . . . 12229/29 (100%)122 aa. [EP796913-A2, 24Sep. 1997]AAM80136Human protein SEQ ID NO 3782- 90 . . . 16631/82 (37%)8e−06Homo sapiens, 883 aa. 78 . . . 15848/82 (57%)[WO200157190-A2, 9 Aug. 2001]AAM79152Human protein SEQ ID NO 1814- 90 . . . 16631/82 (37%)8e−06Homo sapiens, 919 aa.114 . . . 19448/82 (57%)[WO200157190-A2, 9 Aug. 2001]AAB23176Human RalGDS (hRalGDS) 90 . . . 16631/82 (37%)8e−06protein-Homo sapiens, 852 aa. 58 . . . 13848/82 (57%)[CN1257923-A, 28 Jun. 2000]

[0476] In a BLAST search of public sequence datbases, the NOV31a protein was found to have homology to the proteins shown in the BLASTP data in Table 31D.

153TABLE 31DPublic BLASTP Results for NOV31aIdentities/NOV31aSimilaritiesProteinResidues/for theAccessionProtein/MatchMatchedExpectNumberOrganism/LengthResiduesPortionValueO15211Ral guanine 1 . . . 148148/1481e−80nucleotide(100%)dissociation 1 . . . 148148/148stimulator-like 2(100%)(RalGDS-likefactor) (RAS-associated proteinRAB2L)—Homosapiens (Human),777 aa.Q61193Ral guanine 1 . . . 148129/1482e−70nucleotide (87%)dissociation 1 . . . 148135/148stimulator-like 2 (91%)(RalGDS-likefactor)—Musmusculus (Mouse),778 aa.Q96KK6CICF0811.4.2 15 . . . 148107/1462e−49(RAB2, member (73%)RAS oncogene 12 . . . 157109/146family-like, (74%)isoform 2)—Homosapiens (Human),268 aa (fragment).Q9DE48Ras-associated 56 . . . 14238/871e−09protein— (43%)Brachydanio rerio13 . . . 9755/87(Zebrafish) (Zebra (62%)danio), 359 aa(fragment).BAA36193GDS-related149 . . . 17729/294e−09protein—Homo(100%)sapiens (Human), 94 . . . 12229/29122 aa.(100%)

[0477] PFam analysis predicts that the NOV31a protein contains the domains shown in the Table 31E.

154TABLE 31EDomain Analysis of NOV31aPfamNOV31aIdentities/SimilaritiesExpectDomainMatch Regionfor the Matched RegionValueRasGEFN86 . . . 14320/66 (30%)8.6e−0639/66 (59%)

Example 32

[0478] The NOV32 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 32A.

155TABLE 32ANOV32 Sequence AnalysisSEQ ID NO: 771543 bpNOV32a,AATGGGATGCAGAGGAAGGAGAGGAGGATGAAGGAGCCAGGATGCGGGGCAGTGGGGACG122816-01DNA SequenceGGGGGTTGCTATCTGGGCACTGGGTGAGGGGAGAGCTTGTTCCCCCAAGGACGCCTGCCACCAGGTGTCCTTGCCACACCTTGTTCCCCAAGGACACCCACCAAACCTGTGCCCTGGTGCGGGGGATAGAACTGACCTTTCAGAGGCTGGAGGCCCGGGGCACAGGCAGCCAAGGCCGCATCCTTTTGGGAAGAACTGGAGTGAAGGAAGCCACTTCAGAGGACGTAGTGGGTCCAGCTGACTTAGGAGTGGGTCAGCGCCGGGTGGAGAGGAGGGAGGCTAGTTCCCTGGTGGGGTAGCCTGGCAACATTCCCATTCCACCGCACCTGGCCAGCTGCCATCTTGGCAGAGCCAGGGGGAGATGCACCAGGGAGTTTGGAGTCAGGAAGGCAGAGTTGTGTGGGCTGAAGTCTGCGGGAACCCCAGGGTGACACAGGCAAGGGGTAGAAGTCAGAGTGGGGACCAAACCATAGACTGGGGCCCTGGGTTCTGCAGAGGTGTGGATGGGGCAGGTGGCAGGTGCTCCAGTGGGGGCCCCAGGTGAGGCCCTGATGGCCCTCCTGGGGCAATAAAGACATCATGGGAAGGGGGCTTTGTGGTTTGCCTCTGCTCTCGTCGGGCGATCTGGCTTTAGCCTTCAGGAGGAGGTAAGCAGAGGAGATCAGTGCCTGTTTCTGACCCCAGGAGGGCCTTGTTGGGCTCCAACCTAGACCCTTCCGGCTTCAGGTCCCAAGAGAAGTCCCCCCCTAACTCTGACCCCCCTAACTGCGATCAGGGGTCTGCCATTGCCCGCTTTTCTCTGCCTGATCTGGGGACTCAGGAGAGGCCACGGCAGCCACAGCCTAGGGGTGGTTCAGTCCCTGGCCCACAGTCTGGTCAGTTGAGTCCTTCTGGGAACCGGGGCTATGAAAACTTTCGTCTTTGGGGACCGGTACCCATGAAGGAAAACTTTCCTGAGGGGGTGAGGACCAAAGAATCAAGATCCTTTTCAGGCCTGATAGCCAAGATGATGAGAACTTTTAGATAAGGCTGTGGGGAGAGTCCCTGGCCTTTTGAGCATCCTGCTTGGGCACACGGGGAATAACCTTTCTCCAGCTTCCAGTGTGAACTGAGAAAGAGAAAGGGAAACCCTGTCTTTGGAGAAGCTGGGATCTTCCCAGCACCAGAAACTTCTGCAGGCCCCTGCCTGGCCCACGGCTAACCTTTGGGTGGGACTGGAGTTTCCTGAACAGGGAACAAGGGAGCCTTCCGCAGAGCTCTGATGGGCAGGCCTCCGAGGGCCTGTGCTGTGTGCTGTTAGGATAGCTTGGTGTTGTCTATACCCCATTAGTAAGTTTTGTCTGAGTGTGTCCTCGCTGTTCATTGTCTAATTTGGTAACATTTATTTTGGTCCTGACCCCTTCTGCTGCTGCTGGGTTTAAGCTTCAGTGCAGGTGGAATGACATTCAAATAAAGAAACACTTTCTATCACCCAAAAAAAAAAAAORF Start: ATG at 7ORF Stop: TAG at 355SEQ ID NO:78116 aaMW at 12642.4DaNOV32a,MQRKERRMKEPGCGAVGRGLLSGHWVRGELVPPRTPATRCPCHTLFPKDTHQTCALVRCG122816-01Protein SequenceGIELTFQRLEARGTGSQGRILLGRTGVKEATSEDVVGPADLGVGQRRVERREASSLVG

[0479] Further analysis of the NOV32a protein yielded the following properties shown in Table 32B.

156TABLE 32BProtein Sequence Properties NOV32aPSort0.6500 probability located in cytoplasm; 0.2264 probabilityanalysis:located in lysosome (lumen); 0.1000 probability located inmitochondrial matrix space; 0.0000 probability located inendoplasmic reticulum (membrane)SignalPNo Known Signal Sequence Predictedanalysis:

[0480] A search of the NOV32a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 32C.

157TABLE 32CGeneseq Results for NOV32aNOV32aIdentities/Protein/Residues/Similarities forGenseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAB40400Human ORFX32 . . . 7316/44 (36%)4.2ORF164 poly-56 . . . 9921/44 (47%)peptide sequenceSEQ ID NO: 328—Homo sapiens,125 aa.[WO200058473-A2,05 OCT. 2000]AAB84576Amino acid 5 . . . 4518/41 (43%)5.5sequence of a14 . . . 5323/41 (55%)mature chimpanzeeEP2 peptide—Pantroglodytes, 89 aa.[WO200149702-A1,12 JUL. 2001]AAB84575Amino acid 5 . . . 4518/41 (43%)5.5sequence of a14 . . . 5323/41 (55%)mature human EP2peptide—Homosapiens, 89 aa.[WO200149702-A1,12 JUL. 2001]AAB84564Amino acid 5 . . . 4518/41 (43%)5.5sequence of a38 . . . 7723/41 (55%)chimpanzee EP2peptide—Pantroglodytes, 113 aa.[WO200149702-A1,12 JUL. 2001]AAB84563Amino acid 5 . . . 4518/41 (43%)5.5sequence of a38 . . . 7723/41 (55%)human EP2peptide—Homosapiens, 113 aa.[WO200149702-A1,12 JUL. 2001]

[0481] In a BLAST search of public sequence datbases, the NOV32a protein was found to have homology to the proteins shown in the BLASTP data in Table 32D.

158TABLE 32DPublic BLASTP Results for NOV32aIdentities/NOV32aSimilaritiesProteinResidues/for theAccessionProtein/MatchMatchedExpectNumberOrganism/LengthResiduesPortionValueQ9GKW6Hypothetical 12.9 1 . . . 116 92/116 (79%)7e−47kDa protein— 1 . . . 116100/116 (85%)Macaca fascicularis(Crab eatingmacaque)(Cynomolgusmonkey), 116 aa.Q9RJG8AraC family19 . . . 9728/93 (30%)0.67transcriptional123 . . . 21538/93 (40%)regulator—Streptomycescoelicolor, 327 aa.Q9HMW0Oligopeptide ABC11 . . . 9827/88 (30%)3.4 transporter ATP-271 . . . 34839/88 (43%)binding—Halobacterium sp.(strain NRC-1),440 aa.

Example 33

[0482] The NOV33 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 33A.

159TABLE 33ANOV33 Sequence AnalysisSEQ ID NO: 79636 bpNOV33a,CACCCGGCAATGGCGGCCTCCACGGCCTCGCAACGGCCCCTCAAGGGGATCCTGAAGGCG122825-01DNA SequenceACAACACCTCTACGACTTCCTCTATGGTGGCGTCGGCCGAACATCCCCGTGGGAGTGTCCACGAGCAGCTGAGCAAAAAATCCCAGAAGTGGGATGAAATGAACATCCTGGCGACATATCGTCCAGCAGACAAAGACTATGGTTTAATGAAAATAGATGAACCAAGCACTCCTTACCATAGTACGATGGGTGATGATGAAGATGCATGTAGTGATACAGAAACCACTGAAGCTATGGCAACAGATAGCCTTGCTAAGAACTTAGCTGCTGCTGAAGGCTTGGAGCCAAAGTATCAGGTTCAGGAACAAGAAAGCAGTGGAGAGGAGGATAGTGACCTCTCACCTGAAGAACGAGAAAAAAAGCGACAATTTGAAATGAGAAGGACGCTTCACTACAATGAAGGACTCAATATCAAACTAGCTAGACAATTAATTTCAAAAGACCTACACGATGATGACAAAGTTGAAGAAATGTTAGAGACTGCACATGGAGAAAGCATGAATACGGAAGAATCAAATCAAGGATCTACTGCAAGTGACCAACAGCAAAATAAATCACGAAGTTCATAGAAGGGATTTORF Start: ATG at 10ORF Stop: TAG at 625SEQ ID NO: 80205 aaMW at 22862.6DaNOV33a,MAASTASQRPLKGILKDNTSTTSSMVASAEHPRGSVHEQLSKKSQKWDEMNILATYRPCG122825-01Protein SequenceADKDYGLMKIDEPSTPYHSTMGDDEDACSDTETTEAMATDSLAKNLAAAEGLEPKYQVQEQESSGEEDSDLSPEEREKKRQFEMRRTLHYNEGLNIKLARQLISKDLHDDDKVEEMLETAHGESMNTEESNQGSTASDQQQNKSRSS

[0483] Further analysis of the NOV33a protein yielded the following properties shown in Table 33B.

160TABLE 33BProtein Sequence Properties NOV33aPSort0.4500 probability located in cytoplasm; 0.3600 probabilityanalysis:located in mitochondrial matrix space; 0.1000 probabilitylocated in lysosome (lumen); 0.0000 probability located inendoplasmic reticulum (membrane)SignalPNo Known Signal Sequence Predictedanalysis:

[0484] A search of the NOV33a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 33C.

161TABLE 33CGeneseq Results for NOV33aNOV33aIdentities/Protein/Residues/Similarities forGenseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueABG15494Novel human 3 . . . 126 95/124 (76%)2e−49diagnostic protein205 . . . 328104/124 (83%)#15485—Homosapiens, 333 aa.[WO200175067-A2, 11 OCT.2001]ABG15494Novel human 3 . . . 126 95/124 (76%)2e−49diagnostic protein205 . . . 328104/124 (83%)#15485—Homosapiens, 333 aa.[WO200175067-A2, 11 OCT.2001]ABB65144Drosophila 1 . . . 205 72/206 (34%)3e−27melanogaster 1 . . . 186111/206 (52%)polypeptide SEQID NO 22224—Drosophilamelanogaster,205 aa.[WO200171042-A2, 27 SEP.2001]ABB62316Drosophila 34 . . . 202 59/180 (32%)5e−17melanogastor 13 . . . 184 93/180 (50%)polypeptide SEQID NO 13740—Drosophilamelanogaster,293 aa.[WO200171042-A2, 27 SEP.2001]AAG28006Arabidopsis46 . . . 205 43/182 (23%)6e−04thaliana protein10 . . . 186 68/182 (36%)fragment SEQ IDNO: 33062—Arabidopsisthaliana, 191 aa.[EP1033405-A2,06 SEP. 2000]

[0485] In a BLAST search of public sequence datbases, the NOV33a protein was found to have homology to the proteins shown in the BLASTP data in Table 33D.

162TABLE 33DPublic BLASTP Results for NOV33aIdentities/NOV33aSimilaritiesProteinResidues/for theAccessionProtein/MatchMatchedExpectNumberOrganism/LengthResiduesPortionValueQ96PQ5Protein1 . . . 205205/205 (100%) e−114phosphatase1 . . . 205205/205 (100%)inhibitor 2—Homo sapiens(Human), 205 aaCAB41680Inhibitor 2 of1 . . . 205181/205 (88%) e−100protein1 . . . 205190/205 (92%) phosphatase 1—Homo sapiens(Human), 205 aa(fragment).P41236Protein2 . . . 205180/204 (88%) 3e−99 phosphatase1 . . . 204189/204 (92%) inhibitor 2(IPP-2)—Homosapiens (Human),204 aa.I46876phosphoprotein1 . . . 205173/205 (84%) 4e−95 phosphatase1 . . . 205188/205 (91%) inhibitor 2—rabbit, 205 aa.P11845Protein2 . . . 205172/204 (84%) 2e−94 phosphatase1 . . . 204187/204 (91%) inhibitor 2(IPP-2)—Oryctolaguscuniculus(Rabbit), 204 aa.

Example 34

[0486] The NOV34 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 34A.

163TABLE 34ANOV34 Sequence AnalysisSEQ ID NO:811045 bpNOV34a,ACATGGGCAAGAGCATCCCCCAATACCTGGGGCAACTGGACATCCGCAAAAGCGTAGTCG122843-01DNA SequenceCAGCCTGGCCACAGGCGCCGGGGCGATCTACCTGCTCTACAAGGCCATCAAGGCTGGCATAAAATGCAAACCACCCCTCTGTAGCAACTCACCCATCTGCATCGCCCGTGCAGTCGAGCGAGAGCGGCACGGGCGGGACTCAGGTGAGCTCCGGAGGCTCCTCAACTCTTTGGAGTGCAAACAGGATGAGTATGCCAAGAGCATGATCCTGCACAGTATCACTCGCTGTGTGTACTTGCTGGAGGCTGAGGCCTCTGCTTGTACTACGGATGACATCGTGTTGCTGGGCTACATGCTGGATGACAAGGACAACAGTGTCAAAACCCAAGCTCTGAATACACTTAAAGCTTTCTCTGGCATCAGAAAATTCAGGCTCAAAATCCAGGAACACTCCATCAAAGTACTCGAACTGATCTCCACCATCTGGGACACGGAACTGCACATTGCGGGCCTCAGACTCCTCAACAACCTTCCACTGCCCGACTATGTGCATCCACAGCTGCGACGGGTGATGCCTGCCTTGATGGAGATCCTGCAGTCAGACTACATCCTGGCACAGGTGCAAGCCGTACGACTGCTGAGCTACCTGGCACAGAAGAATGACCTTCTCTATGACATTCTCAACTGCCAGGTGAGATCCAACTTCCTAAACCTGTTCCAGCCCACACAGTCAGGGAGTCTCCTGTATGAGGTACTGGTGTTTGCTGAGCGGCTGAGTGAGGGCCGGAACGCACCCCACTACCACGTGGTGAAATGGCATTACAACGAACAGTCCCTGCATGAATCCCTCTTTGGGGAAGAGTCCCGACTGGCAGACCGACTACTTGCCCTGGTCATCCACCCTGAGGAAGATGTTCAGATCCAGGCCTGCAAGGTCATTGTCAGCCTGCAGTATCCCCAGGACTTGAGAGCCCGGCCCTCCTCCTGCCAGCCCAGTCGTTCCTACTTTAAAAACACGGAATAAAATTAAGGAGAGCCAATAAATGAORF Start: ATG at 3ORF Stop: TAA at 1020SEQ ID NO: 82339 aaMW at 38537.1DaNOV34a,MCKSIPQYLGQLDIRKSVVSLATGAGAIYLLYKAIKAGIKCKPPLCSNSPTCIARAVECG122843-01Protein SequenceRERHGRDSGELRRLLNSLECKQDEYAKSMILHSITRCVYLLEAEASACTTDDIVLLGYMLDDKDNSVKTQALNTLKAFSGIRKFRLKIQEHSIKVLELISTIWDTELHIAGLRLLNNLFLPDYVHPQLRRVMPALMEILQSDYILAQVQAVRLLSYLAQKNDLLYDILNCQVRSNNFLNLFQPTQSGSLLYEVLVFAERLSEGRNAPHYHVVKWHYNEQSLHESLFGEESRLANDRLLALVIHPEEDVQIQACKVIVSLQYPQDLRARPSSCQPSRSYFKNTESEQ ID NO: 831048 bpNOV34b,ACATGGGCAAGAGCATCCCCCAATACCTGGGGCAACTGGACATCCGCAAAAGCGTAGTCG122843-02DNA SequenceCAGCCTGGCCACAGGCGCCGGGGCGATCTACCTGCTCTACAAGGCCATCAAGGCTGGCATAAAATGCAAACCACCCCTCTGTAGCAACTCACCCATCTGCATCGCCCGCCTGGCAGTCGAGCGAGAGCGGCACGGGCGGGACTCAGGTGAGCTCCGGAGGCTCCTCAACTCTTTGGAGTGCAAACAGGATGAGTACGCCAAGAGCATGATCCTGCACAGTATCACTCGCTGTGTGTACTTGCTGGAGGCTGAGGCCTCTGCTTGTACTACGGATGACATCGTGTTGCTGGGCTACATGCTGGATGACAAGGACAACAGTGTCAAAACCCAAGCTCTGAATACACTTAAAGCTTTCTCTGGCATCAGAAAATTCAGGCTCAAAATCCAGGAGCACTCCATCAAAGTACTCGAACTGATCTCCACCATCTGGGACACGGAACTGCACATTGCGGGCCTCAGACTCCTCAACAACCTTCCACTGCCCGACTATGTGCATCCACAGCTGCGACGGGTGATGCCTGCCTTGATGGAGATCCTGCAGTCAGACTACATCCTGGCACAGGTGCAAGCCGTACGACTGCTGAGCTACCTGGCACAGAAGAATGACCTTCTCTATGACATTCTCAACTGCCAGGTTCACTCCAACTTCCTAAACCTGTTCCAGCCCACACAGTCAGGGAGTCTCCTGTATGAGGTACTGGTGTTTGCTGAGCGGCTGAGTGAGGGCTGGAACGCACCCCACTACCACGTGGTGAAATGGCATTACAACGAACAGTCCCTGCATGAATCCCTCTTTGGGGAAGAGTCCCGACTGGCAGACCGACTACTTGCCCTGGTCATCCACCCTGAGGAAGATGTTCAGATCCAGGCCTGCAAGGTCATTGTCAGCCTGCAGTATCCCCAGGACTTGAGAGCCCGGCCCTCCCCCTGCCAGCCCAGTCGTTCCTACTTTAAAAACACCGAATAAAATTAAGGAGAGCCAATAAATGAORF Start: ATG at 3ORF Stop: TAA at 1023SEQ ID NO: 84340 aaMW at 38671.2DaNOV34b,MGKSIPQYLGQLDIRKSVVSLATGAGAIYLLYKAIKAGIKCKPPLCSNSPICIARLAVCG122843-02Protein SequenceERERHGRDSGELRRLLNSLECKQDEYAKSMILHSITRCVYLLEAEASACTTDDIVLLGYMLDDKDNSVKTQALNTLKAFSGIRKFRLKIQEHSIKVLELISTIWDTELHIAGLRLLNNLPLPDYVHPQLRRVMPALMEILQSDYILAQVQAVRLLSYLAQKNDLLYDILNCQVHSNFLNLFQPTQSCSLLYEVLVFAERLSEGWNAPHYHVVKWHYNEQSLHESLFGEESRLADRLLALVIHPEEDVQIQACKVIVSLQYPQDLRARPSPCQPSRSYFKNTE

[0487] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 34B.

164TABLE 34BComparison of NOV34a against NOV34b.ProteinNOV34a Residues/Identities/SimilaritiesSequenceMatch Residuesfor the Matched RegionNOV34b1 . . . 339336/340 (98%)1 . . . 340336/340 (98%)

[0488] Further analysis of the NOV34a protein yielded the following properties shown in Table 34C.

165TABLE 34CProtein Sequence Properties NOV34aPSort0.4500 probability located in cytoplasm; 0.3000 probabilityanalysis:located in microbody (peroxisome); 0.1000 probability locatedin mitochondrial matrix space; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0489] A search of the NOV34a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 34D.

166TABLE 34DGeneseq Results for NOV34aNOV34aIdentities/Residues/Similarities forGeneseqProtein/Organism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAM96687Human reproductive system related256 . . . 335 66/80 (82%) 6e−31antigen SEQ ID NO: 5345 - Homo1 . . . 80 69/80 (85%)sapiens, 80 aa. [WO200155320-A2, 02-AUG-2001]AAM94964Human reproductive system related26 . . . 87 59/63 (93%)2e−26antigen SEQ ID NO: 3622 - Homo7 . . . 69 60/63 (94%)sapiens, 80 aa. [WO200155320-A2, 02-AUG-2001]AAB41588Human ORFX ORF13521 . . . 55 55/55 (100%)1e−24polypeptide sequence SEQ ID1 . . . 55 55/55 (100%)NO: 2704 - Homo sapiens, 108 aa.[WO200058473-A2,05-OCT-2000]AAY88300Human TANGO 187-3 protein -21 . . . 312 71/298 (23%)3e−11Homo sapiens, 308 aa.14 . . . 305136/298 (44%)[WO200018904-A2,06-APR-2000]AAB88425Human membrane or secretory68 . . . 312 60/246 (24%)2e−10protein clone PSEC0198 - Homo97 . . . 340116/246 (46%)sapiens, 343 aa. [EP1067182-A2,10-JAN-2001]

[0490] In a BLAST search of public sequence datbases, the NOV34a protein was found to have homology to the proteins shown in the BLASTP data in Table 34E.

167TABLE 34EPublic BLASTP Results for NOV34aNOV34aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ96LL8CDNA FLJ25390 1 . . . 339329/340 (96%)0.0fis, clone 1 . . . 330329/340 (96%)TST02370—Homosapiens (Human),330 aa.Q9DAN74930511111Rik 1 . . . 336282/337 (83%) e−162protein—Mus 1 . . . 337309/337 (91%)musculus (Mouse),340 aa.Q9D5644930511111Rik 1 . . . 336282/337 (83%) e−162protein—Mus 1 . . . 337308/337 (90%)musculus (Mouse),340 aa.Q9CUN32810037C14Rik10 . . . 311 76/308 (24%)4e−12 protein—Mus99 . . . 384133/308 (42%)musculus (Mouse),388 aa (fragment).Q9CZ872810037C14Rik10 . . . 311 76/313 (24%)5e−11 protein—Mus 3 . . . 302137/313 (43%)musculus (Mouse),306 aa.

Example 35

[0491] The NOV35 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 35A.

168TABLE 35ANOV35 Sequence AnalysisSEQ ID NO: 85914 bpNOV35a,AATTCGGCACGAGGCAGCGTCGCGCGGCCCAGTTCCCTTTTCCGGTCGGCGTGGTCTTCG124890-02DNA SequenceGCGAGTGGAGTGTCCGCTGTGCCCGGGCCTGCACCATGAGCGTCCCGGCCTTCATCGACATCAGTGAAGAAGATCAGGTTAGAAAATGGATTTCTGACTGGAATCTCACCACTGAAAAAAAGCACACCCTTTTAAGACTACTTTATGAGGCACTTGTGGATTGTAAGAAGAGTGATGCTGCTTCAAAAGTCATGGTGGAATTGCTCGGAAGTTACACAGAGGACAATGCTTCCCAGGCTCGAGTTGATGCCCACAGGTGTATTGTACGAGCATTGAAAGATCCAAATGCATTTCTTTTTGACCACCTTCTTACTTTAAAACCAGTCAAGTTTTTGGAAGGCGAGCTTATTCATGATCTTTTAACCATTTTTGTGAGTGCTAAATTGGCATCATATGTCAAGTTTTATCAGAATAATAAAGACTTCATTGATTCACTTGGCCTGTTACATGAACAGAATATGGCAAAAATGAGACTACTTACTTTTATGGGAATGGCAGTAGAAAATAAGGAAATTTCTTTTGACACAATGCAGCAAGAACTTCAGATTGGAGCTGATGATGTTGAAGCATTTGTTATTGACGCCGTAAGAACTAAAATGGTCTACTGCAAAATTGATCAGACCCAGAGAAAAGTAGTTGTCAGTCATAGCACACATCGGACATTTGGAAAACAGCAGTGGCAACAACTGTATGACACACTTAATGCCTGGAAACAAAATCTGAACAAAGTGAAAAACAGCCTTTTGAGTCTTTCTGATACCTGAGTTTTTATGCTTATAATTTTTGTTCTTTGAAAAAAAAGCCCTAAATCATAGTAAAACATTATAAACTAAAAAAAAAAAAAAAAAAAAAAAAAORF Start: ATG at 94ORF Stop: TGA at 820SEQ ID NO:86242 aaMW at 27864.8DaNOV35a,MSVPAFIDISEEDQVRKWISDWNLTTEKKHTLLRLLYEALVDCKKSDAASKVMVELLGCG124890-02Protein SequenceSYTEDNASQARVDAHRCTVRALKEPNAFLFDHLLTLKPVKFLEGELIHDLLTIFVSAKLASYVKFYQNNKDFIDSLGLLHEQNMAKMRLLTFMCMAVENKEISFDTMQQELQIGADDVEAFVIDAVRTKMVYCKIDQTQRKVVVSHSTHRTFGKQQWQQLYDTLNAWKQNLNKVKNSLLSLSDT

[0492] Further analysis of the NOV35a protein yielded the following properties shown in Table 35B.

169TABLE 35BProtein Sequence Properties NOV35aPSort0.4500 probability located in cytoplasm; 0.3906 probabilityanalysis:located in microbody (peroxisome); 0.1000 probability locatedin mitochondrial matrix space; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0493] A search of the NOV35a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 35C.

170TABLE 35CGeneseq Results for NOV35aNOV35aIdentities/Protein/Residues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAA013511Human poly- 10 . . . 242231/233 (99%) e−130peptide SEQ ID185 . . . 417232/233 (99%)NO 27403—Homo sapiens,417 aa.[WO200164835-A2, 07 SEP.2001]AAW73398Human secreted 10 . . . 242231/233 (99%) e−130protein encoded 79 . . . 311232/233 (99%)by Gene No. 2—Homo sapiens,312 aa.[WO9854206-A1, 03 DEC1998]AAW73434Human secreted 10 . . . 242231/233 (99%) e−130protein encoded142 . . . 374232/233 (99%)by Gene No. 2—Homo sapiens,374 aa.[WO9854206-A1, 03 DEC.1998]AAY05796Human herpes 10 . . . 242231/233 (99%) e−130simplex virus142 . . . 374232/233 (99%)receptor B5T74—Human herpessimplex virus,374 aa.[WO9920761-A2, 29 APR.1999]ABB63793Drosophila 13 . . . 240121/228 (53%)1e−64 melanogaster147 . . . 373170/228 (74%)polypeptide SEQID NO 18171—Drosophilamelanogaster,387 aa.[WO200171042-A2, 27 SEP.2001]

[0494] In a BLAST search of public sequence datbases, the NOV35a protein was found to have homology to the proteins shown in the BLASTP data in Table 35D.

171TABLE 35DPublic BLASTP Results for NOV35aNOV35aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ96KM8DJ69B10.1 10 . . . 242231/233 (99%) e−130(GA17 protein)142 . . . 374232/233 (99%) (Hypothetical42.5 kDaprotein)—Homo sapiens(Human), 374 aa.Q991X4Similar to 10 . . . 242230/233 (98%) e−129dendritic cell142 . . . 374231/233 (98%) protein—Musmusculus(Mouse), 374 aa.O60735GA17 protein— 10 . . . 242226/233 (96%) e−128Homo sapiens142 . . . 374229/233 (97%) (Human), 374 aa.Q9BXW1PNAS-125— 53 . . . 239187/187 (100%) e−103Homo sapiens 1 . . . 187187/187 (100%)(Human), 206 aa.Q9V6X8CG8309 13 . . . 240121/228 (53%) 3e−64 protein—147 . . . 373170/228 (74%) Drosophilamelanogaster(Fruit fly),387 aa.

Example 36

[0495] The NOV36 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 36A.

172TABLE 36ANOV36 Sequence AnalysisSEQ ID NO:871269 bpNOV36a,CGGCCGGCCTGGGCTCGGGGGCTCCGGGCTCTGGGCTCTGGGTGCGCGGACCGGGCCACG59266-01DNA SequenceGGCTGCTTGAAGACCTCGCGACCTGTGTCAGCAGAGCCGCCCTGCACCACCATGTGCATCATCTTCTTTAAGTTTGATCCTCGCCCTGTTTCCAAAAACGCGTACAGGCTCATCTTGGCAGCCAACAGGGATGAATTCTACAGCCGACCCTCCAAGTTAGCTGACTTCTGGGGGAACAACAACGAGATCCTCAGTGGGCTGGACATGGAGGAAGGGAAGGAAGGAGGCACATGGCTGGGCATCAGCACACGTGGCAAGCTGGCAGCACTCACCAACTACCTGCAGCCGCAGCTGGACTGGCAGGCCCGAGGGCGAGGTGAACTTGTCACCCACTTTCTGACCACTGACGTGGACAGCTTGTCCTACCTGAAGAAGGTCTCTATGGAGGGCCATCTGTACAATGGCTTCAACCTCATAGCAGCCGACCTGAGCACAGCAAAGGGAGACGTCATTTGCTACTATGGGAACCGAGGGGAGCCTGATCCTATCGTTTTGACGCCAGGCACGTACGGGCTGAGCAACGCGCTGCTGGAGACTCCCTGGAGGAAGCTGTGCTTTGGGAAGCAGCTCTTCCTGGAGGCTGTGGAACGGAGCCAGGCGCTGCCCAAGGATGTGCTCATCGCCAGCCTCCTGGATGTGCTCAACAATGAAGAGGCGCAGCTGCCAGACCCGGCCATCGAGGACCAGGGTGGGGAGTACGTGCAGCCCATGCTGAGCAAGTACGCGGCTGTGTGCGTGCGCTGCCCTGGCTACGGCACCAGAACCAACACTATCATCCTGGTAGATGCGGACGGCCACGTGACCTTCACTGAGCGTAGCATGATGGACAAGGACCTCTCCCACTGGGAGACCAGAACCTATGAGTTCACACTGCAGAGCTAACCCCACCTCTGGGCCTGGCCAGTGGGCTCCTGGGGGGCCCTGCCTTGAGGGGCACTGTGGACAGGAAACCTTCCTTTGCCATACTGCATTGCACTGCCCGTGCCTTGGCCAGCATCCCCCGGATCAGGGCCCTGTGGTTTGCGTGTTACCCATCTGTGTCCCCATGCCCAGTTCAGGGTCTGCCTTTATGCCAGTGAGGAGCAGCACAGTCTGATACTAGGTCTAGGACCGGCCGAGGTATACCATGAACATGTGCATACACCTGAGCCCACTCTTGCACATGTACACAGGCACTCACATGGCACACACATACACTCCTGCGTGTGCACORF Start: ATG at 110ORF Stop: TAA at 938SEQ ID NO: 88276 aaMW at 30936.7DaNOV36a,MCIIFFKFDPRPVSKNAYRLILAANRDEFYSRFSKLADFWGNNNEILSCLDMEEGKEGCG59266-01Protein SequenceGTWLGISTRCKLAALTNYLQPQLDWQARGRGELVTHFLTTDVDSLSYLKKVSMEGHLYNGFNLIAADLSTAKGDVICYYGNRGEPIDPIVLTPGTYGLSNALLETPWRKLCFGKQLFLEAVERSQALPKDVLTASLLDVLNNEEAQLPDPAIEDQGGEYVQPMLSKYAAVCVRCPGYGTRTNTIILVDADGHVTFTERSMMDKDLSHWETRTYEFTLQSSEQ ID NO: 891509 bpNOV36b,CGGCCGGCCTGGGCTCGGGGGCTCCGGGCTCTGGGCTCTGGGTGCGCGGACCGGGCCACG59266-02DNA SequenceGGCTGCTTGAAGACCTCGCGACCTGTGTCAGCAGAGCCGCCCTGCACCACCATGTGCATCATCTTCTTTAAGTTTGATCCTCGCCCTGTTTCCAAAAACGCGTACAGGTAACCCCCTCGCTCTGCATCTGCTGCGCCCTGCAGGGTCCTGGGTGCCCAGCCAGTTCTCATGCCACCCAAGCTGCTGTGTGCAGGAAGGTGTGTGGGCCAGGACGGGGCTGCACAGGCCTGGCACTGCCCTCCAGGACAGGGTCACTCAGTCTGGGATGCTGTCAGAATGCCTCTCGGGGCGGGGACTCCAGTCAATGTACAAAGACGTGAAGACTCAGCCACAGAAGGCAGCCACAGGCTCATCTTGGCAGCCAACAGGGATGAATTCTACAGCCGACCCTCCAAGTTAGCTGACTTCTGGGGGAACAACAACGAGATCCTCAGTGGGCTGGACATGGAGGAAGGCAAGGAAGGAGGCACATGGCTGGGCATCAGCACACGTGGCAAGCTGGCAGCACTCACCAACTACCTGCAGCCGCAGCTGGACTGGCAGGCCCGAGGGCGAGGTGAACTTGTCACCCACTTTCTGACCACTGACGTGGACAGCTTGTCCTACCTGAAGAAGGTCTCTATGGAGGGCCATCTGTACAATGGCTTCAACCTCATAGCAGCCGACCTGAGCACAGCAAAGGGAGACGTCATTTGCTACTATGGGAACCGAGGGGAGCCTGATCCTATCGTTTTGACGCCAGGCACGTACGGGCTGAGCAACGCGCTGCTGGAGACTCCCTGGAGGAAGCTGTGCTTTGGGAAGCACGTCTTCCTGGAGGCTGTGGAACGGAGCCAGGCGCTGCCCAAGGATGTGCTCATCGCCAGCCTCCTGGATGTGCTCAACAATGAAGAGGCGCAGCTGCCAGACCCGGCCATCGAGGACCAGGGTGGGGAGTACGTGCAGCCCATGCTGAGCAAGTACGCGGCTGTGTGCGTGCGCTGCCCTGGCTACGGCACCAGAACCAACACTATCATCCTGGTAGATGCCGACGGCCACGTGACCTTCACTGAGCGTAGCATGATGGACAAGGACCTCTCCCACTGGGAGACCAGAACCTATGAGTTCACACTGCAGAGCTAACCCCACCTCTGGGCCTGGCCAGTGGGCTCCTGGGGGGCCCTGCCTTGAGGGGCACTGTGGACAGGAAACCTTCCTTTGCCATACTGCATTGCACTGCCCGTGGCTTGGCCAGCATCCCCCGGATCAGGGCCCTGTGGTTTGCGTGTTACCCATCTGTGTCCCCATGCCCAGTTCAGGGTCTGCCTTTATGCCAGTGAGGAGCAGCAGAGTCTGATACTAGGTCTAGGACCGGCCGAGGTATACCATGAACATGTGGATACACCTGAGCCCACTCTTGCACATGTACACAGGCACTCACATGGCACACACATACACTCCTGCGTGTGCACORF Start: ATG at 227ORF Stop: TAA at 1178SEQ ID NO:90317 aaMW at 34952.1DaNOV36b,MPPKLLCAGRCVGQDGAAQAWHCPPGQGHSVWDAVRMPLGAGTRVNVQRREDSATEGSCG59266-02Protein SequenceHRLILAANRDEFYSRPSKLADFWCNNNEILSGLDMEEGKEGGTWLCISTRGKLAALTNYLQPQLDWQARGRGELVTHFLTTDVDSLSYLKKVSMEGHLYNGFNLIAADLSTAKGDVICYYGNRGEPDPIVLTPGTYGLSNALLETPWRKLCFGKQLFLEAVERSQALPKDVLIASLLDVLNNEEAQLPDPAIEDQGGEYVQPMLSKYAAVCVRCRGYGTRTNTIILVDADGHVTFTERSMMDKDLSHWETRTYEFTLQSSEQ ID NO:911111 bpNOV36c,ATACAGGTAACCCCCTCGCTCTGCATCTGCTGCGCCCTGCAGGGTCCTGGGTGCCCAGCG59266-03DNA SequenceCCAGTTCTCATGCCACCCAAGCTGCTGTGTGCAGGAAGGTGTGTGGGCCAGGACGGGGCTGCACAGGCCTGGCACTGCCCTCCAGGACAGGGTCACTCAGTGTGGGATGCTGTCAGAATCCCTCTCGGGGCGGGGACTCCAGTCAATGTACAAAGACGTGAAGACTCAGCCACAGAAGGCAGCCACAGGCTCATCTTGGCAGCCAACAGGGATGAATTCTACAGCCGACCCTCCAACTTAGCTGACTTCTGGGGGAACAACAACGAGATCCTCAGTGGGCTGGACATGGAGGAAGGCAAGGAAGGAGGCACATGGCTGGGCATCAGCACACGTGGCAAGCTGGCAGCACTCACCAACTACCTGCAGCCGCAGCTGGACTGGCAGGCCCGAGGGCGAGGTGAACTTGTCACCCACTTTCTGACCACTGACGTGGACAGCTTGTCCTACCTGAAGAAGGTCTCTATGGAGGGCCATCTGTACAATGGCTTCAACCTCATAGCAGCCGACCTGAGCACAGCAAAGGGAGGGCCATCTGTACAATGGCTTCAACCTCATAGCAGCCGACCTGAGCACAGCAAAGGGAGACGTCATTTGCTACTATGGGAACCGAGGGGAGCCTGATCCTATCGTTTTGACGCCAGGCACCTACGGGCTGAGCAACGCGCTGCTGGAGACTCCCTGGAGGAAGCTGTGCTTTGGGAAGCAGCTCTTCCTGGAGGCTGTGGAACGGAGCCAGGCGCTGCCCAAGGATGTGCTCATCGCCAGCCTCCTGGATGTGCTCAACAATGAAGAGGCGCAGCTGCCAGACCCGGCCATCGAGGACCAGGGTGGGGAGTACGTGCAGCCCATGCTGAGCAAGTACGCGGCTGTGTGCGTGCGCTGCCCTGGCTACGGCACCAGAACCAACACTATCATCCTGGTAGATGCGGAGGCCCACGTGACCTTCACTGAGCGTAGCATGATGGACAAGGACCTCTCCCACTGGGAGACCAGAACCTATGAGTTCACACTGCAGAGCTAACCCCACCTCTGGGCCTGGCCAGTGGGCTCCTGGGGGGCCCTGCCTTGAGGGGCACTGTGGACAGCAAACCTTCCTTTGCCATACTGCATTORF Start: ATG at 68ORF Stop: TAA at 1019SEQ ID NO:92317 aaMW at 34952.1DaNOV36c,MPPKLLCAGRCVGQDGAAQAWHCPPGQGHSVWDAVRMPLGAGTPVNVQRREDSATEGSCG59266-03Protein SequenceHRLILAANRDEFYSRFSKLADFWGNNNEILSGLDMEEGKEGGTWLGISTRCKLAALTNYLQPQLDWQARGRGELVTHFLTTDVDSLSYLKKVSMEGHLYNGFNLIAADLSTAKGDVICYYGNRGEPDPTVLTPGTYGLSNALLETPWRKLCFGKQLFLEAVERSQALPKDVLIASLLDVLNNEEAQLPDPAIEDQGGEYVQPMLSKYAAVCVRCPGYGTRTNTIILVDADGHVTFTERSMMDKDLSHWETRTYEFTLQS

[0496] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 36B.

173TABLE 36BComparison of NOV36a against NOV36b and NOV36c.ProteinNOV36a Residues/Identities/SimilaritiesSequenceMatch Residuesfor the Matched RegionNOV36b14 . . . 276258/263 (98%)55 . . . 317262/263 (99%)NOV36c14 . . . 276258/263 (98%)55 . . . 317262/263 (99%)

[0497] Further analysis of the NOV36a protein yielded the following properties shown in Table 36C.

174TABLE 36CProtein Sequence Properties NOV36aPSort0.4598 probability located in microbody (peroxisome); 0.4292analysis:probability located in mitochondrial matrix space; 0.1726probability located in lysosome (lumen); 0.1082 probabilitylocated in mitochondrial inner membraneSignalPNo Known Signal Sequence Predictedanalysis:

[0498] A search of the NOV36a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 36D.

175TABLE 36DGeneseq Results for NOV36aIdentities/NOV36aSimilaritiesProtein/Residues/for theGeneseqOrganism/LengthMatchMatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAB42789Human ORFX127 . . . 276150/1506e−85ORF2553 poly-(100%)peptide sequence 29 . . . 178150/150SEQ ID NO:(100%)5106—Homosapiens, 178 aa.[WO200058473-A2,05 OCT. 2000]AAB42777Human ORFX14 . . . 7052/571e−24ORF2541 poly- (91%)peptide sequence 55 . . . 11156/57SEQ ID NO: (98%)5082—Homosapiens, 111 aa.[WO200058473-A2,05 OCT. 2000]AAM31605Peptide #5642152 . . . 20150/502e−21encoded by probe(100%)for measuring 1 . . . 5050/50placental gene(100%)expression—Homosapiens, 50 aa.[WO200157272-A2,09 AUG. 2001]AAM71326Human bone152 . . . 20150/502e−21marrow expressed(100%)probe encoded 1 . . . 5050/50protein SEQ ID NO:(100%)31632—Homosapiens, 50 aa.[WO200157276-A2,09 AUG. 2001]AAM58810Human brain152 . . . 20150/502e−21expressed single(100%)exon probe encoded 1 . . . 5050/50protein SEQ ID NO:(100%)30915—Homosapiens, 50 aa.[WO200157275-A2,09 AUG. 2001]

[0499] In a BLAST search of public sequence datbases, the NOV36a protein was found to have homology to the proteins shown in the BLASTP data in Table 36E.

176TABLE 36EPublic BLASTP Results for NOV36aNOV36aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ96M16CDNA FLJ3289914 . . . 276250/263 (95%) e−145fis, clone19 . . . 273254/263 (96%) TEST12005408,highly similar toSER/THR-richprotein T10 inDGCR region—Homo sapiens(Human), 273 aa.P54797Ser/Thr-rich 1 . . . 276240/276 (86%) e−142protein T10 in 1 . . . 276260/276 (93%) DGCR region—Mus musculus(Mouse), 276 aa.Q8TCS0Hypothetical 24.953 . . . 276224/224 (100%) e−130kDa protein— 1 . . . 224224/224 (100%)Homo sapiens(Human), 224 aa(fragment).Q99K56Hypothetical 16.7 1 . . . 151134/151 (88%) 2e−76kDa protein— 1 . . . 151145/151 (95%) Mus musculus(Mouse), 151 aa.Q9J5E1ORF FPV070 1 . . . 276121/278 (43%) 4e−61T10 gene 1 . . . 273177/278 (63%) product—Fowlpox virus(FPV), 273 aa.

Example 37

[0500] The NOV37 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 37A.

177TABLE 37ANOV37 Sequence AnalysisSEQ ID NO:931547 bpNOV37a,TGGCCCTCAGGTGGGATGCTATGGAATATGATGAGAAGCTGGCCCGTTTCCGGCAGGCCG97563-01DNA sequenceCCACCTCAACCCCTTCAACAAGCAGTCTGGGCCGAGACAGCATGAGCAGGGCCCTGGGGAGGAGGTCCCGGACGTCCTGCCTGAGCTGCCCCCTGGGGAGCCGGAATTCCGCTGCCCTGAACGCGTGATGGATCTCGGCCTGTCTGAGGACCACTTCTCCCGCCCTGTGGGTCTGTTCCTGGCCTCTGACGTCCAGCAGCTGCGGCAGGCGATCGAGGAGTGCAAGCAGGTGATTCTGGAGCTGCCCGAGCAGTCGGAGAAGCAGAAGGATGCCGTGGTGCGACTCATCCACCTCCGGCTGAAGCTCCAGGAGCTGAAGGACCCCAATGAGGATGAGCCAAACATCCGAGTGCTCCTTGAGCACCGCTTTTACAAGGAGAAGAGCAAGAGCGTCAAGCAGACCTGTGACAAGTGTAACACCATCATCTGGGGGCTCATTCAGACCTGGTACACCTGCACAGGGTGTTATTACCGCTGTCACAGTAAGTGCTTGAACCTCATCTCCAAGCCCTGTGTGAGCTCCAAAGTCAGCCACCAAGCTGAATACGAACTGAACATCTGCCCTGAGACAGGGCTGGACAGCCAGGATTACCGCTGTGCCGAGTGCCGGGCGCCCATCTCTCTGCGGGGTGTGCCCAGTGACGCCAGGCAGTGCGACTACCCCGGCCGGTACTACTGCAGCCACTGCCACTGGAACGACCTGGCTGTGATCCCTGCACGCGTTGTACACAACTGGGACTTTGAGCCTCGAAAGGTTTCTCGCTGCAGCATGCGCTACCTGGCGCTGATGGTGTCTCGGCCCGTACTCAGGCTCCGGGAGATCAACCCTCTGCTGTTCAGCTACGTGGAGGAGCTGGTGGAGATTCGCAAGCTGCGCCAGGACATCCTGCTCATGAAGCCGTACTTCATCACCTGCAGGGAGGCCATGGAGGCTCGTCTGCTGCTGCAGGACCTCCTGGACGTGCATGCCGGCCGCCTGGGCTGCTCGCTCACCGAGATCCACACGCTCTTCGCCAAGCACATCAAGCTGGACTGCGAGCGGTGCCAGGCCAAGGGCTTCGTGTGTGAGCTCTGCAGAGAGGGCGACGTGCTGTTCCCGTTCGACAGCCACACGTCTGTGTGCGCCGACTGCTCCGCGGTCTTCCACAGGGACTGCTACTACGACAACTCCACCACTTGTCCCAAGTGTGCCCGGCTCAGCCTGAGGAAGCAGTCGCTCTTCCAGGAGCCAGGTCCCGATGTGGAGGCCTAGCGCCGAGGAACAGTGCTGGGCACCCCGCCTGGCCCGCCAGGACCCACCCTGCCAACATCAAGTTGTTCCTTCTGCTCCGGAGACCCCTGGGGTGCGGCCCTGGCCCCCTCCACCCCTGCTGGGCCACAGCGGGTGGGCAGTGTCAAGGCCCGCTGTCTCCCAGGTGCTTGCTGGGACTCGGGGCGGCTGCACCTGGCTGTCACCTGGGTGTGCTGCTGTGAGGGGTCCTTGCGTGGCORF Start: ATG at 21ORF Stop: TAG at 1308SEQ ID NO:94429 aaMW at 49656.4DaNOV37a,MEYDEKLARFRQAHLNPFNKQSGPRQHEQGPGEEVPDVLPELPPGEPEFRCPERVMDLCG97563-01Protein SequenceGLSEDHFSRFVGLFLASDVQQLRQAIEECKQVILELPEQSEKQKDAVVRLIHLRLKLQELKDPNEDEPNIRVLLEHRFYKEKSKSVKQTCDKCNTIIWGLTQTWYTCTGCYYRCHSKCLNLTSKPCVSSKVSHQAEYELNICPETCLDSQDYRCAECRAPISLRGVPSEARQCDYPGRYYCSHCHWNDLAVIPARVVHNWDFEPRKVSRCSMRYLALMVSRPVLRLREINPLLFSYVEELVEIRKLRQDILLMKPYFITCREAMEARLLLQDLLDVHAGRLGCSLTETHTLFAKHIKLDCERCQAKGFVCELCREGDVLFPFDSHTSVCADCSAVFHRDCYYDNSTTCPKCARLSLRKQSLFQEPGPDVEASEQ ID NO:951736 bpNOV37b,CTCCTGTCTTCACTGAAGGCAAGCCATCATGCTTTTGGCCACACTTGGGTCAGTTACTCG97563-02DNA SequenceTTTTTGGACAGATGCGAGGCGGCGGTCAGCAGGTGCCGAACCCACGGCCAGGCTTCCGTGGCCAGCAGCCCTAGAGGAATGGCCATCCTGTCCCTGCGAGCCCCTGGGCCCTGGCAGGCGATGCAGGTGGGATGCTATGGAATATGATGAGAAGCTGGCCCGTTTCCGGCAGGCCCACCTCAACCCCTTCAACAAGCAGTCTGGGCCGAGACAGCATGAGCAGGGCCCTGGGGAGGAGGTCCCGGACGTCACTCCTGAAGAGGCCCTGCCTGAGCTGCCCCCTGGGGAGCCGGAATTCCGCTGCCCTGAACGCGTGATGGATCTCGGCCTGTCTGAGGACCACTTCTCCCGCCCTGTGGGTCTGTTCCTGGCCTCTGACGTCCAGCAGCTGCGGCAGGCGATCGAGGAGTGCAAGCAGGTGATTCTGGAGCTGCCCGAGCAGTCGGAGAAGCAGAAGGATGCCGTGGTGCGACTCATCCACCTCCGGCTGAAGCTCCAGGAGCTGAAGGACCCCAATGAGGATGAGCCAAACATCCGAGTGCTCCTTGAGCACCGCTTTTACAAGGAGAAGAGCAAGAGCGTCAAGCAGACCTGTGACAAGTGTAACACCATCATCTGGGGGCTCATTCAGACCTGGTACACCTGCACAGGGTGTTATTACCGCTGTCACAGTAAGTGCTTGAACCTCATCTCCAAGCCCTGTGTGAGCTCCAAAGTCAGCCACCAAGCTGAATACGAACTGAACATCTGCCCTGAGACAGGGCTGGACACCCAGGATTACCGCTGTGCCGAGTGCCGGGCGCCCATCTCTCTGCGGGGTGTGCCCAGTGAGGCCAGGCAGTGCGACTACACCGGCCAGTACTACTGCAGCCACTGCCACTGGAACGACCTGGCTGTGATCCCTGCACGCGTTGTACACAACTGGGACTTTGAGCCTCGAAAGGTTTCTCGCTGCAGCATGCGCTACCTGGCGCTGATGGTGTCTCGGCCCGTACTCAGGCTCCGGGAGATCAACCCTCTGCTGTTCAGCTACGTGGAGGAGCTGGTGGAGATTCGCAAGCTGCGCCAGGACATCCTGCTCATGAAGCCGTACTTCATCACCTGCAGGGAGGCCATGGAGGCTCGTCTGCTGCTGCAGGACCTCCTGGACGTGCATGCCGGCCGCCTGGGCTGCTCGCTCACCGAGATCCACACGCTCTTCGCCAAGCACATCAAGCTGGACTGCGAGCGGTGCCAGGCCAAGGGCTTCGTGTGTGAGCTCTGCAGAGAGGGCGACGTGCTGTTCCCGTTCGACAGCCACACGTCTGTGTGCGCCGACTGCTCCGCGGTCTTCCACAGGGACTGCTACTACGACAACTCCACCACTTGTCCCAAGTGTGCCCGGCTCAGCCTGAGGAAGCAGTCGCTCTTCCAGGAGCCAGGTCCCGATGTGGAGGCCTAGCGCCGAGGAACAGTGCTGGGCACCCCGCCTGGCCCGCCAGGACCCACCCTGCCAACATCAAGTTGTTCCTTCTGCTCCGGAGACCCCTGGGGTGCGGCCCTGGCCCCCTCCACCCCTGCTGGGCCAGAGCGGGTGGGCAGTGTCAAGGCCCGCTGTCTCCCAGGTGCTTGCTGGGACTCGGGGCGGCTGCACCTGGCTGTCACCTGGGTGTGCTGCTCTGAGGGGTCCTTGCGTGGCORF Start: ATG at 195ORF Stop: TAG at 1497SEQ ID NO: 96434aaMW at 50159.9DaNOV37b,MEYDEKLARFRQAHLNPFNKQSGPRQHEQGPGEEVPDVTPEEALPELPPGEPEFRCPECG97563-02Protein SequenceRVMDLGLSEDHFSRPVGLFLASDVQQLRQAIEECKQVILELPEQSEKQKDAVVRLIHLRLKLQELKDPNEDEPNIRVLLEHRFYKEKSKSVKQTCDKCNTIIWGLIQTWYTCTGCYYRCHSKCLNLISKPCVSSKVSHQAEYELNICPETGLDSQDYRCAECRAPISLRGVPSEARQCDYTGQYYCSHCHWNDLAVIPARVVHNWDFEPRKVSRCSMRYLALMVSRPVLRLREINPLLFSYVEELVEIRKLRQDILLMKPYFITCREAMEARLLLQDLLDVHAGRLGCSLTEIHTLFAKHIKLDCERCQAKGFVCELCREGDVLFPFDSHTSVCADCSAVFHRDCYYDNSTTCPKCARLSLRKQSLFQEPGPDVEASEQ ID NO:971445 bpNOV37c,TGGCCATCCTGTCCCTGCGAGCCCCTGGGCCCTGGCAGGCGATGCAGGTGGGATGCTACG97563-03DNA SequenceTGGAATATGATGAGAAGCTGGCCCGTTTCCGGCAGGCCCACCTCAACCCCTTCAACAAGCAGTCTGGGCCGAGACAGCATGAGCAGGGCCCTGGGGAGGAGGTCCCGGACGTCACTCCTGAAGAGGCCCTGCCTGAGCTGCCCCCTGGGGAGCCGGAATTCCGCTGCCCTGAACGCGTGATGGATCTCGGCCTGTCTGAGGACCACTTCTCCCGCCCTGTGGGTCTGTTCCTGGCCTCTGACGTCCAGCAGCTGCGGCAGGCGATCGAGGAGTGCAAGCAGGTGATTCTGGAGCTGCCCGAGCAGTCGGAGAAGCAGAAGGATGCCGTGGTGCGACTCATCCACCTCCGGCTGAAGCTCCAGGAGCTGAAGGACCCCAATGAGGATGAGCCAAACATCCGAGTGCTCCTTGAGCACCGCTTTTACAAGGAGAAGAGCAAGAGCGTCAAGCAGACCTGTGACAAGTGTAACACCATCATCTGGGGGCTCATTCAGACCTGGTACACCTGCACAGGGTGTTATTACCGCTGTCACAGTAAGTGCTTGAACCTCATCTCCAAGCCCTGTGTGAGCTCCAAAGTCAGCCACCAAGCTGAATACGAACTGAACATCTGCCCTGAGACAGGGCTGGACAGCCAGGATTACCGCTGTGCCGAGTGCCGGGCGCCCATCTCTCTGCGGGGTGTGCCCAGTGAGGCCAGGCAGTGCGACTACACCGGCCAGTACTACTGCAGCCACTGCCACTGGAACGACCTGGCTGTGATCCCTGCACGCGTTGTACACAACTGGGACTTTGAGCCTCGAAAGGTTTCTCGCTGCAGCATGCGCTACCTGGCGCTGATGGTGTCTCGGCCCGTACTCAGGCTCCGGGAGATCAACCCTCTGCTGTTCAGCTACGTGGAGGAGCTGGTGGAGATTCGCAAGCTGCGCCAGGACATCCTGCTCATGAAGCCGTACTTCATCACCTGCAGGGAGGCCATGGAGGCTCGTCTGCTGCTGCAGGACCTCCTGGACGTGCATGCCGGCCGCCTGGGCTGCTCGCTCACCGAGATCCACACGCTCTTCGCCAAGCACATCAAGCTGGACTGCGAGCGGTGCCAGGCCAAGGGCTTCGTGTGTGAGCTCTGCAGAGAGGGCGACGTGCTGTTCCCGTTCGACAGCCACACGTCTGTGTGCGCCGACTGCTCCGCGGTCTTCCACAGGGACTGCTACTACGACAACTCCACCACTTGTCCCAAGTGTGCCCGGCTCAGCCTGAGGAAGCAGTCGCTCTTCCAGGAGCCAGGTCCCGATGTGGAGGCCTAGCGCCGAGGAACAGTGCTGGGCACCCCGCCTGGCCCGCCAGGACCCACCCTGCCAACATCAAGTTGTTCCTTCTGCTCCGGAGAORF Start: ATG at 58ORF Stop: TAG at 1360SEQ ID NO:98434 aaMW at 50159.9DaNOV37c,MEYDEKLARFRQAHLNPFNKQSGPRQHEQGPGEEVPDVTPEEALPELPPGEPEFRCPECG97563-03Protein SequenceRVMDLGLSEDHFSRPVGLELASDVQQLRQAIEECKQVILELPEQSEKQKDAVVRLIHLRLKLQELKDPNEDEPNIRVLLEHRFYKEKSKSVRQTCDKCNTIIWGLIQTWYTCTGCYYRCHSKCLNLISKPCVSSKVSHQAEYELNICPETGLDSQDYRCAECRAPISLRGVPSEARQCDYTGQYYCSHCHWNDLAVIPARVVHNWDFEPRKVSRCSMRYLALMVSRPVLRLREINPLLFSYVEELVEIRKLRQDILLMKPYFITCREAMEARLLLQDLLDVHAGRLGCSLTEIHTLFAKHIKLDCERCQAKGFVCELCREGDVLFPFDSHTSVCADCSAVFHRDCYYDNSTTCPKCARLSLRKQSLFQEPGPDVEASEQ ID NO:991444 bpNOV37d,CGGCCGCGTCGACGATGCAGGTGGGATGCTATGGAATATGATGAGAAGCTGGCCCGTTCG97563-04DNA SequenceTCCGGCAGGCCCACCTCAACCCCTTCAACAAGCAGTCTGGGCCGAGACAGCATGAGCAGGGCCCCTGGGGAGGAGGTCCCGGACGTCACTCCTGAAGAGGCCCTGCCTGAGCTGCCCCCTGGGGAGCCGGAATTCCGCTGCCCTGAACGCGTGATGGATCTCGGCCTGTCTGAGGACCACTTCTCCCGCCCTGTGGGTCTGTTCCTGGCCTCTGACGTCCAGCAGCTGCGGCAGGCGATCGAGGAGTGCAAGCAGGTGATTCTGGAGCTGCCCGAGCAGTCGGAGAAGCAGAAGGATGCCGTGGTGCGACTCATCCACCTCCGGCTGAAGCTCCAGGAGCTGAAGGACCCCAATGAGGATGAGCCAAACATCCGAGTGCTCCTTGAGCACCGCTTTTACAAGGAGAAGAGCAAGAGCGTCAAGCAGACCTGTGACAAGTGTAACACCATCATCTGGGGGCTCATTCAGACCTGGTACACCTGCACAGGGTGTTATTACCGCTGTCACAGTAAGTGCTTGAACCTCATCTCCAAGCCCTGTGTGAGCTCCAAAGTCAGCCACCAAGCTGAATACGAACTGAACATCTGCCCTGAGACAGGGCTGGACAGCCAGGATTACCGCTGTGCCGAGTGCCGGGCGCCCATCTCTCTGCGGGGTGTGCCCAGTGAGGCCAGGCAGTGCGACTACACCGGCCAGTACTACTGCAGCCACTGCCACTGGAACGACCTGGCTGTGATCCCTGCACGCGTTGTACACAACTGGGACTTTGAGCCTCGAAAGGTTTCTCGCTGCAGCATGCGCTACCTGGCGCTGATGGTGTCTCGGCCCGTACTCAGGCTCCGGGAGATCAACCCTCTGCTGTTCAGCTACGTGGAGGAGCTGGTGGAGATTCGCAAGCTGCGCCAGGACATCCTGCTCATGAAGCCGTACTTCATCACCTGCAGGGAGGCCATGGAGGCTCGTCTGCTGCTGCAGCTCCAGGATCGGCAGCATTTTGTGGAGAACGACGAGATGTACTCTGTCCAGGACCTCCTGGACGTGCATGCCGGCCGCCTGGGCTGCTCGCTCACCGAGATCCACACGCTCTTCGCCAAGCACATCAAGCTGGACTGCGAGCGGTGCCAGGCCAAGGGCTTCGTGTGTGAGCTCTGCAGAGAGGGCGACGTGCTGTTCCCGTTCGACAGCCACACGTCTGTGTGCGCCGACTGCTCCGCGGTCTTCCACAGGGACTGCTACTACGACAACTCCACCACTTGTCCCAAGTGTGCCCGGCTCAGCCTGAGGAAGCAGTCGCTCTTCCAGGAGCCAGGTCCCGATGTGGAGGCCTAGCGCCGAGGAACAGTGCTGGGCACCCCGCCTGGCCCGCCAGGACCCACCCTGCCAACAORF Start: ATG at 26ORF Stop: TAG at 1385SEQ ID NO: 100453 aaMW at 52238.2DaNOV37d,MLWNMMRSWPVSCRPTSTPSTSSLCRDSMSRAPGEEVPDVTPEEALPELRPGEPEFRCCG97563-04Protein SequencePERVMDLGLSEDHFSRPVGLFLASDVQQLRQAIEECKQVILELPEQSEKQKDAVVRLIHLRLKLQELKUPNEDEPNIRVLLEHRFYKEKSKSVKQTCDKCNTIIWGLIQTWYTCTGCYYRCHSKCLNLISKPCVSSKVSHQAEYELNICPETGLDSQDYRCAECRAPISLRGVPSEARQCDYTGQYYCSHCHWNDLAVIPARVVHNWDFEPRKVSRCSMRYLALMVSRPVLRLREINPLLFSYVEELVEIRKLRQDILLMKPYFITCREAMEARLLLQLQDRQHFVENDEMYSVQDLLDVHAGRLCCSLTEIHTLFAKHIKLDCERCQAKGFVCELCREGDVLFPFDSHTSVCADCSAVFHRDCYYDNSTTCPKCARLSLRKQSLPQEPGPDVEASEQ ID NO: 1011526 bpNOV37e,GCAGGTGGGATGCTATGGAATATGATGAGAAGCTGGCCCGTTTCCGGCAGGCCCACCTCG97563-05DNA SequenceCAACCCCTTCAACAAGCAGTCTGGGCCGAGACAGCATGAGCGGGGCCCTGGGGAGGAGGTCCCGGACGTCACTCCTGAAGAGGCCCTGCCTGAGCTGCCCCCTGGGGAGCCGGAATTCCGCTGCCCTGAACGCGTGATGGATCTCGGCCTGTCTGAGGACCACTTCTCCCACCCTGTGCTGCGGCAGGCGATCGAGGAGTGCAAGCAGGTGATTCTGGAGCTGCCCGAGCAGTCGGAGAAGCAGAAGGATGCCGTGGTGCGACTCATCCACCTCCGGCTGAAGCTCCAGGAGCTGAAGGACCCCAATGAGGATGAGCCAAACATCCGAGTGCTCCTTGAGCACCGCTTTTACAAGGAGAAGAGCAAGAGCGTCAAGCAGACCTGTGACAAGTGTAACACCATCATCTGGGGGCTCATTCAGACCTGGTACACCTGCACAGGGTGTTATTACCGCTGTCACAGTAAGTGCTTGAACCTCATCTCCAAGCCCTGTGTGAGCTCCAAAGTCAGCCACCAAGCTGAATACGAACTGAACATCTGCCCTGAGACAGGGCTGGACAGCCAGGATTACCGCTGTGCCGAGTGCCGGGCGCCCACCTCTCTGCGGGGTGTGCCCAGTGAGGCCAGGCAGTGCGACTACACCGGCCAGTACTACTGCAGCCACTGCCACTGGAACGACCTGGCTGTGATCCCTGCACGCGTTGTACACAACTGGGACTTTGAGCCTCGAAAGGTTTCTCGCTGCAGCATGCGCTACCTGGCGCTGATGGTGTCTCGGCCCGTACTCAGGCTCCGGGAGATCAACCCTCTGCTGTTCAGCTACGTGGAGGAGCTGGTGGAGATTCGCAAGCTGCGCCAGGACATCCTGCTCATGAAGCCGTACTTCATCACCTGCAGGGAGGCCATGGAGGCTCGTCTGCTGCTGCAGGACCTCCTGGACGTGCATGCCGGCCGCCTGGGCTGCTCGCTCACCGAGATCCACACGCTCTTCCGCAAGCACATCAAGCTGGACTGCGAGCGGTGCCAGGCCAAGGGCTTCGTGTGTGAGCTCTGCAGAGAGGGCGACGTGCTGTTCCCGTTCGACAGCCACACGTCTGTGTGCGCCGACTGCTCCGCGGTCTTCCACAGGGACTGCTACTACGACAACTCCACCACTTGTCCCAAGTGTGCCCGGCTCAGCCTGAGGAAGCAGTCGCTCTTCCAGGAGCCAGGTCCCGATGTGGAGGCCTAGCGCCGAGGAACAGTGCTGGGCACCCCGCCTGGCCCGCCAGGACCCACCCTGCCAACATCAAGTTGTTCCTTCTGCTCCGGAGACCCCTGGGGTGCGGCCCTGGCCCCCTCCACCCCTGCTGGGCCAGAGCGGGTGGGCAGTGTCAAGGCCCGCTGTCTCCCAGGTGCTTGCTGGGACTCGGGGCGGCTGCACCTGGCTGTCACCTGGGTGTGCTGCTGTGAGGGGTCCTTGCGTGGCORF Start: ATG at 15ORF Stop: TAG at 1287SEQ ID NO: 102424 aaMW at 49097.7DaNOV37c,MEYDEKLARFRQAHLNPFNKQSGPRQHERGPGEEVPDVTPEEALPELPPGEPEFRCPECG97563-05Protein SequenceRVMDLGLSEDHFSHPVLRQAIEECKQVILELPEQSEKQKDAVVRLIHLRLKLQELKDPNEDEPNIRVLLEHRFYKEKSKSVKQTCDKCNTTIWGLIQTWYTCTGCYYRCHSKCLNLISKPCVSSKVSHQAEYELNICPETGLDSQDYRCAECRAPTSLRGVPSEARQCDYTGQYYCSHCHWNDLAVIPARVVHNWDFEPRKVSRCSMRYLALMVSRPVLRLREINPLLFSYVEELVEIRKLRQDILLMKPYFITCREAMEARLLLQDLLDVHAGRLGCSLTEIHTLFAKHIKLDCERCQAKGFVCELCREGDVLFPFDSHTSVCADCSAVFHRDCYYDNSTTCPKCARLSLRKQSLFQEPGPDVEA

[0501] Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 37B.

178TABLE 37BComparison of NOV37a against NOV37b through NOV37e.ProteinNOV37a Residues/Identities/SimilaritiesSequenceMatch Residuesfor the Matched RegionNOV37b 1 . . . 429417/434 (96%) 1 . . . 434418/434 (96%)NOV37c 1 . . . 429417/434 (96%) 1 . . . 434418/434 (96%)NOV37d29 . . . 429387/423 (91%)31 . . . 453389/423 (91%)NOV37e 1 . . . 429404/434 (93%) 1 . . . 424406/434 (93%)

[0502] Further analysis of the NOV37a protein yielded the following properties shown in Table 37C.

179TABLE 37CProtein Sequence Properties NOV37aPsort0.4500 probability located in cytoplasm; 0.3000 probabilityanalysis:located in microbody (peroxisome); 0.1000 probability locatedin mitochondrial matrix space; 0.1000 probability located inlysosome (lumen)SignalPNo Known Signal Sequence Predictedanalysis:

[0503] A search of the NOV37a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 37D.

180TABLE 37DGeneseq Results for NOV37aNOV37aIdentities/Protein/Residues/Similarities forGeneseqOrganism/LengthMatchthe MatchedExpectIdentifier[Patent #, Date]ResiduesRegionValueAAG93324Human protein 1 . . . 429427/451 (94%)0.0HP10370—Homo 1 . . . 451428/451 (94%)sapiens, 451 aa.[WO200142302-A1, 14 JUN.2001]AAM42123Human poly- 1 . . . 288283/294 (96%) e−169peptide SEQ ID 52 . . . 345284/294 (96%)NO 7054—Homosapiens, 345 aa.[WO200153312-A1, 26 JUL.2001]AAB41909Human ORFX 1 . . . 251249/256 (97%) e−150ORF1673 poly- 1 . . . 256250/256 (97%)peptide sequenceSEQ ID NO:3346—Homosapiens, 263 aa.[WO200058473-A2, 05 OCT.2000]AAB42275Human ORFX253 . . . 429177/194 (91%)3e−99 ORF2039 poly- 1 . . . 194177/194 (91%)peptide sequenceSEQ ID NO:4078—Homosapiens, 194 aa.[WO200058473-A2, 05 OCT.2000]AAM40337Human poly- 1 . . . 167167/172 (97%)2e−94 peptide SEQ ID 1 . . . 172167/172 (97%)NO 3482—Homosapiens, 197 aa.[WO200153312-A1, 26 JUL.2001]

[0504] In a BLAST search of public sequence datbases, the NOV37a protein was found to have homology to the proteins shown in the BLASTP data in Table 37E.

181TABLE 37EPublic BLASTP Results for NOV37aNOV37aIdentities/ProteinResidues/Similarities forAccessionProtein/Matchthe MatchedExpectNumberOrganism/LengthResiduesPortionValueQ99J78Similar to 1 . . . 429401/448 (89%)0.0hypothetical protein 1 . . . 448412/448 (91%)FLJ20186—Musmusculus (Mouse),448 aa.Q9NXL0CDNA FLJ20186 1 . . . 167167/172 (97%)5e−94fis, clone 1 . . . 172167/172 (97%)COLF0428(Hypothetical 23.0kDa protein)—Homo sapiens(Human), 197 aa.Q9VTT9CG11534 protein 75 . . . 419135/382 (35%)1e−71(GH12489P)— 86 . . . 466207/382 (53%)Drosophilamelanogaster(Fruit fly), 492 aa.O01738Hypothetical 56.5 92 . . . 417127/357 (35%)9e−59kDa protein—115 . . . 470190/357 (52%)Caenorhabditiselegans, 486 aa.Q8TEL9FLJ00174 protein—194 . . . 420 78/246 (31%)4e−33Homo sapiens385 . . . 627130/246 (52%)(Human), 628 aa(fragment).

[0505] PFam analysis predicts that the NOV37a protein contains the domains shown in the Table 37F.

182TABLE 37FDomain Analysis of NOV37aPfamNOV37aIdentities/SimilaritiesExpectDomaimMatch Regionfor the Matched RegionValueDAG_PE-bind134 . . . 18416/54 (30%)0.0001937/54 (69%)zf-C3HC4393 . . . 409 7/28 (25%)0.23 16/28 (57%)PHD367 . . . 41211/53 (21%)0.13 24/53 (45%)

Example B

Sequencing Methodology and Identification of NOVX Clones

[0506] 1. GeneCalling™ Technology: This is a proprietary method of performing differential gene expression profiling between two or more samples developed at CuraGen and described by Shimkets, et al., “Gene expression analysis by transcript profiling coupled to a gene database query” Nature Biotechnology 17:198-803 (1999). cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then digested with up to as many as 120 pairs of restriction enzymes and pairs of linker-adaptors specific for each pair of restriction enzymes were ligated to the appropriate end. The restriction digestion generates a mixture of unique cDNA gene fragments. Limited PCR amplification is performed with primers homologous to the linker adapter sequence where one primer is biotinylated and the other is fluorescently labeled. The doubly labeled material is isolated and the fluorescently labeled single strand is resolved by capillary gel electrophoresis. A computer algorithm compares the electropherograms from an experimental and control group for each of the restriction digestions. This and additional sequence-derived information is used to predict the identity of each differentially expressed gene fragment using a variety of genetic databases. The identity of the gene fragment is confirmed by additional, gene-specific competitive PCR or by isolation and sequencing of the gene fragment.

[0507] 2. SeqCalling™ Technology: cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate (gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then sequenced using CuraGen's proprietary SeqCalling technology. Sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations.

[0508] 3. PathCalling™ Technology: The NOVX nucleic acid sequences are derived by laboratory screening of cDNA library by the two-hybrid approach. cDNA fragments covering either the full length of the DNA sequence, or part of the sequence, or both, are sequenced. In silico prediction was based on sequences available in CuraGen Corporation's proprietary sequence databases or in the public human sequence databases, and provided either the full length DNA sequence, or some portion thereof.

[0509] The laboratory screening, was performed using the methods summarized below:

[0510] cDNA libraries were derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then directionally cloned into the appropriate two-hybrid vector (Gal4-activation domain (Gal4-AD) fusion). Such cDNA libraries as well as commercially available cDNA libraries from Clontech (Palo Alto, Calif.) were then transferred from E. coli into a CuraGen Corporation proprietary yeast strain (disclosed in U.S. Pat. Nos. 6,057,101 and 6,083,693, incorporated herein by reference in their entireties).

[0511] Gal4-binding domain (Gal4-BD) fusions of a CuraGen Corportion proprietary library of human sequences was used to screen multiple Gal4-AD fusion cDNA libraries resulting in the selection of yeast hybrid diploids in each of which the Gal4-AD fusion contains an individual cDNA. Each sample was amplified using the polymerase chain reaction (PCR) using non-specific primers at the cDNA insert boundaries. Such PCR product was sequenced; sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations.

[0512] Physical clone: the cDNA fragment derived by the screening procedure, covering the entire open reading frame is, as a recombinant DNA, cloned into pACT2 plasmid (Clontech) used to make the cDNA library. The recombinant plasmid is inserted into the host and selected by the yeast hybrid diploid generated during the screening procedure by the mating of both CuraGen Corporation proprietary yeast strains N 106′ and YULH (U.S. Pat. Nos. 6,057,101 and 6,083,693).

[0513] 4. RACE: Techniques based on the polymerase chain reaction Such as rapid amplification of cDNA ends (RACE), were used to isolate or complete the predicted sequence of the cDNA of the invention. Usually multiple clones were sequenced from one or more human samples to derive the sequences for fragments. Various human tissue samples from different donors were used for the RACE reaction. The sequences derived from these procedures were included in the SeqCalling Assembly process described in preceding paragraphs.

[0514] 5. Exon Linking: The NOVX target sequences identified in the present invention were subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case of the reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) of the DNA or protein sequence of the target sequence, or by translated homology of the predicted exons to closely related human sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain—amygdala, brain—cerebellum, brain—hippocampus, brain—substantia nigra, brain—thalamus, brain—whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma—Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The PCR product derived from exon linking was cloned into the pCR2.1 vector from Invitrogen. The resulting bacterial clone has an insert covering the entire open reading frame cloned into the pCR2.1 vector. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component of the assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported herein.

[0515] 6. Physical Clone: Exons were predicted by homology and the intron/exon boundaries were determined using standard genetic rules. Exons were Further selected and refined by means of similarity determination using multiple BLAST (for example, tBlastN, BlastX, and BlastN) searches, and, in some instances, GeneScan and Grail. Expressed sequences from both public and proprietary databases were also added when available to further define and complete the gene sequence. The DNA sequence was then manually corrected for apparent inconsistencies thereby obtaining the sequences encoding the full-length protein.

[0516] The PCR product derived by exon linking, covering the entire open reading frame, was cloned into the pCR2.1 vector from Invitrogen to provide clones used for expression and screening, purposes.

Example C

Quantitative Expression Analysis of Clones in Various Cells and Tissues

[0517] The quantitative expression of various clones was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell lines and tissues using real time quantitative PCR (RTQ PCR). RTQ PCR was performed on an Applied Biosystems ABI PRISM® 7700 or an ABI PRISM® 7900 FIT Sequence Detection System. Various collections of samples are assembled on the plates, and referred to as Panel 1 (containing normal tissues and cancer cell lines), Panel 2 (containing samples derived from tissues from normal and cancer sources), Panel 3 (containing cancer cell lines), Panel 4 (containing cells and cell lines from normal tissues and cells related to inflammatory conditions), Panel SD/51 (containing human tissues and cell lines with an emphasis on metabolic diseases), AI_comprehensive_panel (containing normal tissue and samples from autoimmune/autoinflammatory diseases). Panel CNSD.01 (containing samples from normal and diseased brains) and CNS_neurodegeneration_panel (containing samples from normal and Alzheimer's diseased brains).

[0518] RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s: 18s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon.

[0519] First, the RNA samples were normalized to reference nucleic acids such as Constitutively expressed genes (for example, β-actin and GAPDH). Normalized RNA (5 ul) was converted to cDNA and analyzed by RTQ-PCR using One Step RT-PCR Master Mix Reagents (Applied Biosystems; Catalog No. 4309169) and genie-specific primers according to the manufacturer's instructions.

[0520] In other cases, non-normalized RNA samples were converted to single strand cDNA (sscDNA) using Superscript II (Invitrogen Corporation; Catalog No. 18064-147) and random hexamers according to the manufacturer's instructions. Reactions containing up to 10 μg of total RNA were performed in a volume of 20 μl and incubated for 60 minutes at 42° C. This reaction can be scaled up to 50 μg of total RNA in a final volume of 100 μl. sscDNA samples are then normalized to reference nucleic acids as described previously, using 1×TaqMan® Universal Master mix (Applied Biosystems; catalog No.4324020), following the manufacturer's instructions.

[0521] Probes and primers were designed for each assay according to Applied Biosystems Primer Express Software package (version 1 for Apple Computer's Macintosh Power PC) or a similar algorithm using the target sequence as input. Default settings were used for reaction conditions and the following parameters were set before selecting primers: primer concentration=250 nM, primer melting temperature (Tm) range=58°-60° C., primer optimal Tm=59° C., maximum primer difference=2° C., probe does not have 5′G, probe Tm must be 10° C. greater than primer Tm, amplicon size 75 bp to 100 bp. The probes and primers selected (see below) were synthesized by Synthegen (Houston, Tex., USA). Probes were double purified by HPLC to remove uncoupled dye and evaluated by mass spectroscopy to verify coupling of reporter and quencher dyes to the 5′ and 3′ ends of the probe, respectively. Their final concentrations were: forward and reverse primers, 900 nM each, and probe 200 nM.

[0522] PCR conditions: When working with RNA samples, normalized RNA from each tissue and each cell line was spotted in each well of either a 96 well or a 384-well PCR plate (Applied Biosystems). PCR cocktails included either a single gene specific probe and primers set, or two multiplexed probe and primers sets (a set specific for the target clone and another gene-specific set multiplexed with the target probe). PCR reactions were set up using TaqMan® One-Step RT-PCR Master Mix (Applied Biosystems, Catalog No. 4313803) following manufacturer's instructions. Reverse transcription was performed at 48° C. for 30 minutes followed by amplification/PCR cycles as follows: 95° C. 10 min. then 40 cycles of 95° C. for 15 seconds, 60° C. for 1 minute. Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression is then obtained by taking the reciprocal of this RNA difference and multiplying by 100.

[0523] When working with sscDNA samples, normalized sscDNA was used as described previously for RNA samples. PCR reactions containing one or two sets of probe and primers were set up as described previously, using 1×TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification was performed as follows: 95° C. 10 min. then 40 cycles of 95° C. for 15 seconds, 60° C. for 1 minute. Results were analyzed and processed as described previously.

Panels 1, 1.1, 1.2, and 1.3D

[0524] The plates for Panels 1, 1.1, 1.2 and 1.3D include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in these panels are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer-, gastric cancer and pancreatic cancer. Cell lines used in these panels are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on these panels are comprised of samples derived from all major organ systems from single adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver fetal liver, adult lung, fetal lung various regions of the brain the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose.

[0525] In the results for Panels 1, 1.1, 1.2 and 1.3D, the following abbreviations are used:

[0526] ca.=carcinoma,

[0527] *=established from metastasis,

[0528] met=metastasis,

[0529] s cell var=small cell variant,

[0530] non-s=non-sm=non-small,

[0531] squam=squamous,

[0532] pl. eff=pl effusion=pleural effusion,

[0533] glio=glioma,

[0534] astro=astrocytoma, and

[0535] neuro=neuroblastoma.

General_screening_panel_v1.4, v1.5 and v1.6

[0536] The plates for Panels 1.4, v1.5 and v1.6 include two control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in Panels 1.4, v1.5 and v1.6 are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in Panels 1.4, v1.5 and v1.6 are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on Panels 1.4, v1.5 and v1.6 are comprised of pools of samples derived from all major organ systems from 2 to 5 different adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. Abbreviations are as described for Panels 1, 1.1, 1.2, and 1.3D.

Panels 2D, 2.2, 2.3 and 2.4

[0537] The plates for Panels 2D, 2.2, 2.3 an 2.4 generally include two control wells and 94 test samples composed of RNA or cDNA isolated from human tissue procured by surgeons working in close cooperation with the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative (NDRI) or from Ardais or Clinomics. The tissues are derived from human malignancies and in cases where indicated many malignant tissues have “matched margins” obtained from noncancerous tissue just adjacent to the tumor. These are termed normal adjacent tissues and are denoted “NAT” in the results below. The tumor tissue and the “matched margins” are evaluated by two independent pathologists (the surgical pathologists and again by a pathologist at NDRI/CHTN/Ardais/Clinomics). Unmatched RNA samples from tissues without malignancy (normal tissues) were also obtained from Ardais or Clinomics. This analysis provides a gross histopathological assessment of tumor differentiation grade. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical stage of the patient. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated “NAT”, for normal adjacent tissue, in Table RR). In addition, RNA and cDNA samples were obtained from various human tissues derived from autopsies performed on elderly people or sudden death victims (accidents, etc.). These tissues were ascertained to be free of disease and were purchased from various commercial sources such as Clontech (Palo Alto, Calif.), Research Genetics, and Invitrogen. General oncology screening panel_v—2.4 is an updated version of Panel 2D.

HASS Panel v1.0

[0538] The HASS panel v1.0 plates are comprised of 93 cDNA samples and two controls. Specifically, 81 of these samples are derived from cultured human cancer cell lines that had been subjected to serum starvation, acidosis and anoxia for different time periods as well as controls for these treatments, 3 samples of human primary cells, 9 samples of malignant brain cancer (4 medulloblastomas and 5 glioblastomas) and 2 controls. The human cancer cell lines are obtained from ATCC (American Type Culture Collection) and fall into the following tissue groups: breast cancer, prostate cancer, bladder carcinomas, pancreatic cancers and CNS cancer cell lines. These cancer cells are all cultured under standard recommended conditions. The treatments used (serum starvation, acidosis and anoxia) have been previously published in the scientific literature. The primary human cells were obtained from Clonetics (Walkersville, Md.) and were grown in the media and conditions recommended by Clonetics. The malignant brain cancer samples are obtained as part of a collaboration (Henry Ford Cancer Center) and are evaluated by a pathologist prior to CuraGen receiving the samples. RNA was prepared from these samples using the standard procedures. The genomic and chemistry control wells have been described previously.

Panels 3D and 3.1

[0539] The plates of Panels 3D and 3.1 are comprised of 94 cDNA samples and two control samples. Specifically, 92 of these samples are derived from cultured human cancer cell lines, 2 samples of human primary cerebellar tissue and 2 controls. The human cell lines are generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: Squamous cell carcinoma of the tongue, breast cancer, prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon, lung and CNS cancer cell lines. In addition, there are two independent samples of cerebellum. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. The cell lines in panel 3D and 1.3D are of the most common cell lines used in the scientific literature. Oncology_cell_line_screening_panel_v3.2 is an updated version of Panel 3. The cell lines in panel 3D, 3.1, 1.3D and oncology cell line screening_panel_v3.2 are of the most common cell lines used in the scientific literature.

Panels 4D, 4R, and 4.1D

[0540] Panel 4 includes samples on a 96 well plate (2 control wells, 94 test samples) composed of RNA (Panel 4R) or cDNA (Panels 4D/4.1D) isolated from various human cell lines or tissues related to inflammatory conditions. Total RNA from control normal tissues such as colon and lung (Stratagene, La Jolla, Calif.) and thymus and kidney (Clontech) was employed. Total RNA from liver tissue from cirrhosis patients and kidney from lupus patients was obtained from BioChain (Biochain Institute, Inc., Hayward, Calif.). Intestinal tissue for RNA preparation from patients diagnosed as having Crohn's disease and ulcerative colitis was obtained from the National Disease Research Interchange (NDRI) (Philadelphia, Pa.).

[0541] Astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, human umbilical vein endothelial cells were all purchased from Clonetics (Walkersville, Md.) and grown in the media supplied for these cell types by Clonetics. These primary cell types were activated with various cytokines or combinations of cytokines and/or 12-14 hours, as indicated. The following cytokines were used; IL-1 beta at approximately 1-5 ng/ml, TNF alpha at approximately 5-10 ng/ml, IFN gamma at approximately 20-50 ng/ml, IL-4 at approximately 5-10 ng/ml, IL-9 at approximately 5-10 ng/ml, IL-13 at approximately 5-10 ng/ml. Endothelial cells were sometimes starved for various times by culture in the basal media from Clonetics with 0.1% serum.

[0542] Mononuclear cells were prepared from blood of employees at CuraGen Corporation, using Ficoll. LAK cells were prepared from these cells by culture in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco/Life Technologies, Rockville, Md.), 1 mM sodium pyruvate (Gibco), mer-captoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) and Interleukin 2 for 4-6 days. Cells were then either activated with 10-20 ng/ml PMA and 1-2 μg/ml ionomycin, IL-12 at 5-10 ng/ml, IFN gamma at 20-50 ng/ml and IL-18 at 5-10 ng/ml for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 0 mM Hepes (Gibco) with PHA (phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5 μg/ml. Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from two donors, isolating the mononuclear cells using Ficoll and mixing the isolated mononuclear cells 1:1 at a final concentration of approximately 2×106 cells/ml in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol

[0543] (5.5×10−5M) (Gibco), and 10 mM Hepes (Gibco). The MLR was cultured and samples taken at various tine points ranging from 1-7 days for RNA preparation.

[0544] Monocytes were isolated from mononuclear cells using CD14 Miltenyi Beads, +ve VS selection columns and a Vario Magnet according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone, Logan, Utah), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco), 50 ng/ml GMCSF and 5 ng/ml IL-4 for 5-7 days. Macrophages were prepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco) and 10% AB Human Serum or MCSF at approximately 50 ng/ml Monocytes, macrophages and dendritic cells were stimulated for 6 and 12-14 hours with lipopolysaccharide (LPS) at 10 ng/ml. Dendritic cells were also stimulated with anti-CD40 monoclonal antibody (Pharmingen) at 10 μg/ml and 12-14 hours.

[0545] CD4 lymphocytes, CD8 lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection columns and a Vario Magnet according to the manufacturer's instructions. CD45RA and CD45RO CD4 lymphocytes were isolated by depleting mononuclear cells of CD8, CD56, CD14 and CD19 cells using CD8, CD56, CD14 and CD19 Miltenyl beads and positive selection. CD45RO beads were then used to isolate the CD45RO CD4 lymphocytes with the remaining cells being CD45PA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8 lymphocytes were placed in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×105M (Gibco), and 10 mM Hepes (Gibco) and plated at 106cells/ml onto Falcon 6 well tissue culture plates that had been coated overnight with 0.5 μg/ml anti-CD28 (Pharmingen) and 3 ug/ml anti-CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA preparation. To prepare chronically activated CD8 lymphocytes, we activated the isolated CD8 lymphocytes for 4 days on anti-CD28 and anti-CD3 coated plates and then harvested the cells and expanded them in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) and IL-2. The expanded CD8 cells were then activated again with plate bound anti-CD3 and anti-CD28 for 4 days and expanded as before. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culture. The isolated NK cells were cultured in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) and IL-2 for 4-6 days before RNA was prepared.

[0546] To obtain B cells, tonsils were procured from NDRI. The tonsil was cut up with sterile dissecting scissors and then passed through a sieve. Tonsil cells were then spun down and resupended at 106 cells/m in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco). To activate the cells, we used PWM at 5 μg/ml or anti-CD40 (Pharmingen) at approximately 10 μg/ml and IL-4 at 5-10ling/mil. Cells were harvested for RNA preparation at 24, 48 and 72 hours.

[0547] To prepare the primary and secondary Th1/Th2 and Tr1 cells, six-well Falcon plates were coated overnight with 10 μg/ml anti-CD28 (Pharmingen) and 2 μg/ml OKT3 (ATCC), and then washed twice with PBS. Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, Md.) were cultured at 105-106cells/ml in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco) and IL-2 (4 ng/ml). IL-12 (5 ng/ml) and anti-IL4 (1 μg/ml) were used to direct to Th1, while IL-4 (5 ng/ml) and anti-IFN gamma (1 μg/ml) were used to direct to Th2 and IL-10 at 5 ng/ml was used to direct to Tr1. After 4-5 days, the activated Th1, Th2 and Tr1 lymphocytes were washed once in DMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco) and IL-2 (1 ng/ml). Following this, the activated Th1, Th2 and Tr1 lymphocytes were re-stimulated for 5 days with anti-CD28/OKT3 and cytokines as described above, but with the addition of anti-CD95L (1 μg/ml) to prevent apoptosis. After 4-5 days, the Th1, Th2 and Tr1 Lymphocytes were washed and then expanded again with IL-2 for 4-7 days. Activated Th1 and Th2 lymphocytes were maintained in this way for a maximum of three cycles. RNA was prepared from primary and secondary Th1, Th2 and Tr1 after 6 and 24 hours following the second and third activations with plate bound anti-CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures in Interleukin 2.

[0548] The following leukocyte cells lines were obtained from the ATCC: Ramos, EOL-1, KU-812. EOL, cells were Further differentiated by culture in 0.1 mM dbcAMP at 5×105cells/ml for 8 days, changing the media every 3 days and adjusting the cell concentration to 5×105cells/ml. For the culture of these cells, we used DMEM or RPMI (as recommended by the ATCC), with the addition of 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco). RNA was either prepared from resting cells or cells activated with PMA at 10 ng/ml and ionomycin at 1 μg/ml for 6 and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumor line NCI-H292 were also obtained from the ATCC. Both were cultured in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco). CCD1106 cells were activated for 6 and 14 hours with approximately 5 ng/ml TNF alpha and 1 ng/ml IL-1 beta, while NCI-H292 cells were activated for 6 and 14 hours with the following cytokines: 5 ng/ml IL-4, 5 ng/1 ml IL-9, 5 ng/ml IL-13 and 25 ng/ml IFN gamma.

[0549] For these cell lines and blood cells, RNA was prepared by lysing approximately 107cells/ml using Trizol (Gibco BRL). Briefly, {fraction (1/10)} volume of bromochloropropane (Molecular Research Corporation) was added to the RNA sample, vortexed and after 10 minutes at room temperature the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor The aqueous phase was removed and placed in a 51 ml Falcon Tube. An equal volume of isopropanol was added and left at −20° C. overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34 rotor and washed in 70% ethanol. The pellet was redissolved in 300 μl of RNAse-free water and 35 μt buffer (Promega) 5 μl DTT, 7 μl RNAsin and 8 μl DNAse were added. The tube was incubated at 37° C. for 30 minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re-precipitated with {fraction (1/10)} volume of 3M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down and placed in RNAse free water. RNA was stored at −80° C.

AI_comprehensive panel_v1.0

[0550] The plates for AI_comprehensive panel_v1.0 include two control wells and 89 test samples comprised of cDNA isolated firm surgical and postmortem human tissues obtained from the Backus Hospital and Clinomics (Frederick, Md.). Total RNA was extracted from tissue samples from the Backus Hospital in the Facility at CuraGen. Total RNA from other tissues was obtained from Clinomics.

[0551] Joint tissues including synovial fluid, synovium, bone and cartilage were obtained from patients undergoing total knee or hip replacement surgery at the Backus Hospital. Tissue samples were immediately snap frozen in liquid nitrogen to ensure that isolated RNA was of optimal quality and not degraded. Additional samples of osteoarthritis and rheumatoid arthritis joint tissues were obtained from Clinomics. Normal control tissues were supplied by Clinomics and were obtained during autopsy of trauma victims.

[0552] Surgical specimens of psoriatic tissues and adjacent matched tissues were provided as total RNA by Clinomics. Two male and two female patients were selected between the ages of 25 and 47. None of the patients were taking prescription drugs at the time samples were isolated.

[0553] Surgical specimens of diseased colon from patients with ulcerative colitis and Crohns disease and adjacent matched tissues were obtained from Clinomics. Bowel tissue from three female and three male Crohn's patients between the ages of 41-69 were used. Two patients were not on prescription medication while the others were taking dexamethasone, phenobarbital, or tylenol. Ulcerative colitis tissue was from three male and four female patients. Four of the patients were taking lebvid and two were on phenobarbital.

[0554] Total RNA from post mortem lung tissue from trauma victims with no disease or with emphysema, asthma or COPD was purchased from Clinomics. Emphysema patients ranged in age from 40-70 and all were smokers, this age range was chosen to focus on patients with cigarette-linked emphysema and to avoid those patients with alpha-1anti-trypsin deficiencies. Asthma patients ranged in age from 36-75, and excluded smokers to prevent those patients that could also have COPD. COPD patients ranged in age from 35-80 and included both smokers and non-smokers. Most patients were taking corticosteroids, and bronchodilators.

[0555] In the labels employed to identify tissues in the AI_comprehensive panel_v1.0 panel, the following abbreviations are used:

[0556] AI=Autoimmunity

[0557] Syn=Synovial

[0558] Normal=No apparent disease

[0559] Rep22/Rep20=individual patients

[0560] RA=Rheumatoid arthritis

[0561] Backus=From Backus Hospital

[0562] OA=Osteoarthritis

[0563] (SS) (BA) (MF)=Individual patients

[0564] Adj=Adjacent tissue

[0565] Match control=adjacent tissues

[0566] -M=Male

[0567] -F=Female

[0568] COPD=Chronic obstructive pulmonary disease

Panels 5D and 5I

[0569] The plates for Panel 5D and 5I include two control wells and a variety of cDNAs isolated from human tissues and cell lines with an emphasis on metabolic diseases. Metabolic tissues were obtained from patients enrolled in the Gestational Diabetes study. Cells were obtained during different stages in the differentiation of adipocytes from human mesenchymal stem cells. Human pancreatic islets were also obtained.

[0570] In the Gestational Diabetes study subjects are young (18-40 years), otherwise healthy women with and without gestational diabetes undergoing, routine (elective) Caesarean section. After delivery of the infant, when the surgical incisions were being repaired/closed, the obstetrician removed a small sample (<1 cc) of the exposed metabolic tissues during the closure of each surgical level. The biopsy material was rinsed in sterile saline, blotted and fast frozen within 5 minutes from the time of removal. The tissue was then flash frozen in liquid nitrogen and stored, individually, in sterile screw-top tubes and kept on dry ice for shipment to or to be picked up by CuraGen. The metabolic tissues of interest include uterine wall (smooth muscle), visceral adipose, skeletal muscle (rectus) and subcutaneous adipose. Patient descriptions are as follows:

[0571] Patient 2 Diabetic Hispanic, overweight, not on insulin

[0572] Patient 7-9 Nondiabetic Caucasian and obese (BMI>30)

[0573] Patient 10 Diabetic Hispanic, overweight, on insulin

[0574] Patient II Nondiabetic African American and overweight

[0575] Patient 12 Diabetic Hispanic on insulin

[0576] Adipocyte differentiation was induced in donor progenitor cells obtained from Osirus (a division of Clonetics/BioWhittaker) in triplicate, except for Donor 3U which had only two replicates. Scientists at Clonetics isolated, grew and differentiated human mesenchymal stein cells (HuMSCs) for CuraGen based on the published protocol found in Mark F. Pittenger, et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells Science Apr. 2, 1999: 143-147. Clonetics provided Trizol lysates or frozen pellets suitable for mRNA isolation and ds cDNA production. A general description of each donor is as follows:

[0577] Donor 2 and 3 U: Mesenchymal Stein cells, Undifferentiated Adipose

[0578] Donor 2 and 3 AM: Adipose, AdiposeMidway Differentiated

[0579] Donor 2 and 3 AD: Adipose, Adipose Differentiated

[0580] Human cell lines were generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following, tissue groups: kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver HepG2 cancer cells, heart primary stromal cells, and adrenal cortical adenoma cells. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. All samples were processed at CuraGen to produce single stranded cDNA.

[0581] Panel 5I contains all samples previously described with the addition of pancreatic islets from a 58 year old female patient obtained from the Diabetes Research Institute at the University of Miami School of Medicine. Islet tissue was processed to total RNA at an outside source and delivered to CuraGen for addition to panel 5I.

[0582] In the labels employed to identify tissues in the 5D and 5I panels, the following abbreviations are used:

[0583] GO Adipose=Greater Omentum Adipose

[0584] SSK=Skeletal Muscle

[0585] UT=Uterus

[0586] PL=Placenta

[0587] AD=Adipose Differentiated

[0588] AM=Adipose Midway Differentiated

[0589] U=Undifferentiated Stem Cells

Panel CNSD.01

[0590] The plates for Panel CNSD.01 include two control wells and 94 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

[0591] Disease diagnoses are taken froth patient records. The panel contains two brains from each of the following diagnoses: Alzheimer's disease, Parkinson's disease, Huntington's disease, Progressive Supernuclear Palsy, Depression, and “Normal controls”. Within each of these brains, the following regions are represented: cingulate gyrus, temporal pole, globus palladus, substantia nigra, Brodman Area 4 (primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9 (prefrontal cortex), and Brodman area 17 (occipital cortex). Not all brain regions are represented in all cases; e.g., Huntington's disease is characterized in part by neurodegeneration in the globus palladus, thus this region is impossible to obtain from confirmed Huntington's cases. Likewise Parkinson's disease is characterized by degeneration of the substantia nigra making this region more difficult to obtain. Normal control brains were examined for neuropathology and found to be free of any pathology consistent with neurodegeneration.

[0592] In the labels employed to identity tissues in the CNS panel, the following abbreviations are used:

[0593] PSP=Progressive supranuclear palsy

[0594] Sub Nigra=Substantia nigra

[0595] Glob Palladus=Globus palladus

[0596] Temp Pole=Temporal pole

[0597] Cing Gyr=Cingulate gyrus

[0598] BA 4=Brodman Area 4

Panel CNS_Neurodegeneration_V1.0

[0599] The plates for Panel CNS_Neurodegeneration_V1.0 include two control wells and 47 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean Hospital) and the Human Brain and Spinal Fluid Resource Center (VA Greater Los Angeles Healthcare System). Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

[0600] Disease diagnoses are taken from patient records. The panel contains six brains from Alzheimer's disease (AD) patients, and eight brains from “Normal controls” who showed no evidence of dementia prior to death. The eight normal control brains are divided into two categories: Controls with no dementia and no Alzheimer's like pathology (Controls) and controls with no dementia but evidence of severe Alzheimer's like pathology, (specifically senile plaque load rated as level 3 on a scale of 0-3; 0=no evidence of plaques, 3=severe AD senile plaque load). Within each of these brains, the following regions are represented: hippocampus, temporal cortex (Brodman Area 21), parietal cortex (Brodman area 7), and occipital cortex (Brodman area 17). These regions were chosen to encompass all levels of neurodegeneration in AD. The hippocampus is a region of early and severe neuronal loss in AD; the temporal cortex is known to show neurodegeneration in AD after the hippocampus; the parietal cortex shows moderate neuronal death in the late stages of the disease; the occipital cortex is spared in AD and therefore acts as a “control” region within AD patients. Not all brain regions are represented in all cases.

[0601] In the labels employed to identify tissues in the CNS_Neurodegeneration_V1.0 panel, the following abbreviations are used:

[0602] AD=Alzheimer's disease brain; patient was demented and showed AD-like pathology upon autopsy

[0603] Control=Control brains; patient not demented, showing no neuropathology

[0604] Control (Path)=Control brains; patent not demented but showing sever AD-like pathology

[0605] SupTemporal Ctx=Superior Temporal Cortex

[0606] InfTemporal Ctx=Inferior Temporal Cortex

[0607] A. CG102232-01: FADD-Interacting Protein (FIP) Like

[0608] Expression of gene CG102232-01 was assessed using the primer-probe sets Ag668 and Ag890, described in Tables AA and AB. Results of the RTQ-PCR runs are shown in Tables AC and AD.

183TABLE AAProbe Name Ag668PrimersSequencesLengthStart PositionSEQ ID NoForward5′-tcctgactcatcctctcagact-3′221692103ProbeTET-5′-actcaggctacgcaatttgctcttga-2616411043′-TAMRAReverse5′-aaacccaactctttggatcagt-3′221619105

[0609]

184

TABLE AB

Probe Name Ag890

Primers
Sequences
Length
Start Position
SEQ ID No

Forward
5′-tgttgaagtcctctgctgttg-3′
21
1551
106

Probe
TET-5′-cttccaggtcttgttcaacagctgga-3′-TAMRA,
26
1515
107

Reverse
5′-ttgaagagctctttggaatctg-3′
22
1491
108

[0610]

185

TABLE AC

Panel 1.1

Rel. Exp.

Rel. Exp.

(%) Ag668,

(%) Ag668,

Run

Run

Tissue Name
109456728
Tissue Name
109456728

Adrenal gland
17.9
Renal ca. UO-31
10.5

Bladder
32.5
Renal ca. RXF 393
4.5

Brain (amygdala)
13.1
Liver
8.6

Brain (cerebellum)
100.0
Liver (fetal)
7.2

Brain (hippocampus)
28.1
Liver ca.
12.7

(hepatoblast) HepG2

Brain (substantia
64.6
Lung
11.9

nigra
)

Brain (thalamus)
39.0
Lung (fetal)
15.5

Cerebral Cortex
42.6
Lung ca. (non-s.
23.8

cell) HOP-62

Brain (fetal)
27.2
Lung ca (large cell)
18.8

NCI-H460

Brain (whole)
45.7
Lung ca. (non-s.
20.4

cell) NCI-H23

glio/astro U-118-MG
11.8
Lung ca. (non-s. cl)
32.3

NCI-H522

astrocytoma SF-539
19.3
Lung ca. (non-sm.
16.0

cell) A549

astrocytoma SNB-75
10.8
Lung ca (s. cell
6.4

var.) SHP-77

astrocytoma SW1783
7.3
Lung ca. (small cell)
14.4

LX-1

glioma U251
6.5
Lung ca. (small cell)
9.1

NCI-H69

glioma SF-295
21.2
Lung ca (squam.)
18.3

SW 900

glioma SNB-19
18.3
Lung ca. (squam.)
6.8

NCI-H596

glio/astro U87-MG
22.5
Lymph node
13.6

neuro*; met SK-N-AS
22.8
Spleen
8.7

Mammary gland
18.0
Thymus
6.9

Breast ca. BT-549
8.9
Ovary
15.2

Breast ca. MDA-N
23.2
Ovarian ca.
19.5

IGROV-1

Breast ca.* (pl. ef)
22.5
Ovarian ca.
22.4

T47D

OVCAR-3

Breast ca.* (pl. ef)
16.3
Ovarian ca.
16.8

MCF-7

OVCAR-4

Breast ca.* (pl. ef)
14.3
Ovarian ca.
22.5

MDA-MB-231

OVCAR-5

Small intestine
19.2
Ovarian ca.
16.2

OVCAR-8

Colorectal
2.4
Ovarian ca.*
21.3

(ascites) SK-OV-3

Colon ca HT29
12.4
Pancreas
67.8

Colon ca CaCo-2
31.0
Pancreatic ca.
3.4

CAPAN 2

Colon ca. HCT-15
7.5
Pituitary gland
31.0

Colon ca. HCT-116
11.6
Placenta
20.3

Colon ca HCC-2998
13.6
Prostate
23.0

Colon ca. SW480
7.7
Prostate ca.* (bone
23.8

met) PC-3

Colon ca* SW620
15.7
Salivary gland
42.0

(SW480 met)

Stomach
14.7
Trachea
9.9

Gastiric ca (liver met)
26.8
Spinal cord
22.4

NCI-N87

Heart
40.9
Testis
18.2

Skeletal muscle
11.3
Thyroid
17.6

(Fetal)

Skeletal muscle
80.7
Uterus
9.0

Endothelial cells
17.8
Melanoma M14
11.3

Heart (Fetal)
8.7
Melanoma LOX
5.8

IMV1

Kidney
44.1
Melanoma
24.0

UACC-62

Kidney (fetal)
16.0
Melanoma
31.4

SK-MEL-28

Renal ca. 786-0
8.4
Melanoma* (met)
19.5

SK MET-5

Renal ca. A498
11.9
Melanoma
3.5

Hs688(A).T

Renal ca ACHN
9.5
Melanoma* (met)
8.8

Hs688(B)T

Renal ca TK-10
14.9

[0611]

186

TABLE AD

Panel 1.2

Rel. Exp.

Rel. Exp.

(%) Ag890,

(%) Ag890,

Run

Run

Tissue Name
118840807
Tissue Name
118840807

Endothelial cells
0.0
Renal ca. 786-0
0.0

Heart (Fetal)
0.0
Renal ca. A498
0.0

Pancreas
66.9
Renal ca RXF 393
0.0

Pancreatic ca
0.0
Renal ca. ACHN
0.0

CAPAN 2

Adrenal Gland
1.2
Renal ca. UO-31
0.0

Thyroid
0.2
Renal ca TK-10
0.0

Salivary gland
0.0
Liver
0.0

Pituitary gland
28.5
Liver (fetal)
0.0

Brain (fetal)
1.7
Liver ca.
0.0

(hepatoblast) HepG2

Brain (whole)
100.0
Lung
0.0

Brain (amygdala)
2.8
Lung (fetal)
0.0

Brain (cerebellum)
11.1
Lung ca. (small
0.0

cell) LX-1

Brain (hippocampus)
33.4
Lung ca. (small
0.0

cell) NCI-H69

Brain (thalamus)
1.8
Lung ca. (s. cell
0.0

var.) SHP-77

Cerebral Cortex
29.7
Lung ca. (large cell)
0.1

NCI-H460

Spinal cord
2.5
Lung ca. (non-sm.
0.0

cell) A549

glio/astro U87-MG
0.0
Lung ca. (non-s.
0.0

cell) NCI-H23

glio/astro U-118-MG
0.0
Lung ca. (non-s.
0.0

cell) HOP-62

astrocytoma SW1783
0.0
Lung ca. (non-s. cl)
6.0

NCI-H522

neuro*; met SK-N-AS
0.0
Lung ca. (squam.)
0.0

SW 900

astrocytoma SF-539
0.0
Lung ca. (squam.)
0.0

NCI-H596

astrocytoma SNB-75
0.0
Mammary gland
0.8

glioma SNB-19
0.0
Breast ca.* (pl. ef)
0.0

MCF-7

glioma U251
0.0
Breast ca* (pl. ef)
0.0

MDA-MB-231

glioma SF-295
0.0
Breast ca* (pl ef)
0.0

T47D

Heart
0.1
Breast ca. BT-549
0.0

Skeletal Muscle
57.4
Breast ca. MDA-N
0.0

Bone marrow
0.0
Ovary
0.0

Thymus
0.0
Ovarian ca.
0.2

OVCAR-3

Spleen
0.0
Ovarian ca
0.0

OVCAR-4

Lymph node
0.0
Ovarian ca.
0.4

OVCAR-5

Colorectal Tissue
0.0
Ovarian ca
0.0

OVCAR-8

Stomach
0.0
Ovarian ca.
0.0

IGROV-1

Small intestine
0.1
Ovarian ca. (ascites)
0.3

SK-OV-3

Colon ca. SW480
0.0
Uterus
0.0

Colon ca.* SW620
0.0
Placenta
0.1

(SW480 met)

Colon ca. HT29
0.0
Prostate
0.1

Colon ca. HCT-116
0.0
Prostate ca.* (bone
0.0

met) PC-3

Colon ca. CaCo-2
0.0
Testis
9.5

Colon ca. Tissue
0.0
Melanoma
0.0

ODO3866)

Hs688(A).T

Colon ca HCC-2998
0.0
Melanoma* (met)
0.0

Hs688(B).T

Gastric ca* (liver
0.5
Melanoma
0.2

met) NCI-N87

UACC-62

Bladder
3.5
Melanoma M14
0.0

Trachea
0.0
Melanoma LOX
0.0

IMVI

Kidney
0.0
Melanoma* (met)
0.0

SK-MEL-5

Kidney (fetal)
0.7

[0612] Panel 1.1 Summary: Ag668 Expression of the CG102232-01 gene is highest in cerebellum (CT=23). This gene is expressed at high levels in all of the samples on this panel.

[0613] Among tissues with metabolic or endocrine function, this gene is expressed at high levels in pancreas, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0614] In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0615] Panel 1.2 Summary: Ag890 Expression of the CG102232-01 gene is highest in brain (CT=23.6). In addition, this gene is expressed at high to moderate levels hi all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Interestingly, expression of this gene appears to be downregulated in CNS cancer cell lines when compared to normal brain tissue.

[0616] Among tissues with metabolic or endocrine function, this gene is expressed at high levels in pancreas, adrenal gland, thyroid, pituitary gland, skeletal muscle, and heart. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0617] B. CG102931-01: ATPASE, H+ Transporting, Lysosomal (Vacuolar Proton Pump)

[0618] Expression of gene CG102931-01 was assessed using the primer-probe set Ag4253, described in Table BA.

[0619] Table BA. Probe Name Ag4253

187TABLE BAProbe Name Ag4253StartPrimersSequencesLengthPositionSEQ ID NoForward5′-gctctggagaggatgaatactg-3′22152109ProbeTET-5′-aacctccaagtccaacctgtcttataa-3′-27175110TAMRAReverse5′-gaagtcaggaatagcgaatttg-3′22205111

[0620] C. CG104307-03 and CG104307-05: FGF-17 Like

[0621] Expression of gene CG104307-03 and variant CG104307-05 was assessed using, the primer-probe sets Ag4832 and Ag4833, described in Tables CA and CB. Results of the RTQ-PCR runs are shown in Tables CC and CD.

188TABLE CAProbe Name Ag4832PrimersSequencesLengthStart PositionSEQ ID NoForward5′-ggagaacaactatacggccttcc-3′23408112ProbeTET-5′-ctggttcatggccttcac-3′-TAMRA18450113Reverse5′-tggttctggcggctgcc-3′17470114

[0622]

189

TABLE CB

Probe Name Ag4833

Primers
Sequences
Length
Start Position
SEQ ID No

Forward
5′-cacttcatcaagcgcctcta-3′
20
497
115

Probe
TET-5′-ccaaccacgccgagaagcagaag-3′-TAMRA
23
537
116

Reverse
5′-agcccacaaactcgaactg-3′
19
560
117

[0623]

190

TABLE CC

CNS_neurodegeneration_v1.0

Rel. Exp.
Rel. Exp.

Rel. Exp.
Rel. Exp.

(%) Ag4833,
(%) Ag4833,

(%) Ag4833,
(%) Ag4833,

Run
Run

Run
Run

Tissue Name
249271250
269217290
Tissue Name
249271250
269217290

AD 1 Hippo
15.3
18.8
Control (Path)
23.2
22.7

3 Temporal

Ctx

AD 2 Hippo
14.0
8.1
Control (Path)
24.0
21.2

4 Temporal

Ctx

AD 3 Hippo
15.1
17.0
AD 1
54.7
45.1

Occipital Ctx

AD 4 Hippo
10.2
4.7
AD 2
0.0
0.0

Occipital Ctx

(Missing)

AD 5 hippo
80.1
42.9
AD 3
39.2
35.6

Occipital Ctx

AD 6 Hippo
26.8
23.3
AD 4
15.6
9.0

Occipital Ctx

Control 2 Hippo
1.3
5.5
AD 5
18.6
18.9

Occipital Ctx

Control 4 Hippo
11.6
6.9
AD 6
6.7
7.7

Occipital Ctx

Control (Path) 3
7.5
7.8
Control 1
10.3
2.6

Hippo

Occipital Ctx

AD 1 Temporal
39.8
33.9
Control 2
19.5
22.7

Ctx

Occipital Ctx

AD 2 Temporal
27.2
25.9
Control 3
54.0
44.8

Ctx

Occipital Ctx

AD 3 Temporal
40.3
17.9
Control 4
20.6
10.7

Ctx

Occipital Ctx

AD 4 Temporal
27.4
20.6
Control (Path)
42.6
20.0

Ctx

1 Occipital

Ctx

AD 5 Inf
53.2
34.2
Control (Path)
14.6
18.4

Temporal Ctx

2 Occipital

Ctx

AD 5
34.2
33.0
Control (Path)
7.7
1.6

SupTemporal

3 Occipital

Ctx

Ctx

AD 6 Inf
79.6
56.3
Control (Path)
53.2
38.4

Temporal Ctx

4 Occipital

Ctx

AD 6 Sup
100.0
100.0
Control 1
17.4
11.7

Temporal Ctx

Parietal Ctx

Control 1
22.4
14.5
Control 2
87.1
62.0

Temporal Ctx

Parietal Ctx

Control 2
13.7
12.8
Control 3
10.2
13.4

Temporal Ctx

Parietal Ctx

Control 3
27.0
17.8
Control (Path)
24.5
13.3

Temporal Ctx

1 Parietal Ctx

Control 4
31.0
35.8
Control (Path)
15.5
15.5

Temporal Ctx

2 Parietal Ctx

Control (Path) 1
16.6
17.6
Control (Path)
18.6
14.7

Temporal Ctx

3 Parietal Ctx

Control (Path) 2
19.5
18.7
Control (Path)
31.0
18.7

Temporal Ctx

4 Parietal Ctx

[0624]

191

TABLE CD

General_screening_panel_v1.5

Rel. Exp.

Rel. Exp.

(%) Ag4833,

(%) Ag4833,

Run

Run

Tissue Name
228787595
Tissue Name
228787595

Adipose
0.0
Renal ca. TK-10
26.4

Melanoma*
0.0
Bladder
8.3

Hs688(A).T

Melanoma*
0.0
Gastric ca. (liver
2.7

Hs688(B).T

met.) NCI-N87

Melanoma* M14
0.0
Gastric ca. KATO
2.6

III

Melanoma*
0.0
Colon ca. SW-948
1.9

LOXIMVI

Melanoma* SK-
0.0
Colon ca SW480
18.7

MEL-5

Squamous cell
0.0
Colon ca.* (SW480
8.4

carcinoma SCC-4

met) SW620

Testis Pool
2.3
Colon ca. HT29
0.0

Prostate ca.* (bone
0.0
Colon ca. HCT-116
6.3

met) PC-3

Prostate Pool
0.3
Colon ca. CaCo-2
0.6

Placenta
0.0
Colon cancer tissue
0.1

Uterus Pool
3.4
Colon ca. SW1116
3.1

Ovarian ca. OVCAR-3
4.0
Colon ca. Colo-205
0.0

Ovarian ca. SK-OV-3
4.5
Colon ca. SW-48
0.0

Ovarian ca. OVCAR-4
0.0
Colon Pool
2.2

Ovarian ca. OVCAR-5
6.8
Small Intestine Pool
2.3

Ovarian ca. IGROV-1
1.4
Stomach Pool
0.9

Ovarian ca. OVCAR-8
6.8
Bone Marrow Pool
3.2

Ovary
4.9
Fetal Heart
0.0

Breast ca MCF-7
0.5
Heart Pool
2.7

Breast ca. MDA-
3.1
Lymph Node Pool
5.6

MB-231

Breast ca BT 549
0.0
Fetal Skeletal
0.0

Muscle

Breast ca T47D
0.0
Skeletal Muscle
0.8

Pool

Breast ca MDA-N
1.1
Spleen Pool
19.9

Breast Pool
5.2
Thymus Pool
10.6

Trachea
0.8
CNS cancer (glio/
0.0

astro) U87-MG

Lung
0.0
CNS cancer (glio/
1.4

astro) U-118-MG

Fetal Lung
6.0
CNS cancer (neuro;
0.9

met) SK-N-AS

Lung ca. NCI-N417
0.0
CNS cancer (astro)
0.0

SF-539

Lung ca. LX-1
17.9
CNS cancer (astro)
1.0

SNB-75

Lung ca. NCI-H146
5.8
CNS cancer (glio)
3.7

SNB-19

Lung ca. SHP-77
8.9
CNS cancer (glio)
4.0

SF-295

Lung ca A549
1.4
Brain (Amygdala)
15.1

Pool

Lung ca NCI-H526
2.0
Brain (cerebellum)
92.7

Lung ca. NCI-H23
1.5
Brain (fetal)
100.0

Lung ca. NCI-H460
1.6
Brain
22.2

(Hippocampus) Pool

Lung ca. HOP-62
0.7
Cerebral Cortex
12.8

Pool

Lung ca NCI-H522
0.0
Brain (Substantia
10.9

nigra) Pool

Liver
0.0
Brain (Thalamus)
22.1

Pool

Fetal Liver
1.2
Brain (whole)
12.2

Liver ca. HepG2
9.5
Spinal Cord Pool
4.5

Kidney Pool
7.4
Adrenal Gland
13.5

Fetal Kidney
4.1
Pituitary gland Pool
1.7

Renal ca 786-0
0.0
Salivary Gland
0.0

Renal ca A498
0.0
Thyroid (female)
0.2

Renal ca ACHN
1.5
Pancreatic ca.
0.0

CAPAN2

Renal ca. UO-31
2.4
Pancreas Pool
10.1

[0625] CNS_neurodegeneration_v1.0 Summary: Ag4833 Two experiments with same probe and primer sets are in excellent agreement. This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

[0626] General_screening panel_v1.5 Summary: Ag4833 Highest expression of this gene is detected in fetal brain and cerebellum (CTs=30). In addition, moderate levels of expression of this gene is also detected in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. This gene codes for a variant of fibroblast growth factor-17 (FGF-17). Recently, it has been shown that FGF-17 along with FGF-8 regulate proliferation and differentiation of midline cerebellar structures and mice lacking FGF-17 and a copy of FGF-8 gene show developmental defects and an ataxic gait. Therefore, based on homology the FGF-17 encoded by this gene may also play a role in cerebellar growth and therapeutic modulation of this gene may be beneficial in the treatment of any cerebellum related developmental defects.

[0627] In addition, moderate to low expression of this gene is also detected in number of cancer cell lines derived from brain, colon, liver, renal, gastric, lung and ovarian cancers. Therefore, therapeutic modulation of this gene may be useful in the treatment of these cancers.

[0628] Low levels of expression of this gene are also detected in pancrease and adrenal gland. Therefore, therapeutic modulation of this gene may also be useful in the treatment of metabolically related disease such as diabetes and obesity.

[0629] Ag4832 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0630] Oncology_cell_line_screening_panel_v3.1 Summary: Ag4832 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0631] Panel 4.1D Summary: Ag4832 Expression of this gene is low/undetectable (CT's>35) across all of the samples on this panel.

[0632] D. CG105707-01: Single Pass Transmembrane Protein

[0633] Expression of gene CG105707-01 was assessed using the primer-probe sets Ag4296 and Ag4396, described in Tables DA and DB. Results of the RTQ-PCR runs are shown in Tables DC, DD and DE.

[0634] Table DA. Probe Name Ag4296

192TABLE DAProbe Name Ag4296PrimersSequencesLengthStart PositionSEQ ID NoForward5′-acctgaaagaactggaggaaaa-3′222303118ProbeTET-5′-tcactagcattcattctgtggccttg-3′-TAMRA262350119Reverse5′-gttcttggctcactgaagtcat-3′222376120

[0635]

193

TABLE DB

Probe Name Ag4396

Primers
Sequences
Length
Start Position
SEQ ID No

Forward
5′-acctgaaagaactggaggaaaa-3′
22
2303
121

Probe
TET-5′-tcactagcattcattctgtggccttg-3′-TAMRA
26
2350
122

Reverse
5′-gttcttggctcactgaagtcat-3′
22
2376
123

[0636]

194

TABLE DB

CNS_neurodegeneration_v1.0

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag4296, Run
Ag4396, Run

Ag4296, Run
Ag4396, Run

Tissue Name
224073755
224504220
Tissue Name
224073755
224504220

AD 1 Hippo
32.3
27.0
Control (Path)
3.7
5.6

3 Temporal

Ctx

AD 2 Hippo
48.3
58.2
Control (Path)
62.9
89.5

4 temporal

Ctx

AD 3 Hippo
26.8
16.0
AD 1
25.0
1.2

Occipital Ctx

AD 4 Hippo
20.6
19.1
AD 2
0.0
0.0

Occipital Ctx

(Missing)

AD 5 hippo
89.5
70.7
AD 3
6.5
5.0

Occipital Ctx

AD 6 Hippo
46.7
51.1
AD 4
26.4
25.7

Occipital Ctx

Control 2 Hippo
45.4
33.4
AD 5
11.4
34.6

Occipital Ctx

Control 4 Hippo
7.0
10.4
AD 6
52.1
9.4

Occipital Ctx

Control (Path) 3
5.6
7.5
Control 1
1.2
0.6

Hippo

Occipital Ctx

AD 1 Temporal
25.5
21.9
Control 2
36.1
30.6

Ctx

Occipital Ctx

Ad 2 Temporal
44.4
43.2
Control 3
19.2
27.7

Ctx

Occipital Ctx

AD 3 Temporal
17.6
15.1
Control 4
4.0
3.1

Ctx

Occipital Ctx

AD 4 Temporal
38.4
29.9
Control (Path)
87.7
76.3

Ctx

1 Occipital

Ctx

AD 5 Inf
88.9
74.7
Control (Path)
24.3
21.8

Temporal Ctx

2 Occipital

Ctx

AD 5
54.3
77.9
Control (Path)
0.4
1.8

SupTemporal

3 Occipital

Ctx

Ctx

AD 6 Inf
45.4
46.7
Control (Path)
25.7
26.1

Temporal Ctx

4 Occipital

Ctx

AD 6 Sup
42.3
40.9
Control 1
5.8
5.0

Temporal Ctx

Parietal Ctx

Control 1
5.2
5.5
Control 2
55.5
41.8

Temporal Ctx

Parietal Ctx

Control 2
36.3
25.5
Control 3
23.2
17.1

Temporal Ctx

Parietal Ctx

Control 3
38.2
32.8
Control (Path)
82.4
68.3

Temporal Ctx

1 Parietal Ctx

Control 4
14.0
12.2
Control (Path)
31.4
40.1

Temporal Ctx

2 Parietal Ctx

Control (Path) 1
100.0
100.0
Control (Path)
2.6
2.8

Temporal Ctx

3 Parietal Ctx

Control (Path) 2
85.9
67.4
Control (Path)
80.7
80.1

Temporal Ctx

4 Parietal Ctx

[0637]

195

TABLE DD

General_screening_panel_v1.4

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag4296, Run
Ag4396, Run

Ag4296, Run
Ag4396, Run

Tissue Name
222184254
222641544
Tissue Name
222184254
222641544

Adipose
0.7
0.3
Renal ca. 1K-10
0.6
1.2

Melanoma*
0.0
0.0
Bladder
0.1
0.0

Hs688(A) T

Melanoma*
0.0
0.0
Gastric ca. (liver
0.0
0.0

Hs688(B).T

met) NCl-NC87

Melanoma*
0.0
0.0
Gastric ca. KATO
0.0
0.0

M14

111

Melanoma*
0.0
0.0
Colon ca. SW-948
0.0
0.0

LOXIMVI

Melanoma* SK-
0.0
0.0
Colon ca. SW480
0.0
0.0

MEL-5

Squamous cell
0.0
0.0
Colon ca. (SW480
0.0
0.0

carcinoma SCC-

met) SW620

4

Testis Pool
1.7
0.9
Colon ca. 11129
0.0
0.0

Prostate ca.*
0.0
0.0
Colon ca. HCT-116
0.0
0.0

(bone met) PC-

3

Prostate Pool
1.3
1.0
Colon ca. CaCo-2
0.0
0.0

Placenta
0.0
0.0
Colon cancer tissue
0.0
0.0

Uterus Pool
0.0
0.0
Colon ca SW1116
0.0
0.0

Ovarian ca.
0.0
0.0
Colon ca. Colo-205
0.0
0.0

OVCAR-3

Ovarian ca. SK-
0.2
0.7
Colon ca. SW-480
0.0
0.0

OV-3

Ovarian ca.
0.0
0.0
Colon Pool
0.0
0.2

OVCAR-4

Ovarian ca
0.0
0.0
Small Intestine
0.2
0.1

OVCAR-5

Pool

Ovarian ca.
0.0
0.0
Stomach Pool
0.5
0.0

IGROV-1

Ovarian ca
0.0
0.0
Bone Marrow Pool
0.0
0.0

OVCAR-8

Ovary
2.0
2.3
Fetal Heart
0.0
0.0

Breast ca. MCT-
0.0
0.0
Heart Pool
0.0
0.0

7

Breast ca.
0.0
0.0
Lymph Node Pool
0.3
0.6

MDA-MB-231

Breast ca. B1
0.0
0.0
Fetal Skeletal
0.0
0.0

549

Muscle

Breast ca. T47D
0.0
0.0
Skeletal Muscle
0.0
0.0

Pool

Breast ca.
0.0
0.0
Spleen Pool
1.5
1.3

MDA-N

Breast Pool
0.0
0.1
Thymus Pool
0.1
0.2

Trachea
0.1
0.2
CNS cancer
0.0
0.0

(glio/astro) U87-

MG

Lung
0.1
0.0
CNS cancer
0.3
0.0

(glio/astro) U-118-

MG

Fetal Lung
0.0
0.0
CNS cancer
0.3
0.2

(neuro;met) SK-N-

AS

Lung ca. NCl-
0.0
0.0
CNS cancer (astro)
0.0
0.0

N417

SF-539

Lung ca. LX-1
0.0
0.0
CNS cancer (astro)
0.2
0.0

SNB-75

Lung ca. NCl-
2.0
2.2
CNS cancer (glio)
0.0
0.0

H146

SNB-19

Lung ca. SHP-
2.4
0.6
CNS cancer (glio)
1.1
0.3

77

SF-295

Lung ca. A549
0.0
0.0
Brain (Amygdala)
37.1
31.6

Pool

Lung ca. NCl-
0.3
0.0
Brain (cerebellum)
6.5
10.9

H526

Lung ca. NCl-
0.1
0.2
Brain (fetal)
100.0
100.0

H23

Lung ca. NCl-
0.0
0.0
Brain
59.9
50.0

H460

(Hippocampus)

Pool

Lung ca. HOP-
0.0
0.0
Cerebral Cortex
90.1
78.5

62

Pool

Lung ca. NCl-
0.0
0.3
Brain (Substantia
42.9
36.3

H522

nigra) Pool

Liver
0.0
0.0
Brain (Thalamus)
92.0
82.9

Pool

Fetal Liver
0.0
0.3
Brain (whole)
74.7
65.1

Liver ca.
0.0
00
Spinal Cord Pool
11.0
6.3

HepG2

Kidney Pool
0.0
0.0
Adrenal Gland
1.5
1.3

Fetal Kidney
0.0
0.2
Pituitary gland
1.7
1.0

Pool

Renal ca. 786-0
0.0
0.0
Salivary Gland
0.1
0.0

Renal ca. A498
0.0
0.2
Thyroid (female)
0.0
0.0

Renal ca.
0.0
0.0
Pancreatic ca.
0.0
0.0

ACHN

CAPAN2

Renal ca. UO-
0.0
0.0
Pancreas Pool
0.5
0.0

31

[0638]

196

TABLE DE

Panel 4.1

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag4296, Run
Ag4396, Run

Ag4296, Run
Ag4396, Run

Tissue Name
181981947
187513671
Tissue Name
181981947
187513671

Secondary Th1 act
16.7
15.6
HUVEC IL-1beta
0.0
0.0

Secondary Th2 act
14.0
18.2
HUVEC IFN gamma
0.0
0.0

Secondary Tr1 act
24.3
13.7
HUVEC TNF alpha +
0.0
0.0

IFN gamma

Secondary Th1 rest
0.0
3.0
HUVEC TNF alpha +
0.0
0.0

IL4

Secondary Th2 rest
0.0
0.0
HUVEC IL-11
0.0
0.0

Secondary Tr1 rest
0.0
0.0
Lung Microvascular
0.0
0.0

EC none

Primary Th1 act
0.0
0.0
Lung Microvascular
0.0
0.0

EC TNFalpha + IL-

1beta

Primary Th2 act
0.0
0.0
Microvascular
0.0
0.0

Dermal EC none

Primary Tr1 act
0.0
5.4
Microvascular
0.0
0.0

Dermal EC

TNFalpha + IL-1beta

Primary Th1 rest
3.5
0.0
Bronchial epithelium
0.0
0.0

TNFalpha + IL1beta

Primary Th2 rest
0.0
0.0
Small airway
0.0
0.0

epithelium none

Primary Tr1 rest
6.0
0.0
Small airway
0.0
0.0

epithelium TNFalpha +

IL-1beta

CD45RA CD4
10.2
3.7
Coronery artery
0.0
0.0

lymphocyte act

SMC rest

CD45RO CD4
18.9
24.5
Coronery artery
0.0
0.0

lymphocyte act

SMC TNFalpha +

IL-1beta

CD8 lymphocyte act
67.4
40.3
Astrocytes rest
0.0
0.0

Secondary CD8
18.2
20.4
Astrocytes TNFalpha +
0.0
0.0

lymphocyte rest

IL-1beta

Secondary CD8
26.2
8.1
KU-812 (Basophil)
0.0
0.0

lymphocyte act

rest

CD4 lymphocyte
0.0
4.7
KU-812 (Basophil)
0.0
0.0

none

PMA/ionomycin

2ry
3.7
15.9
CCD1106
0.0
0.0

Th1/Th2/Tr1_anti-

(Keratinocytes) none

CD95 CH11

LAK cells rest
22.8
18.3
CCD1106
0.0
0.0

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
100.0
100.0
Liver cirrhosis
0.0
4.7

LAK cells IL-2 + IL-
28.5
18.6
NCl-H292 none
0.0
0.0

12

LAK cells IL-2 + IFN
23.2
11.5
NCl-H292 IL-4
0.0
0.0

gamma

LAK cells IL-2 + IL-
28.9
40.6
NCl-H292 IL-9
0.0
0.0

18

LAK cells
0.0
8.6
NCl-H292 IL-13
0.0
0.0

PMA/ionomycin

NK Cells IL-2 rest
29.9
74.2
NCl-H292 IFN
0.0
0.0

gamma

Two Way MLR 3
14.5
23.2
HPAEC none
0.0
0.0

day

Two Way MLR 5
27.4
26.2
HPAEC TNF alpha +
0.0
0.0

day

IL-1 beta

Two Way MLR 7
11.3
15.6
Lung fibroblast none
0.0
0.0

day

PBMC rest
0.0
0.0
Lung fibroblast TNF
0.0
0.0

alpha + IL-1 beta

PBMC PWM
8.4
9.3
Lung fibroblast IL-4
0.0
0.0

PBMC PHA-L
16.7
0.0
Lung fibroblast IL-9
0.0
0.0

Ramos (B cell) none
0.0
0.0
Lung fibroblast IL-
0.0
0.0

13

Ramos (B cell)
0.0
0.0
Lung fibroblast IFN
0.0
0.0

ionomycin

gamma

B lymphocytes
4.8
0.0
Dermal fibroblast
0.0
0.0

PWM

CCD1070 rest

B lymphocytes
11.0
4.2
Dermal fibroblast
29.3
33.0

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
0.0
0.0

CCD1070 IL-1 beta

EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
0.0
0.0

PMA-ionomycin

IFN gamma

Dendritic cells none
0.0
0.0
Dermal fibroblast IL-
0.0
0.0

4

Dendritic cells LPS
0.0
0.0
Dermal fibroblasts
0.0
0.0

rest

Dendritic cells anti-
0.0
0.0
Neutrophils
0.0
0.0

CD40

TNFa + LPS

Monocytes rest
0.0
0.0
Neutrophils rest
4.6
3.4

Monocytes LPS
3.6
0.0
Colon
0.0
0.0

Macrophages rest
0.0
0.0
Lung
0.0
4.0

Macrophages LPS
0.0
0.0
Thymus
0.0
0.0

HUVEC none
0.0
0.0
Kidney
0.0
0.0

HUVEC started
0.0
0.0

[0639] AI_comprehensive panel_v1.0 Summary: Ag4396 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0640] CNS_neurodegeneration_v1.0 Summary: Ag4396/Ag4296 Two experiments with same probe and primer sets are in excellent agreement. This panel confirms the expression of this gene at low levels in the brain in an independent group of individuals. This gene is found to be slightly down-regulated in the temporal cortex of Alzheimer's disease patients. Therefore, up-regulation of this gene or its protein product, or treatment with specific agonists for this receptor may be of use in reversing the dementia, memory loss, and neuronal death associated with this disease.

[0641] General_screening_panel_v1.4 Summary: Ag4396/Ag4296 Two experiments with same probe and primer sets are in excellent agreement, with highest expression of this gene in fetal brain (CTs=29). High expression of this gene is seen in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, expression of this gene may be used to differentiate brain samples from other samples used in this panel. Furthermore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0642] In addition, low levels of expression of this gene are also seen in two lung cancer cell lines. Therefore, therapeutic modulation of this gene may be useful in the treatment of lung cancer.

[0643] Panel 4.1D Summary: Ag4396/Ag4296 Two experiments with same probe and primer sets are in excellent agreement, with highest expression of this gene in IL-2 treated LAK cells. Therefore, expression of this gene may be used to distinguish this sample from other samples used in this panel. Low levels of expression of this gene is also seen in IL-2 treated NK cells. These killer cells are involved in tumor immunology and cell clearance of virally and bacterial infected cells as well as tumors. Therefore, modulation of the function of the protein encoded by this gene through the application of a small molecule drug or antibody may alter the functions of these cells and lead to improvement of symptoms associated with these conditions.

[0644] E. CG108369-01: Beta-Ketoacyl Synthase

[0645] Expression of gene CG108369-01 was assessed using the primer-probe sets A4356 and Ag4357, described in Tables EA and EB. Results of the RTQ-PCR runs are shown in Tables EC and ED.

197TABLE EAProbe Name Ag4356PrimersSequencesLengthStart PositionSEQ ID NoForward5′-ggagaaggcaagatggagaa-3′201024124ProbeTET-5′-cgagagcttaaagaacgcaggtggag-3′-TAMRA261053125Reverse5′-tcccttcccttactgagtgc-3′201093126

[0646]

198

TABLE EB

Probe Name Ag4357

Primers
Sequences
Length
Start Position
SEQ ID No

Forward
5′-gaaggcaagatggagaatcc-3′
20
1027
127

Probe
TET-5′-cgagagcttaaagaacgcaggtggag-3′-TAMRA
26
1053
128

Reverse
5′-tcccttcccttactgagtgc-3′
20
1093
129

[0647]

199

TABLE EC

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4357,

(%) Ag4357,

Run

Run

Tissue Name
222523503
Tissue Name
222523503

Adipose
9.8
Renal ca. TK-10
31.6

Melanoma*
23.0
Bladder
20.2

Hs688(A).T

Melanoma*
25.3
Gastric ca. (liver
32.5

Hs688(B).T

met) NCI-N87

Melanoma* M14
33.2
Gastric ca. KATO
40.9

III

Melanoma* LOXIMVI
28.3
Colon ca SW-948
17.8

Melanoma* SK-
31.9
Colon ca SW480
65.5

MEL-5

Squamous cell
12.7
Colon ca.* (SW480
28.5

carcinoma SCC-4

met) SW620

Testis Pool
6.9
Colon ca. HT29
23.0

Prostate ca* (bone
14.0
Colon ca. HCT-116
29.7

met) PC-3

Prostate Pool
7.6
Colon ca. CaCo-2
27.0

Placenta
13.6
Colon cancer tissue
27.0

Uterus Pool
4.2
Colon ca. SW1116
5.4

Ovarian ca OVCAR-3
14.5
Colon ca. Colo-205
3.7

Ovarian ca. SK-OV-3
58.2
Colon ca. SW-48
5.9

Ovanan ca. OVCAR-4
42.0
Colon Pool
15.4

Ovarian ca. OVCAR-5
21.6
Small Intestine Pool
18.8

Ovarian ca. IGROV-1
54.7
Stomach Pool
11.9

Ovarian ca. OVCAR-8
30.8
Bone Marrow Pool
8.4

Ovary
8.5
Fetal Heart
8.3

Breast ca. MCF-7
27.9
Heart Pool
7.7

Breast ca. MDA-MB-
46.0
Lymph Node Pool
17.9

231

Breast ca. BT 549
35.1
Fetal Skeletal
4.8

Muscle

Breast ca. T47D
74.7
Skeletal Muscle
14.0

Pool

Breast ca. MDA-N
16.5
Spleen Pool
15.8

Breast Pool
21.6
Thymus Pool
23.8

Trachea
9.9
CNS cancer (glio/
44.8

astro) U87-MG

Lung
1.7
CNS cancer (glio/
57.0

astro) U-118-MG

Fetal Lung
15.9
CNS cancer (neuro;
31.4

met) SK-N-AS

Lung ca. NCI-N417
16.7
CNS cancer (astro)
13.6

SF-539

Lung ca. LX-1
23.8
CNS cancer (astro)
81.2

SNB-75

Lung ca. NCI-H146
29.5
CNS cancer (glio)
41.5

SNB-19

Lung ca. SHP-77
46.3
CNS cancer (glio)
100.0

SF-295

Lung ca. A549
25.7
Brain (Amygdala)
30.8

Pool

Lung ca. NCI-H526
30.1
Brain (cerebellum)
44.4

Lung ca. NCI-H23
15.5
Brain (fetal)
61.1

Lung ca. NCI-H460
21.0
Brain
27.9

(Hippocampus) Pool

Lung ca. HOP-62
22.4
Cerebral Cortex
33.0

Pool

Lung ca. NCI-H522
23.8
Brain (Substantia
41.5

nigra
) Pool

Liver
5.3
Brain (Thalamus)
47.6

Pool

Fetal Liver
5.7
Brain (whole)
24.0

Liver ca. HepG2
20.9
Spinal Cord Pool
29.9

Kidney Pool
28.7
Adrenal Gland
14.6

Fetal Kidney
7.6
Pituitary gland Pool
13.6

Renal ca. 786-0
28.3
Salivary Gland
3.3

Renal ca. A498
11.8
Thyroid (female)
7.0

Renal ca. ACHN
12.1
Pancreatic ca.
15.3

CAPAN2

Renal ca. UO-31
15.6
Pancreas Pool
22.2

[0648]

200

TABLE ED

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4356,

(%) Ag4356,

Run

Run

Tissue Name
186659562
Tissue Name
186659562

Secondary Th1 act
10.5
HUVEC IL-1beta
15.2

Secondary Th2 act
12.8
HUVEC IFN
5.2

gamma

Secondary Tr1 act
9.9
HUVEC TNF
8.4

alpha + IFN

gamma

Secondary Th1 rest
3.6
HUVEC TNF
22.8

alpha + IL4

Secondary Th2 rest
4.0
HUVEC IL-11
5.7

Secondary Tr1 rest
3.0
Lung Microvascular
24.3

EC none

Primary Th1 act
9.3
Lung Microvascular
25.0

EC TNFalpha +

IL-1 beta

Primary Th2 act
7.1
Microvascular
9.8

Dermal EC none

Primary Tr1 act
9.0
Microsvasular
10.8

Dermal EC

TNFalpha +

IL-1beta

Primary Th1 rest
1.8
Bronchial
6.4

epithelium

TNFalpha +

IL1beta

Primary Th2 rest
1.3
Small airway
7.0

epithelium none

Primary Tr1 rest
3.7
Small airway
9.4

epithelilium

TNFalpha +

IL 1beta

CD45RA CD4
4.6
Cotonery artery
3.5

lymphocyte act

SMC rest

CD45RO CD4
6.5
Coronery artery
6.8

lymphocyte act

SMC TNFalpha +

IL-1beta

CD8 lymphocyte act
7.7
Astrocytes rest
6.5

Secondary CD8
7.6
Astrocytes
15.2

lymphocyte rest

TNFalpha + IL-

1beta

Secondary CD8
7.1
KU-812 (Basophil)
6.6

lymphocyte act

rest

CD4 lymphocyte
2.2
KU-812 (Basophil)
11.5

none

PMA/ionomycin

2ry Th1/Th2/
4.7
CCD1106
5.8

Tr1_anti-CD95

(Keratinocytes)

CH11

none

LAK cells rest
7.1
CCD1106

(Keratinocytes)
8.6

TNFalpha +

IL-1beta

LAK cells IL-2
6.0
Liver cirrhosis
5.1

LAK cells IL-2 +
4.1
NCI-H292 none
4.4

IL-12

LAK cells IL-2 +
3.2
NCI-H292 IL-4
8.2

IFN gamma

LAK cells IL-2 +
5.4
NCI-H292 IL-9
7.1

IL-18

LAK cells PMA/
11.0
NCI-H292 IL-13
8.1

ionomycin

NK Cells IL-2 rest
7.8
NCI-H292 IFN
8.4

gamma

Two Way MLR 3 day
5.4
HPAEC none
4.4

Two Way MLR 5 day
7.3
HPAEC TNF
14.5

alpha + IL 1 beta

Two Way MLR 7 day
4.4
Lung fibroblast
5.9

none

PBMC rest
2.1
Lung fibroblast TNF
9.3

alpha + IL-1 beta

PBMC PWM
14.5
Lung fibroblast IL-4
6.7

PBMC PHA-L
7.6
Lung fibroblast IL-9
11.7

Ramos (B cell) none
2.7
Lung fibroblast
9.0

IL-13

Ramos (B cell)
5.6
Lung fibroblast IFN
5.8

ionomycin

gamma

B lymphocytes PWM
5.8
Dermal fibroblast
8.4

CCD1070 rest

B lymphocytes CD40L
4.2
Dermal fibroblast
8.0

and IL-4

CCD1070 TNF

alpha

EOL-1 dbcAMP
7.0
Dermal fibroblast
8.7

CCD1070 IL-1 beta

EOL-1 dbcAMP
100.0
Dermal fibroblast
2.0

PMA/ionomycin

IFN gamma

Dendritic cells none
8.6
Dermal fibroblast
5.3

IL-4

Dendritic cells LPS
8.1
Dermal Fibroblasts
4.6

rest

Dendritic cells
17.3
Neutrophils TNFa +
2.4

anti-CD40

LPS

Monocytes rest
5.4
Neutrophils rest
1.4

Monocytes LPS
32.1
Colon
1.7

Macrophages rest
11.0
Lung
4.5

Macrophages LPS
5.3
Thymus
8.1

HUVEC none
7.0
Kidney
7.5

HUVEC starved
10.2

[0649] CNS_neurodegeneration_v1.0 Summary: Ag4356 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0650] General_screening_panel_v1.4 Summary: Ag4357 Expression of the CG108369-01 gene is moderate to low in all of the tissues on this panel, with highest expression in a CNS cancer cell line (CT=27.5).

[0651] Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, Such as obesity and diabetes.

[0652] In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0653] Panel 4.1 D Summary: Ag4356 The CG108369-01 gene is expressed at higher levels in the eosinophil cell line EOL-1 stimulated by phorbol ester and ionomycin (CT=28.3) than in resting EOL-1 cells (CT=32.1). Thus, this gene may be important in eosinophil differentiation and expression of this gene could be used to distinguish stimulated eosinophils from resting eosinophils. Furthermore, therapeutic modulation of the activity of this gene or its protein product may be useful in the treatment of parasitic infections, asthma, and hematopoietic disorders involving eosinphils.

[0654] This gene is also expressed at lower levels in a wide range of cell types of significance in the immune response in health and disease. These cells include T-cells, B-cells, endothelial cells, macrophages, monocytes, eosinophils, basophils, neutrophils, peripheral blood mononuclear cells, lung and skin epithelial cells, lung and skin fibroblast cells, as well as normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

[0655] F. CG110646-01: Glutamate Receptor Interacting Protein 2

[0656] Expression of gene CG110646-01 was assessed using the primer-probe set Ag4425, described in Table FA. Results of the RTQ-PCR runs are shown in Tables FB, FC and FD.

201TABLE FAProbe Name Ag4425PrimersSequencesLengthStart PositionSEQ ID NoForward5′-caggtggagtatgatgtggc-3′20709130ProbeTET-5′-ctaatgcttcgggacccttgatggt-3′-TAMRA25746131Reverse5′-gaccctggcgtcttgactat-3′20775132

[0657]

202

TABLE FB

CNS_neurodegeneration_v1.

Rel. Exp.

Rel. Exp.

(%) Ag4425,

(%) Ag4425,

Run

Run

Tissue Name
224506208
Tissue Name
224506208

AD 1 Hippo
7.0
Control (Path) 3
2.2

Temporal Ctx

AD 2 Hippo
15.8
Control (Path) 4
23.8

Temporal Ctx

AD 3 Hippo
2.2
AD 1 Occipital Ctx
15.9

AD 4 Hippo
6.0
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 hippo
100.0
AD 3 Occipital Ctx
8.5

AD 6 Hippo
17.4
AD 4 Occipital Ctx
12.6

Control 2 Hippo
17.4
AD 5 Occipital Ctx
11.2

Control 4 Hippo
4.2
AD 6 Occipital Ctx
65.5

Control (Path) 3 Hippo
4.8
Control 1 Occipital
1.7

Ctx

AD 1 Temporal Ctx
10.3
Control 2 Occipital
94.0

Ctx

AD 2 Temporal Ctx
21.0
Control 3 Occipital
21.3

Ctx

AD 3 Temporal Ctx
3.3
Control 4 Occipital
9.9

Ctx

AD 4 Temporal Ctx
15.4
Control (Path) 1
95.3

Occipital Ctx

AD 5 Inf Temporal
71.2
Control (Path) 2
9.5

Ctx

Occipital Ctx

AD 5 SupTemporal
15.2
Control (Path) 3
4.6

Ctx

Occipital Ctx

AD 6 Inf Temporal
25.0
Control (Path) 4
21.3

Ctx

Occipital Ctx

AD 6 Sup Temporal
31.2
Control 1 Parietal
3.7

Ctx

Ctx

Control 1 Temporal
4.1
Control 2 Parietal
31.0

Ctx

Ctx

Control 2 Temporal
41.5
Control 3 Parietal
19.9

Ctx

Ctx

Control 3 Temporal
6.4
Control (Path) 1
73.7

Ctx

Parietal Ctx

Control 4 Temporal
7.3
Control (Path) 2
14.4

Ctx

Parietal Ctx

Control (Path) 1
43.8
Control (Path) 3
0.8

Temporal Ctx

Parietal Ctx

Control (Path) 2
17.2
Control (Path) 4
27.2

Temporal Ctx

Parietal Ctx

[0658]

203

TABLE FC

General_screening_panel_v1.

Rel. Exp.

Rel. Exp.

(%) Ag4425,

(%) Ag4425,

Run

Run

Tissue Name
222645175
Tissue Name
222645175

Adipose
1.5
Renal ca. TK-10
0.0

Melanoma*
0.0
Bladder
1.2

Hs688(A).T

Melanoma*
0.0
Gastric ca. (liver met.)
7.3

Hs688(B).T

NCI-N87

Melanoma* M14
0.5
Gastric ca. KATO III
0.0

Melanoma*
0.0
Colon ca. SW-948
0.0

LOXIMVI

Melanoma*
1.7
Colon ca. SW480
24.1

SK-MEL-5

Squamous cell
2.3
Colon ca.* (SW480
2.7

carcinoma SCC-4

met) SW620

Testis Pool
3.3
Colon ca. HT29
0.0

Prostate ca.* (bone
4.9
Colon ca. HCT-116
2.9

met) PC-3

Prostate Pool
7.7
Colon ca. CaCo-2
21.0

Placenta
6.2
Colon cancer tissue
1.7

Uterus Pool
2.3
Colon ca. SW1116
2.0

Ovarian ca.
0.4
Colon ca. Colo-205
0.0

OVCAR-3

Ovarian ca
0.4
Colon ca. SW-48
0.0

SK-OV-3

Ovarian ca.
1.2
Colon Pool
3.1

OVCAR-4

Ovarian ca
0.3
Small Intestine Pool
5.9

OVCAR-5

Ovarian ca
0.0
Stomach Pool
1.5

IGROV-1

Ovarian ca.
7.0
Bone Marrow Pool
0.6

OVCAR-8

Ovary
5.3
Fetal Heart
2.4

Breast ca. MCI-7
0.0
Heart Pool
8.9

Breast ca. MDA-
1.2
Lymph Node Pool
3.9

MB-231

Breast ca BT 549
9.4
Fetal Skeletal Muscle
27.4

Breast ca T47D
0.6
Skeletal Muscle Pool
100.0

Breast ca. MDA-N
0.0
Spleen Pool
4.8

Breast Pool
2.8
Thymus Pool
2.7

Trachea
2.6
CNS cancer (glio/
0.5

astro) U87-MG

Lung
2.4
CNS cancer (glio/
3.7

astro) U-118-MG

Fetal Lung
3.3
CNS cancer (neuro;
0.0

met) SK-N-AS

Lung ca. NCI-N417
0.5
CNS cancer (astro)
0.0

SF-539

Lung ca. LX-1
3.6
CNS cancer (astro)
0.0

SNB-75

Lung ca NCI-H146
4.2
CNS cancer (glio)
0.0

SNB-19

Lung ca. SHP-77
0.0
CNS cancer (glio)
0.4

SF-295

Lung ca A549
5.2
Brain (Amygdala)
8.2

Pool

Lung ca. NCI-H526
5.6
Brain (cerebellum)
9.2

Lung ca. NCI-H23
0.4
Brain (fetal)
31.4

Lung ca. NCI-H460
0.4
Brain (Hippocampus)
16.0

Pool

Lung ca. HOP-62
1.1
Cerebral Cortex Pool
13.2

Lung ca. NCI-H522
0.3
Brain (Substantia
13.1

nigra) Pool

Liver
0.3
Brain (Thalamus) Pool
12.1

Fetal Liver
0.0
Brain (whole)
9.0

Liver ca. HepG2
0.0
Spinal Cord Pool
3.9

Kidney Pool
13.9
Adrenal Gland
2.5

Fetal Kidney
2.3
Pituitary gland Pool
2.2

Renal ca. 786-0
0.0
Salivary Gland
1.2

Renal ca A498
0.0
Thyroid (female)
0.8

Renal ca ACHN
1.0
Pancreatic ca.
0.0

CAPAN2

Renal ca. UO-31
0.5
Pancreas Pool
2.6

[0659]

204

TABLE FD

Panel 4.1

Rel. Exp.

Rel. Exp.

(%) Ag4425,

(%) Ag4425,

Run

Run

Tissue Name
190282117
Tissue Name
190282117

Secondary Th1 act
0.0
HUVEC IL-1beta
0.0

Secondary Th2 act
0.0
HUVEC IFN gamma
0.0

Secondary Tr1 act
0.0
HUVEC TNF alpha +
5.0

IFN gamma

Secondary Th1 rest
0.0
HUVEC TNF alpha +
0.0

IL4

Secondary Th2 rest
1.4
HUVEC IL-11
0.0

Secondary Tr1 rest
4.8
Lung Microvascular
0.0

EC none

Primary Th1 act
0.0
Lung Microvascular
0.0

EC TNFalpha +

IL-1beta

Primary Th2 act
0.0
Microvascular Dermal
0.0

EC none

Primary Tr1 act
0.0
Microsvasular Dermal
0.0

EC TNFalpha +

IL-1beta

Primary Th1 rest
0.0
Bronchial epithelium
3.3

TNFalpha + IL1beta

Primary Th2 rest
0.0
Small airway
0.0

epithelium none

Primary Tr1 rest
0.0
Small airway
0.0

epithelium

TNFalpha + IL-1beta

CD45RA CD4
0.0
Coronery artery SMC
0.0

lymphocyte act

rest

CD45RO CD4
0.0
Coronery artery SMC
0.0

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
0.0
Astrocytes rest
0.0

Secondary CD8
0.0
Astrocytes
0.0

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
0.0
KU-812 (Basophil)
0.0

lymphocyte act

rest

CD4 lymphocyte
0.0
KU-812 (Basophil)
0.0

none

PMA/ionomycin

2ry Th1/Th2/
0.0
CCD1106
23.5

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
0.0
CCD1106
3.6

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
0.0
Liver cirrhosis
14.1

LAK cells IL-2 +
0.0
NCI-H292 none
0.0

IL-12

LAK cells IL-2 +
0.0
NCI-H292 IL-4
0.0

IFN gamma

LAK cells IL-2 +
0.0
NCI-H292 IL-9
5.4

IL-18

LAK cells
0.0
NCI-H292 IL-13
5.4

PMA/ionomycin

NK Cells IL-2 rest
0.0
NCI-H292 IFN gamma
3.8

Two Way MLR 3
0.0
HPAEC none
0.0

day

Two Way MLR 5
0.0
HPAEC TNF alpha +
0.0

day

IL-1 beta

Two Way MLR 7
0.0
Lung fibroblast none
2.4

day

PBMC rest
0.0
Lung fibroblast TNF
100.0

alpha + IL-1 beta

PBMC PWM
0.0
Lung fibroblast IL-4
0.0

PBMC PHA-L
0.0
Lung fibroblast IL-9
0.0

Ramos (B cell) none
0.0
Lung fibroblast IL-13
0.0

Ramos (B cell)
0.0
Lung fibroblast IFN
20.4

ionomycin

gamma

B lymphocytes
0.0
Dermal fibroblast
0.0

PWM

CCD1070 rest

B lymphocytes
0.0
Dermal fibroblast
6.7

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0

CCD1070 IL-1 beta

EOL-1 dbcAMP
0.0
Dermal fibroblast IFN
20.3

PMA/ionomycin

gamma

Dendritic cells none
0.0
Dermal fibroblast IL-4
0.0

Dendritic cells LPS
4.6
Dermal Fibroblasts
2.0

rest

Dendritic cells
0.0
Neutrophils TNFa +
0.0

anti CD40

LPS

Monocytes rest
0.0
Neutrophils rest
0.0

Monocytes LPS
0.0
Colon
2.9

Macrophages rest
0.0
Lung
4.9

Macrophages LPS
6.2
Thymus
0.0

HUVEC none
0.0
Kidney
40.6

HUVEC starved
0.0

[0660] CNS_neurodegeneration_v1.0 Summary: Ag4425 This panel confirms the expression of the CG110646-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

[0661] General_screening_panel_v1.4 Summary: Ag4425 Highest expression of the CG110646-01 gene is detected in skeletal muscle (CT=28.8). In addition low to moderate levels of expression of this gene is also seen in other tissues with metabolic or endocrine function including pancreas, adipose, adrenal gland, thyroid, pituitary gland, fetal skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0662] In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders Such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0663] Moderate to low levels of expression of this gene is also seen in number of cancer cell lines derived from gastric, colon, lung, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.

[0664] Panel 4.1D Summary: Ag4425 Highest expression of the CG110646-01 gene is detected in TNF alpha+IL-1 beta treated lung fibroblasts (CT=33.3). Therefore, expression of this gene may be used to differentiate this sample from other samples used in this panel. Furthermore, therapeutic modulation of this gene may be useful in the treatment of inflammatory lung disorders that include chronic obstructive pulmonary disease, asthma, allergy and emphysema.

[0665] In addition, low levels of expression of this gene is also seen in kidney. Therefore, therapeutic modulation of this gene product may be useful in the treatment of inflammatory and autoimmune diseases that affect kidney including lupus erythematosus and glomerulonephritis.

[0666] G. CG110998-01 and CG110998-02: Methylthansferase

[0667] Expression of gene CG110998-01 and full length physical clone was assessed using the primer-probe sets Ag4436 and Ag6784, described in Tables GA and GB. Results of the RTQ-PCR runs are shown in Tables GC, GD, GE, GF and GG. Please note that CG110998-02 corresponds to Ag6784 only.

205TABLE GAProbe Name Ag4436StartPrimersSequencesLengthPositionSEQ ID NoForward5′-tttgtgctgtcagctgttca-3′20474133ProbeTET-5′-tcctgataagatgcaccttgtcttaca-3′-TAMRA27494134Reverse5′-acaagacacttttgcctggtt-3′21541135

[0668]

206

TABLE GB

Probe Name Ag6784

Start

Primers
Sequences
Length
Position
SEQ ID No

Forward
5′-aggcctgtgtgtgccaa-3′
17
761
136

Probe
TET-5′-cagagcaaatttctaaagcctcctaagaacccat-3′TAMRA
34
789
137

Reverse
5′-caggcccaggaccaca-3′
16
827
138

[0669]

207

TABLE GC

CNS_neurodegeneration_v1.0

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag4436, Run
Ag6784, Run

Ag4436, Run
Ag6784, Run

Tissue Name
224534738
277731703
Tissue Name
224534738
277731703

AD 1 Hippo
10.8
16.0
Control (Path)
5.6
10.4

3 Temporal

Ctx

AD 2 Hippo
24.8
25.7
Control (Path)
18.7
17.2

4 Temporal

Ctx

AD 3 Hippo
10.2
12.1
AD 1
13.1
15.8

Occipital Ctx

AD 4 Hippo
5.8
6.7
AD 2
0.0
0.0

Occipital Ctx

(Missing)

AD 5 hippo
63.7
54.0
AD 3
6.7
6.5

Occipital Ctx

AD 6 Hippo
25.3
35.6
AD 4
13.8
14.8

Occipital Ctx

Control 2 Hippo
36.6
6.0
AD 5
11.2
21.2

Occipital Ctx

Control 4 Hippo
8.4
9.6
AD 6
31.2
36.1

Occipital Ctx

Control (Path) 3
6.3
10.3
Control 1
3.3
9.9

Hippo

Occipital Ctx

AD 1 Temporal
13.8
11.9
Control 2
46.7
37.1

Ctx

Occipital Ctx

AD 2 Temporal
22.2
29.7
Control 3
11.8
16.6

Ctx

Occipital Ctx

AD 3 Temporal
3.1
5.8
Control 4
6.7
8.9

Ctx

Occipital Ctx

AD 4 Temporal
12.4
15.4
Control (Path)
67.4
60.7

Ctx

1 Occipital

Ctx

AD 5 Inf
100.0
100.0
Control (Path)
6.1
15.6

Temporal Ctx

2 Occipital

Ctx

AD 5
38.7
51.8
Control (Path)
5.0
9.6

Sup Temporal Ctx

3 Occipital

Ctx

AD 6 Inf
19.1
32.5
Control (Path)
11.6
8.6

Temporal Ctx

4 Occipital

Ctx

AD 6 Sup
25.5
37.6
Control 1
6.5
9.4

Temporal Ctx

Parietal Ctx

Control 1
0.0
9.3
Control 2
26.2
39.2

Temporal Ctx

Parietal Ctx

Control 2
26.4
25.3
Control 3
15.3
15.7

Temporal Ctx

Parietal Ctx

Control 3
9.8
13.0
Control (Path)
47.6
46.0

Temporal Ctx

1 Parietal Ctx

Control 4
6.6
10.8
Control (Path)
25.3
18.6

Temporal Ctx

2 Parietal Ctx

Control (Path) 1
41.5
35.1
Control (Path)
5.1
9.0

Temporal Ctx

3 Parietal Ctx

Control (Path) 2
26.8
30.6
Control (Path)
25.9
17.7

Temporal Ctx

4 Parietal Ctx

[0670]

208

TABLE GD

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4436,

(%) Ag4436,

Run

Run

Tissue Name
219979271
Tissue Name
219979271

Adipose
3.0
Renal ca. TK-10
29.7

Melanoma*
27.2
Bladder
13.1

Hs688(A).T

Melanoma*
23.7
Gastric ca. (liver
18.4

Hs688(B).T

met.) NCI-N87

Melanoma* M14
35.4
Gastric ca. KATO III
47.6

Melanoma*
24.5
Colon ca. SW-948
12.9

LOXIMVI

Melanoma*
51.1
Colon ca. SW480
45.1

SK-MEL-5

Squamous cell
12.8
Colon ca.* (SW480
42.3

carcinoma SCC-4

met) SW620

Testis Pool
8.0
Colon ca. HT29
12.5

Prostate ca.* (bone
94.6
Colon ca. HCT-116
48.0

met) PC-3

Prostate Pool
5.6
Colon ca. CaCo-2
18.3

Placenta
2.0
Colon cancer tissue
10.6

Uterus Pool
2.1
Colon ca. SW1116
9.5

Ovarian ca.
37.9
Colon ca Colo-205
6.1

OVCAR-3

Ovarian ca.
24.0
Colon ca. SW-48
4.8

SK-OV-3

Ovarian ca.
19.5
Colon Pool
5.8

OVCAR-4

Ovarian ca.
29.3
Small Intestine Pool
4.4

OVCAR-5

Ovarian ca.
13.5
Stomach Pool
4.2

IGROV-1

Ovarian ca.
21.6
Bone Marrow Pool
2.8

OVCAR-8

Ovary
3.2
Fetal Heart
4.8

Breast ca. MCF-7
68.3
Heart Pool
2.2

Breast ca. MDA-
64.2
Lymph Node Pool
9.0

MB-231

Breast ca BT 549
95.3
Fetal Skeletal Muscle
4.9

Breast ca. T47D
81.2
Skeletal Muscle Pool
3.7

Breast ca. MDA-N
9.2
Spleen Pool
7.4

Breast Pool
5.7
Thymus Pool
8.6

Trachea
4.7
CNS cancer (glio/
57.8

astro) U87-MG

Lung
1.4
CNS cancer (glio/
82.9

astro) U-118-MG

Fetal Lung
14.6
CNS cancer (neuro;
26.4

met) SK-N-AS

Lung ca. NCI-N47
14.1
CNS cancer (astro)
31.9

SF-539

Lung ca. LX-1
18.2
CNS cancer (astro)
100.0

SNB-75

Lung ca. NCI-H146
11.3
CNS cancer (glio)
17.3

SNB-19

Lung ca. SHP-77
34.6
CNS cancer (glio)
66.0

SF-295

Lung ca. A549
66.9
Brain (Amygdala)
7.4

Pool

Lung ca. NCI-H526
8.0
Brain (cerebellum)
10.9

Lung ca. NCI-H23
42.3
Brain (fetal)
10.9

Lung ca. NCI-H460
21.5
Brain (Hippocampus)
6.9

Pool

Lung ca. HOP-62
26.8
Cerebral Cortex Pool
10.2

Lung ca. NCI-H522
54.3
Brain (Substantia
8.1

nigra) Pool

Liver
0.3
Brain (Thalamus) Pool
15.7

Fetal Liver
8.1
Brain (whole)
8.9

Liver ca. HepG2
8.8
Spinal Cord Pool
9.3

Kidney Pool
9.5
Adrenal Gland
7.8

Fetal Kidney
11.1
Pituitary gland Pool
6.5

Renal ca. 786-0
26.1
Salivary Gland
3.9

Renal ca A498
9.9
Thyroid (female)
6.5

Renal ca. ACHN
7.9
Pancreatic ca.
19.8

CAPAN2

Renal ca. UO-31
32.5
Pancreas Pool
10.4

[0671]

209

TABLE GE

General_screening_panel_v1.6

Rel. Exp.

Rel. Exp.

(%) Ag6784,

(%) Ag6784,

Run

Run

Tissue Name
278017432
Tissue Name
278017432

Adipose
11.9
Renal ca. TK-10
30.8

Melanoma*
21.6
Bladder
17.0

Hs688(A).T

Melanoma*
22.4
Gastric ca. (liver
29.1

Hs688(B).T

met.) NCI-N87

Melanoma* M14
25.5
Gastric ca. KATO III
26.6

Melanoma*
19.1
Colon ca SW-948
10.7

LOXIMVI

Melanoma*
30.8
Colon ca. SW480
26.1

SK-MEL-5

Squamous cell
6.1
Colon ca.* (SW480
27.9

carcinoma SCC-4

met) SW620

Testis Pool
16.8
Colon ca HT29
6.3

Prostate ca.* (bone
100.0
Colon ca. HCT-116
42.3

met) PC-3

Prostate Pool
16.3
Colon ca. CaCo-2
15.5

Placenta
3.1
Colon cancer tissue
9.3

Uterus Pool
9.6
Colon ca. SW1116
3.3

Ovarian ca.
41.5
Colon ca. Colo-205
7.4

OVCAR-3

Ovarian ca.
28.3
Colon ca. SW-48
6.2

SK-OV-3

Ovarian ca.
16.6
Colon Pool
18.6

OVCAR-4

Ovarian ca.
47.3
Small Intestine Pool
25.9

OVCAR-5

Ovarian ca.
20.2
Stomach Pool
17.2

IGROV-1

Ovarian ca.
27.2
Bone Marrow Pool
11.6

OVCAR-8

Ovary
9.2
Fetal Heart
10.4

Breast ca. MCF-7
51.4
Heart Pool
6.3

Breast ca. MDA-
53.2
Lymph Node Pool
32.8

MB-231

Breast ca. BT 549
42.3
Fetal Skeletal Muscle
9.6

Breast ca. T47D
15.4
Skeletal Muscle Pool
1.4

Breast ca. MDA-N
8.1
Spleen Pool
11.7

Breast Pool
25.0
Thymus Pool
22.1

Trachea
11.7
CNS cancer (glio/
39.0

astro) U87-MG

Lung
17.9
CNS cancer (glio/
66.0

astro) U-118-MG

Fetal Lung
33.0
CNS cancer (neuro;
29.1

met) SK-N-AS

Lung ca. NCI-N417
12.1
CNS cancer (astro)
27.5

SF-539

Lung ca. LX-1
15.3
CNS cancer (astro)
87.7

SNB-75

Lung ca. NCI-H146
9.2
CNS cancer (glio)
22.5

SNB-19

Lung ca. SHP-77
35.6
CNS cancer (glio)
58.6

SF-295

Lung ca. A549
55.1
Brain (Amygdala)
29.7

Pool

Lung ca. NCI-H526
6.0
Brain (cerebellum)
83.5

Lung ca. NCI-H23
34.2
Brain (fetal)
41.2

Lung ca. NCI-H460
39.8
Brain (Hippocampus)
27.7

Pool

Lung ca. HOP-62
19.3
Cerebral Cortex Pool
23.3

Lung ca. NCI-H522
65.5
Brain (Substantia
25.3

nigra) Pool

Liver
1.3
Brain (Thalamus) Pool
53.2

Fetal Liver
8.4
Brain (whole)
24.3

Liver ca. HepG2
6.5
Spinal Cord Pool
26.6

Kidney Pool
51.1
Adrenal Gland
7.7

Fetal Kidney
36.9
Pituitary gland Pool
6.7

Renal ca 786-0
32.5
Salivary Gland
6.0

Renal ca. A498
5.4
Thyroid (female)
11.8

Renal ca. ACHN
11.2
Panceatic ca.
14.2

CAPAN2

Renal ca. UO-31
31.2
Pancreas Pool
8.2

[0672]

210

TABLE GF

Panel 4.1D

Rel. Exp. (%) Ag4436,

Rel. Exp. (%) Ag4436,

Tissue Name
Run 190820175
Tissue Name
Run 190820175

Secondary Th1 act
53.2
HUVEC IL-1beta
38.7

Secondary Th2 act
79 6
HUVEC IFN gamma
29.3

Secondary Tr1 act
55.9
HUVEC INF alpha + IFN
36.9

gamma

Secondary Th1 rest
11.8
HUVEC TNF alpha + IL4
32.3

Secondary Th2 rest
33.2
HUVEC IL-11
15.4

Secondary Tr1 rest
18.8
Lung Microvascular EC none
66.0

Primary Th1 act
44.4
Lung Microvascular EC
42.6

TNFalpha + IL-1beta

Primary Th2 act
74.7
Microvascular Dermal EC
26.8

none

Primary Tr1 act
58.2
Microsvasular Dermal EC
20.7

TNFalpha + IL-1beta

Primary Th1 rest
15.4
Bronchial epithelium
30.6

TNFalpha + IL1beta

Primary Th2 rest
11.5
Small airway epithelium none
16.8

Primary Tr1 rest
25.5
Small airway epithelium
36.9

TNFalpha + IL-1beta

CD45RA CD4
66.9
Coronery artery SMC rest
21.2

lymphocyte act

CD4SRO CD4
77.9
Coronery artery SMC
36.3

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
71.7
Astrocytes rest
23.0

Secondary CD8
63.7
Astrocytes TNFalpha + IL-
13.9

lymphocyte rest

1beta

Secondary CD8
25.0
KU-812 (Basophil) rest
9.9

lymphocyte act

CD4 lymphocyte none
14.4
KU-812 (Basophil)
37.9

PMA/ionomycin

2ry Th1/Th2/Tr1_anti-
23.0
CCD 1106 (Keratinocxtes)
77.9

CD95 CH11

none

LAK cells rest
24.0
CCD1106 (Keratinocytes)
57.8

TNFalpha + IL-1beta

LAK cells IL-2
45.1
Liver curhosis
5.7

LAK cells IL-2 + IL-12
37.9
NCI-H292 none
44.1

LAK cells IL-2 + IFN
28.3
NCI-H292 IL-4
71.7

gamma

LAK cells IL-2 + IL-18
45.7
NCI-H292 IL-9
71.2

LAK cells
19.6
NCI-H292 IL-13
63.7

PMA/ionomycin

NK Cells IL-2 rest
49.0
NCI-H292 IFN gamma
64.6

Two Way MLR 3 day
28.5
HPAEC none
29.1

Two Way MLR 5 day
49.0
HPAEC TNF alpha + IL-1beta
47.3

Two Way MLR 7 day
27.7
Lung fibroblast none
58.2

PBMC rest
6.0
Lung fibroblast TNF alpha +
54.0

IL-1beta

PBMC PWM
59.9
Lung fibroblast IL-4
59.9

PBMC PHA-L
32.3
Lung fibroblast IL-9
97.9

Ramos (B cell) none
52.1
Lung fibroblast IL-13
100.0

Ramos (B cell) ionomycin
79.0
Lung fibroblast IFN gamma
62.0

B lymphocytes PWM
29.5
Dermal fibroblast CCD1070
82.4

rest

B lymphocytes CD40L
35.8
Dermal fibioblast CCD1070
74.2

and IL-4

TNF alpha

EOL-1 dbcAMP
34.9
Dermal fibroblast CCD1070
48.6

IL-1beta

EOL-1 dbcAMP
28.1
Dermal fibroblast IFN gamma
32.3

PMA/ionomycin

Dendritic cells none
25.9
Dermal fibroblast IL-4
50.7

Dendritic cells LPS
28.1
Dermal fibroblasts rest
20.2

Dendritic cells anti-CD40
14.7
Neutrophils TNFa + LPS
10.6

Monocytes rest
19.3
Neutrophils rest
8.1

Monocytes LPS
62.9
Colon
3.4

Macrophages rest
22.1
Lung
16.3

Macrophages LPS
20.2
Thymus
25.2

HUVEC none
27.4
Kidney
15.3

HUVEC starved
33.2

[0673]

211

TABLE GG

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4436,

(%) Ag4436,

Run

Run

Tissue Name
268672041
Tissue Name
268672041

Colon cancer 1
27.4
Bladder NAT 2
0.6

Colon NAT 1
16.4
Bladder NAT 3
0.0

Colon cancer 2
39.0
Bladder NAT 4
2.3

Colon NAT 2
20.3
Prostate
42.6

adenocarcinoma 1

Colon cancer 3
80.1
Prostate
7.6

adenocarcinoma 2

Colon NAT 3
17.0
Prostate
31.4

adenocarcinoma 3

Colon malignant
100.0
Prostate
25.9

cancer 4

adenocarcinoma 4

Colon NAT 4
1.9
Prostate NAT 5
4.5

Lung cancer 1
30.6
Prostate
12.9

adenocarcinoma 6

Lung NAT 1
2.5
Prostate
9.9

adenocarcinoma 7

Lung cancer 2
71.7
Prostate
3.7

adenocarcinoma 8

Lung NAT 2
3.2
Prostate
38.4

adenocarcinoma 9

Squamous cell
35.8
Prostate NAT 10
2.6

carcinoma 3

Lung NAT 3
0.6
Kidney cancer 1
26.2

Metastatic melanoma 1
16.3
Kidney NAT 1
12.5

Melanoma 2
8.4
Kidney cancer 2
92.0

Melanoma 3
5.8
Kidney NAT 2
26.8

Metastatic melanoma 4
51.8
Kidney cancer 3
25.0

Metastatic melanoma 5
80.7
Kidney NAT 3
6.4

Bladder cancer 1
5.5
Kidney cancer 4
26.2

Bladder NAT 1
0.0
Kidney NAT 4
21.3

Bladder cancer 2
3.8

[0674] CNS_neurodegeneration_v1.0Summary: Ag4436/Ag6784 These panels do not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene at moderate levels in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

[0675] General_screening_panel_v1.4 Summary: Ag4436 Highest expression of this gene is seen in a brain cancer cell line (CT=28.9). This gene is widely expressed in this panel, with prominent expression seen in brain, colon, gastric, lung, breast, ovarian, and melanoma cancer cell lines. This expression profile suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer.

[0676] Among tissues with metabolic function, this gene is expressed at low but significant levels in pituitary, adipose, adrenal gland, pancreas, thyroid, fetal liver, and adult and fetal skeletal muscle and heart. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, Such as obesity and diabetes.

[0677] This gene is also expressed at low but significant levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0678] In addition, this gene is expressed at much higher levels in fetal lung and liver tissue (CTs=31.5-32.5) when compared to expression in the adult counterpart (CTs=35-37). Thus, expression of this gene may be used to differentiate between the fetal and adult source of these tissues.

[0679] General_screening_panel_v1.6 Summary: Ag6784 Expression of the gene in this panel is ubiquitous, with highest expression in a prostate cancer cell line (CT=29.2). Overall, expression of this gene is in agreement with expression in Panel 1.4. Please see that panel for discussion of utility of this gene in cancer, metabolic and neurological disease.

[0680] Panel 4.1D Summary: Ag4436 Highest expression of this gene is seen in IL-13 treated lung fibroblasts. This gene is also expressed at low but significant levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

[0681] Ag6784 Results from one experiment with this gene are not included. The amp plot indicates that there were experimental difficulties with this run.

[0682] general oncology screening panel_v—2.4 Summary: Ag4436 Highest expression of this gene is seen in a sample derived from colon cancer (CT=31.2). In addition, this gene is more highly expressed in lung, colon and kidney cancer than in the corresponding normal adjacent tissue. Prominent levels of expression are also seen in prostate and melanoma cancers. Thus, expression of this gene could be used as a marker of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of lung, colon and kidney cancer.

[0683] H. CG111347-01: NP25 Variant

[0684] Expression of gene CG111347-01 was assessed using the primer-probe set Ag4438, described in Table HA. Results of the RTQ-PCR runs are shown in Tables HB, HC, HD, HE and HF.

212TABLE HAProbe Name Ag4438PrimersSequencesLengthStart PositionSEQ ID NoForward5′-acggtactgtgcaagctgataa-3′22178139ProbeTET-5′-tttatacccaccaggacaagagccca-3′-TAMRA26204140Reverse5′-tctgcttaaaagccatctttga-3′22247141

[0685]

213

TABLE HB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4438,

(%) Ag4438,

Run

Run

Tissue Name
224534932
Tissue Name
224534932

AD 1 Hippo
6.4
Control (Path) 3
0.9

Temporal Ctx

AD 2 Hippo
22.5
Control (Path) 4
21.5

Temporal Ctx

AD 3 Hippo
1.9
AD 1 Occipital
7.1

Ctx

AD 4 Hippo
3.2
AD 2 Occipital
0.0

Ctx (Missing)

AD 5 hippo
91.4
AD 3 Occipital
1.4

Ctx

AD 6 Hippo
24.5
AD 4 Occipital
11.0

Ctx

Control 2 Hippo
27.5
AD 5 Occipital
19.1

Ctx

Control 4 Hippo
0.9
AD 6 Occipital
54.7

Ctx

Control (Path) 3 Hippo
0.9
Control 1
0.6

Occipital Ctx

AD 1 Temporal Ctx
3.1
Control 2
91.4

Occipital Ctx

AD 2 Temporal Ctx
22.2
Control 3
9.0

Occipital Ctx

AD 3 Temporal Ctx
1.3
Control 4
0.9

Occipital Ctx

AD 4 Temporal Ctx
12.0
Control (Path) 1
98.6

Occipital Ctx

AD 5 Inf Temporal Ctx
100.0
Control (Path) 2
6.0

Occipital Ctx

AD 5 SupTemporal Ctx
24.5
Control (Path) 3
0.6

Occipital Ctx

AD 6 Inf Temporal Ctx
24.7
Control (Path) 4
7.0

Occipital Ctx

AD 6 Sup Temporal Ctx
24.1
Control 1 Parietal
1.6

Ctx

Control 1 Temporal Ctx
1.2
Control 2 Parietal
21.5

Ctx

Control 2 Temporal Ctx
61.1
Control 3 Parietal
22.4

Ctx

Control 3 Temporal Ctx
12.4
Control (Path) 1
95.3

Parietal Ctx

Control 4 Temporal Ctx
2.0
Control (Path) 2
15.0

Parietal Ctx

Control (Path) 1
62.0
Control (Path) 3
0.8

Temporal Ctx

Parietal Ctx

Control (Path) 2
27.2
Control (Path) 4
31.4

Temporal Ctx

Parietal Ctx

[0686]

214

TABLE HC

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4438,

(%) Ag4438,

Run

Run

Tissue Name
219979357
Tissue Name
219979357

Adipose
0.0
Renal ca. TK-10
1.0

Melanoma*
0.0
Bladder
0.1

Hs688(A).T

Melanoma*
0.0
Gastric ca. (liver met.)
0.0

Hs688(B).T

NCI-N87

Melanoma* M14
0.0
Gastric ca. KATO III
0.1

Melanoma*
0.0
Colon ca. SW-948
0.0

LOXIMVI

Melanoma*
0.0
Colon ca. SW480
0.6

SK-MEL-5

Squamous cell
0.6
Colon ca.* (SW480
0.7

carcinoma SCC-4

met) SW620

Testis Pool
0.0
Colon ca. HT29
0.0

Prostate ca.* (bone
5.1
Colon ca. HCT-116
0.3

met) PC-3

Prostate Pool
0.0
Colon ca. CaCo-2
0.0

Placenta
0.1
Colon cancer tissue
0.1

Uterus Pool
0.0
Colon ca. SW1116
0.0

Ovarian ca
0.2
Colon ca. Colo-205
0.0

OVCAR-3

Ovarian ca.
0.1
Colon ca. SW-48
0.0

SK-OV-3

Ovarian ca.
0.1
Colon Pool
0.0

OVCAR-4

Ovarian ca
0.0
Small Intestine Pool
0.3

OVCAR-5

Ovarian ca.
0.0
Stomach Pool
0.1

IGROV-1

Ovarian ca.
0.3
Bone Marrow Pool
0.0

OVCAR-8

Ovary
0.0
Fetal Heart
0.0

Breast ca MCF-7
0.0
Heart Pool
0.0

Breast ca MDA-
0.4
Lymph Node Pool
0.0

MB-231

Breast ca. BT 549
0.0
Fetal Skeletal Muscle
0.0

Breast ca T47D
0.0
Skeletal Muscle Pool
0.0

Breast ca. MBA-N
0.0
Spleen Pool
0.1

Breast Pool
0.0
Thymus Pool
0.1

Trachea
0.6
CNS cancer (glio/
0.9

astro) U87-MG

Lung
0.0
CNS cancer (glio/
1.2

astro) U-118-MG

Fetal Lung
0.1
CNS cancer (neuro;
0.5

met) SK-N-AS

Lung ca. NCI-N417
0.0
CNS cancer (astro)
0.0

SF-539

Lung ca. LX-1
1.1
CNS cancer (astro)
0.1

SNB-75

Lung ca. NCI-H146
100.0
CNS cancer (glio)
0.0

SNB-19

Lung ca. SHP-77
0.1
CNS cancer (glio)
0.1

SF-295

Lung ca A549
0.0
Brain (Amygdala)
46.0

Pool

Lung ca. NCI-H526
1.2
Brain (cerebellum)
62.9

Lung ca. NCI-H23
0.0
Brain (fetal)
37.1

Lung ca. NCI-H460
0.0
Brain (Hippocampus)
30.6

Pool

Lung ca. HOP-62
1.0
Cerebral Cortex Pool
65.1

Lung ca. NCI-H522
0.0
Brain (Substantia
40.6

nigra) Pool

Liver
0.0
Brain (Thalamus) Pool
66.9

Fetal Liver
0.0
Brain (whole)
51.4

Liver ca. HepG2
0.0
Spinal Cord Pool
4.9

Kidney Pool
0.0
Adrenal Gland
1.8

Fetal Kidney
0.2
Pituitary gland Pool
6.2

Renal ca. 786-0
0.0
Salivary Gland
0.0

Renal ca A498
0.0
Thyroid (female)
0.8

Renal ca ACHN
15.4
Pancreatic ca.
0.0

CAPAN2

Renal ca. UO-31
4.4
Pancreas Pool
0.0

[0687]

215

TABLE HD

Panel 4.

Rel. Exp.

Rel. Exp.

(%) Ag4438,

(%) Ag4438,

Run

Run

Tissue Name
191391589
Tissue Name
191391589

Secondary Th1 act
5.6
HUVEC IL-1beta
0.5

Sccondary Th2 act
2.5
HUVEC IFN gamma
0.0

Secondary Tr1 act
5.5
HUVEC TNF alpha +
0.0

IFN gamma

Secondary Th1 rest
0.0
HUVEC TNF alpha +
0.0

IL4

Secondary Th2 rest
0.0
HUVEC IL-11
1.9

Secondary Tr1 rest
0.0
Lung Microvascular
1.1

EC none

Primary Th1 act
0.0
Lung Microvascular
0.6

EC TNFalpha +

IL-1beta

Primary Th2 act
1.8
Microvascular Dermal
0.5

EC none

Primary Tr1 act
1.2
Microvascular Dermal
0.6

EC TNFalpha +

IL-1beta

Primary Th1 rest
0.0
Bronchial
5.7

epithelium

TNFalpha + IL1beta

Primary Th2 rest
0.0
Small airway
1.4

epithelium none

Primary Tr1 rest
0.0
Small airway
10.6

epithelium

TNFalpha + IL-1beta

CD45RA CD4
3.5
Coronery artery SMC
2.7

lymphocyte act

rest

CD45RO CD4
1.9
Coronery artery SMC
3.4

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
0.9
Astrocytes rest
6.7

Secondary CD8
4.9
Astrocytes
5.6

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
1.8
KU-812 (Basophil)
0.8

lymphocyte act

rest

CD4 lymphocyte
0.0
KU-812 (Basophil)
0.5

none

PMA/ionomycin

2ry Th1/Th2/
0.0
CCD1106
49.7

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
27.9
CCD1106
29.1

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
1.6
Liver cirrhosis
1.7

LAK cells IL-2 +
1.7
NCI-H292 none
0.7

IL-12

LAK cells IL-2 +
1.8
NCI-H292 IL-4
0.5

IFN gamma

LAK cells IL-2 +
1.2
NCI-H292 IL-9
1.4

IL-18

LAK cells
62.9
NCI-H292 IL-13
0.9

PMA/ionomycin

NK Cells IL-2 rest
1.2
NCI-H292 IFN gamma
0.0

Two Way MLR 3
7.1
HPAEC none
0.0

day

Two Way MLR 5
30.8
HPAEC TNF alpha +
0.6

day

IL-1 beta

Two Way MLR 7
18.0
Lung fibroblast none
0.6

day

PBMC rest
0.0
Lung fibroblast TNF
0.9

alpha + IL-1 beta

PBMC PWM
0.4
Lung fibroblast IL-4
1.3

PBMC PHA-L
2.4
Lung fibroblast IL-9
2.5

Ramos (B cell) none
0.0
Lung fibroblast IL-13
0.5

Ramos (B cell)
0.0
Lung fibroblast IFN
0.0

ionomycin

gamma

B lymphocytes
3.3
Dermal fibroblast
25.2

PWM

CCD1070 rest

B lymphocytes
0.7
Dermal fibroblast
15.9

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
0.0
Dermal fibroblast
15.3

CCD1070 IL-1 beta

EOL-1 dbcAMP
0.0
Dermal fibroblast
5.0

PMA/ionomycin

IFN gamma

Dendritic cells none
6.0
Dermal fibroblast IL-4
0.5

Dendritic cells LPS
15.3
Dermal fibroblasts rest
0.6

Dendritic cells
1.5
Neutrophils TNFa +
1.1

anti-CD40

LPS

Monocytes rest
0.5
Neutrophils rest
1.6

Monocytes LPS
0.0
Colon
6.2

Macrophages rest
6.0
Lung
6.6

Macrophages LPS
14.1
Thymus
19.6

HUVEC none
1.4
Kidney
100.0

HUVEC starved
0.7

[0688]

216

TABLE HE

Panel CNS_1.1

Rel. Exp.

Rel. Exp.

(%) Ag4438,

(%) Ag4438,

Run

Run

Tissue Name
195308646
Tissue Name
195308646

Cing Gyr
5.1
BA17 PSP2
8.9

Depression2

Cing Gyr
2.8
BA17 PSP
17.0

Depression

Cing Gyr PSP2
5.6
BA17 Huntington's2
8.7

Cing Gyr PSP
6.7
BA17 Huntington's
37.6

Cing Gyr
11.3
BA17 Parkinson's2
35.8

Huntington's2

Cing Gyr
67.4
BA17 Parkinson's
18.0

Huntington's

Cing Gyr
30.4
BA17 Alzheimer's2
3.4

Parkinson's2

Cing Gyr
27.9
BA17 Control2
68.3

Parkinson's

Cing Gyr
5.0
BA17 Control
27.2

Alzheimer's2

Cing Gyr
23.5
BA9 Depression2
7.7

Alzheimer's

Cing Gyr Control2
34.2
BA9 Depression
4.8

Cing Gyr Control
80.7
BA9 PSP2
5.0

Temp Pole
5.1
BA9 PSP
9.9

Depression2

Temp Pole PSP2
4.9
BA9 Huntington's2
10.6

Temp Pole PSP
4.2
BA9 Huntington's
68.8

Temp Pole
35.4
BA9 Parkinson's2
83.5

Huntington's

Temp Pole
29.3
BA9 Parkinson's
23.8

Parkinson's2

Temp Pole
22.1
BA9 Alzheimer's2
9.5

Parkinson's

Temp Pole
4.4
BA9 Alzheimer's
4.5

Alzheimer's2

Temp Pole
2.0
BA9 Control2
87.1

Alzheimer's

Temp Pole Control2
74.2
BA9 Control
21.9

Temp Pole Control
19.1
BA7 Depression
3.5

Glob Palladus
0.7
BA7 PSP2
39.5

Depression

Glob Palladus PSP2
2.3
BA7 PSP
28.1

Glob Palladus PSP
1.9
BA7 Huntington's2
25.2

Glob Palladus
6.7
BA7 Huntington's
43.5

Parkinson's2

Glob Palladus
42.6
BA7 Parkinson's2
48.0

Parkinson's

Glob Palladus
1.6
BA7 Parkinson's
10.4

Alzheimer's2

Glob Palladus
5.8
BA7 Alzheimer's2
4.0

Alzhiemer's

Glob Palladus
5.1
BA7 Control2
42.9

Control2

Glob Palladus
2.9
BA7 Control
53.2

Control

Sub Nigra
3.0
BA4 Depression2
4.9

Depression2

Sub Nigra
0.6
BA4 Depression
10.1

Depression

Sub Nigra PSP2
1.0
BA4 PSP2
19.5

Sub Nigra
17.9
BA4 PSP
7.6

Huntington's2

Sub Nigra
23.0
BA4 Huntington's2
4.4

Huntington's

Sub Nigra
26.8
BA4 Huntington's
49.0

Parkinson's2

Sub Nigra
5.7
BA4 Parkinson's2
100.0

Alzheimer's2

Sub Nigra Control2
15.4
BA4 Parkinson's
40.9

Sub Nigra Control
7.3
BA4 Alzheimer's2
3.6

BA17 Depression2
10.9
BA4 Control2
85.9

BA17 Depression
2.1
BA4 Control
40.6

[0689]

217

TABLE HF

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4438,

(%) Ag4438,

Run

Run

Tissue Name
268672115
Tissue Name
268672115

Colon cancer 1
2.6
Bladder NAT 2
0.0

Colon NAT 1
23.0
Bladder NAT 3
0.0

Colon cancer 2
10.7
Bladder NAT 4
0.0

Colon NAT 2
16.6
Prostate
7.9

adenocarcinoma 1

Colon cancer 3
0.0
Prostate
0.0

adenocarcinoma 2

Colon NAT 3
82.4
Prostate
13.6

adenocarcinoma 3

Colon malignant
0.0
Prostate
1.9

cancer 4

adenocarcinoma 4

Colon NAT 4
5.1
Prostate NAT 5
0.0

Lung cancer 1
0.0
Prostate
1.2

adenocarcinoma 6

Lung NAT 1
0.0
Prostate
0.0

adenocarcinoma 7

Lung cancer 2
100.0
Prostate
6.6

adenocarcinoma 8

Lung NAT 2
0.0
Prostate
0.0

adenocarcinoma 9

Squamous cell
21.6
Prostate NAT 10
0.0

carcinoma 3

Lung NAT 3
1.9
Kidney cancer 1
1.9

Metastatic melanoma 1
0.0
Kidney NAT 1
9.7

Melanoma 2
1.0
Kidney cancer 2
9.7

Melanoma 3
0.0
Kidney NAT 2
53.6

Metastatic melanoma 4
2.0
Kidney cancer 3
1.0

Metastatic melanoma 5
3.5
Kidney NAT 3
28.5

Bladder cancer 1
0.0
Kidney cancer 4
0.0

Bladder NAT 1
0.0
Kidney NAT 4
21.6

Bladder cancer 2
0.0

[0690] CNS_neurodegeneration_v1.0 Summary: Ag4438 This panel confirms the expression of this gene at high levels in the brain in an independent group of individuals. This gene is found to be down-regulated in the temporal cortex of Alzheimer's disease patients. Therefore, Lip-regulation of this gene or its protein product, or treatment with specific agonists for this receptor may be of use in reversing the dementia, memory loss, and neuronal death associated with this disease.

[0691] General_screening_panel_v1.4 Summary: Ag4438 Highest expression of this gene is seen in a lung cancer cell line (CT=25.9). Expression of this gene appears to be highly brain specific with high levels of expression seen in all regions of the brain examined. This gene has homology to NP25, a novel protein that is differentially expressed in neuronal subpopulations (Ren W. Brain Res Mol Brain Res March 1994;22(1-4): 173-85). Based on this expression profile, expression of this gene could be used to differentiate the lung cancer derived sample from other samples on this panel and as a marker of brain tissue. In addition, based on the homology of this protein to NP25 and its localization in the CNS, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0692] Panel 4.1D Summary: Ag4438 Highest expression of this gene is seen in the kidney (CT=30.4). Moderate to low levels of expression are seen in clusters of samples derived from treated and untreated keratinocytes, dermal fibroblasts, macrophages, and dendritic cells, TNF-a and IL-1 beta stimulated small airway and bronchial epithelium, LAK cells stimulated with PMA/ionomycin and colon, thymus, and lung. This widespread expression among samples of significance in the immune response in health and disease suggests that modulation of the expression or function of this gene may be useful in the treatment of autoimmune disorders, including asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

[0693] Panel CNS—1.1 Summary: Ag4438 This panel confirms the expression of this gene at high to moderate levels in the brain in an independent group of individuals. Please see Panel 1.4 for discussion of utility of this gene in the CNS.

[0694] general oncology screening panel_v—2.4 Summary: Ag4438 Highest expression of this gene is seen in lung cancer (CT=32.6). In addition, this gene is more highly expressed in colon and kidney tissue than in the adjacent tumor. Thus, absence of expression of this gene could be used as a marker of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of lung and kidney cancer.

[0695] I. CG111446-01: GTPASE-Activating Protein

[0696] Expression of gene CG111446-01 was assessed using the primer-probe set Ag4442, described in Table IA. Results of the RTQ-PCR runs are shown in Tables IB, IC, ID and IE.

218TABLE IAProbe Name Ag4442PrimersSequencesLengthStart PositionSEQ ID NoForward5′-gaccactaccccaggtttctaa-3′223481142ProbeTET-5′-ttgcttctgatgtgggtccctaacct-3′-TAMRA263512143Reverse5′-cagggtagggaagctgagatta-3′223539144

[0697]

219

TABLE IB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4442,

(%) Ag4442,

Run

Run

Tissue Name
224534977
Tissue Name
224534977

AD 1 Hippo
22.1
Control (Path) 3
15.5

Temporal Ctx

AD 2 Hippo
53.2
Control (Path) 4
100.0

Temporal Ctx

AD 3 Hippo
12.1
AD 1 Occipital Ctx
23.5

AD 4 Hippo
24.8
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 Hippo
59.5
AD 3 Occipital Ctx
13.0

AD 6 Hippo
56.6
AD 4 Occipital Ctx
47.3

Control 3 Hippo
31.2
AD 5 Occipital Ctx
38.4

Control 4 Hippo
19.2
AD 6 Occipital Ctx
20.3

Control (Path) 3
11.7
Control 1 Occipital
7.6

Hippo

Ctx

AD 1 Temporal Ctx
40.9
Control 2 Occipital
41.2

Ctx

AD 2 Temporal Ctx
71.2
Control 3 Occipital
39.5

Ctx

AD 3 Temporal Ctx
23.7
Control 4 Occipital
14.3

Ctx

AD 4 Temporal Ctx
47.3
Control (Path) 1
84.7

Occipital Ctx

AD 5 Inf Temporal
80.7
Control (Path) 2
28.7

Ctx

Occipital Ctx

AD 5 Sup Temporal
51.8
Control (Path) 3
8.2

Ctx

Occipital Ctx

AD 6 Inf Temporal
83.5
Control (Path) 4
48.6

Ctx

Occipital Ctx

AD 6 Sup Temporal
60.7
Control 1 Parietal
17.3

Ctx

Ctx

Control 1 Temporal
16.8
Control 2 Parietal
63.3

Ctx

Ctx

Control 2 Temporal
34.4
Control 3 Parietal
21.2

Ctx

Ctx

Control 3 Temporal
47.0
Control (Path) 1
68.3

Ctx

Parietal Ctx

Control 3 Temporal
39.8
Control (Path) 2
42.0

Ctx

Parietal Ctx

Control (Path) 1
71.7
Control (Path) 3
10.6

Temporal Ctx

Parietal Ctx

Control (Path) 2
59.9
Control (Path) 4
71.7

Temporal Ctx

Parietal Ctx

[0698]

220

TABLE IC

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4442,

(%) Ag4442,

Run

Run

Tissue Name
220005707
Tissue Name
220005707

Adipose
1.6
Renal ca. TK-10
4.6

Melanoma*
0.4
Bladder
3.8

Hs688(A).T

Melanoma*
1.0
Gastric ca. (liver met.)
1.1

Hs688(B).T

NCI-N87

Melanoma* M14
1.8
Gastric ca. KATO III
6.3

Melanoma*
0.5
Colon ca. SW-948
0.4

LOXIMVI

Melanoma*
1.4
Colon ca. SW480
8.0

SK-MEL-5

Squamous cell
0.4
Colon ca.* (SW480
4.2

carcinoma SCC-4

met) SW620

Testis Pool
6.7
Colon ca. HT29
3.3

Prostate ca.* (bone
0.8
Colon ca. HCT-116
7.8

met) PC-3

Prostate Pool
2.1
Colon ca. CaCo-2
4.0

Placenta
0.3
Colon cancer tissue
1.4

Uterus Pool
1.2
Colon ca. SW1116
2.0

Ovarian ca.
4.8
Colon ca. Colo-205
0.6

OVCAR-3

Ovarian ca.
8.0
Colon ca. SW-48
0.8

SK-OV-3

Ovarian ca.
2.3
Colon Pool
3.7

OVCAR-4

Ovarian ca.
7.5
Small Intestine Pool
7.9

OVCAR-5

Ovarian ca.
3.3
Stomach Pool
1.9

IGROV-1

Ovarian ca.
1.4
Bone Marrow Pool
2.4

OVCAR-8

Ovary
1.7
Fetal Heart
15.6

Breast ca. MCF-7
17.1
Heart Pool
1.9

Breast ca. MDA-
7.6
Lymph Node Pool
7.0

MB-231

Breast ca. BT 549
15.8
Fetal Skeletal Muscle
7.6

Breast ca. T47D
12.6
Skeletal Muscle Pool
0.8

Breast ca. MDA-N
1.6
Spleen Pool
3.0

Breast Pool
3.5
Thymus Pool
9.9

Trachea
1.8
CNS cancer (glio/
3.3

astro) U87-MG

Lung
6.5
CNS cancer (glio/
17.2

astro) U-118-MG

Fetal Lung
23.7
CNS cancer (neuro;
4.2

met) SK-N-AS

Lung ca. NCI-N417
1.0
CNS cancer (astro)
5.8

SF-539

Lung ca. LX-1
3.6
CNS cancer (astro)
22.5

SNB-75

Lung ca. NCI-H146
14.7
CNS cancer (glio)
3.1

SNB-19

Lung ca. SHP-77
11.4
CNS cancer (glio)
7.3

SF-295

Lung ca. A549
1.8
Brain (Amygdala)
7.5

Pool

Lung ca. NCI-H526
7.7
Brain (cerebellum)
14.5

Lung ca. NCI-H23
4.3
Brain (fetal)
100.0

Lung ca. NCI-H460
0.5
Brain (Hippocampus)
9.3

Pool

Lung ca. HOP-62
2.2
Cerebral Cortex Pool
8.5

Lung ca. NCI-H522
4.8
Brain (Substantia
12.1

nigra) Pool

Liver
0.0
Brain (Thalamus) Pool
14.7

Fetal Liver
6.3
Brain (whole)
19.5

Liver ca. HepG2
3.1
Spinal Cord Pool
8.7

Kidney Pool
8.3
Adrenal Gland
2.0

Fetal Kidney
32.3
Pituitary gland Pool
2.5

Renal ca. 786-0
5.1
Salivary Gland
0.6

Renal ca. A498
1.8
Thyroid (female)
0.5

Renal ca. ACHN
0.8
Pancreatic ca.
4.8

CAPAN2

Renal ca. UO-31
1.7
Pancreas Pool
4.5

[0699]

221

TABLE ID

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4442,

(%) Ag4442,

Run

Run

Tissue Name
190820182
Tissue Name
190820182

Secondary Th1 act
23.5
HUVEC IL-1beta
5.9

Secondary Th2 act
20.6
HUVEC IFN gamma
17.3

Secondary Tr1 act
31.2
HUVEC TNF alpha +
3.5

IFN gamma

Secondary Th1 rest
5.1
HUVEC TNF alpha +
7.3

IL4

Secondary Th2 rest
12.5
HUVEC IL-11
6.7

Secondary Tr1 rest
11.0
Lung Microvascular
15.0

EC none

Primary Th1 act
4.1
Lung Microvascular
13.3

EC TNFalpha +

IL-1beta

Primary Th2 act
13.5
Microvascular Dermal
8.7

EC none

Primary Tr1 act
11.2
Microsvasular Dermal
4.8

EC TNFalpha +

IL-1beta

Primary Th1 rest
18.3
Bronchial epithelium
1.1

TNFalpha + IL1beta

Primary Th2 rest
5.0
Small airway
0.2

epithelium none

Primary Tr1 rest
37.4
Small airway
2.0

epithelium

TNFalpha + IL-1beta

CD45RA CD4
14.6
Coronery artery SMC
1.5

lymphocyte act

rest

CD45RO CD4
20.3
Coronery artery SMC
0.3

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
17.6
Astrocytes rest
5.5

Secondary CD8
9.6
Astrocytes
3.9

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
8.7
KU-812 (Basophil)
29.9

lymphocyte act

rest

CD4 lymphocyte
10.2
KU-812 (Basophil)
16.6

none

PMA/ionomycin

2ry Th1/Th2/
29.1
CCD1106
4.4

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
13.8
CCD1106
6.9

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
16.8
Liver cirrhosis
4.7

LAK cells IL-2 +
6.6
NCI-H292 none
9.9

IL-12

LAK cells IL-2 +
11.3
NCI-H292 IL-4
9.7

IFN gamma

LAK cells IL-2 +
10.7
NCI-H292 IL-9
11.3

IL-18

LAK cells
2.1
NCI-H292 IL-13
12.0

PMA/ionomycin

NK Cells IL-2 rest
53.6
NCI-H292 IFN gamma
9.2

Two Way MLR 3
7.6
HPAEC none
4.2

day

Two Way MLR 5
5.0
HPAEC TNF alpha +
2.3

day

IL-1 beta

Two Way MLR 7
11.0
Lung fibroblast none
12.2

day

PBMC rest
6.8
Lung fibroblast TNF
2.2

alpha + IL-1 beta

PBMC PWM
9.2
Lung fibroblast IL-4
2.4

PBMC PHA-L
12.0
Lung fibroblast IL-9
9.2

Ramos (B cell) none
18.7
Lung fibroblast IL-13
5.4

Ramos (B cell)
25.3
Lung fibroblast IFN
2.0

ionomycin

gamma

B lymphocytes
8.5
Dermal fibroblast
25.7

PWM

CCD1070 rest

B lymphocytes
23.3
Dermal fibroblast
46.7

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
33.7
Dermal fibroblast
9.9

CCD1070 IL-1 beta

EOL-1 dbcAMP
12.1
Dermal fibroblast IFN
9.9

PMA/ionomycin

gamma

Dendritic cells none
4.5
Dermal fibroblast IL-4
23.7

Dendritic cells LPS
2.4
Dermal Fibroblasts
12.2

rest

Dendritic cells
3.3
Neutrophils TNFa +
0.9

anti-CD40

LPS

Monocytes rest
2.8
Neutrophils rest
2.9

Monocytes LPS
0.7
Colon
3.6

Macrophages rest
3.3
Lung
1.8

Macrophages LPS
0.2
Thymus
100.0

HUVEC none
7.3
Kidney
15.2

HUVEC starved
17.2

[0700]

222

TABLE IE

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4442,

(%) Ag4442,

Run

Run

Tissue Name
268672171
Tissue Name
268672171

Colon cancer 1
7.3
Bladder cancer NAT
1.8

2

Colon cancer NAT 1
1.7
Bladder cancer NAT
1.8

3

Colon cancer 2
5.2
Bladder cancer NAT
4.7

4

Colon cancer NAT 2
3.5
Prostate
37.1

adenocarcinoma 1

Colon cancer 3
15.2
Prostate
5.9

adenocarcinoma 2

Colon NAT 3
13.9
Prostate
7.6

adenocarcinoma 3

Colon malignant
13.6
Prostate
12.8

cancer 4

adenocarcinoma 4

Colon normal
3.7
Prostate cancer
13.2

adjacent tissue 4

NAT 5

Lung cancer 1
20.0
Prostate
6.5

adenocarcinoma 6

Lung NAT 1
2.7
Prostate
5.3

adenocarcinoma 7

Lung cancer 2
100.0
Prostate
2.8

adenocarcinoma 8

Lung NAT 2
3.1
Prostate
15.5

adenocarcinoma 9

Squamous cell
6.8
Prostate NAT 10
4.5

carcinoma 3

Lung NAT 3
0.9
Kidney cancer 1
23.0

metastatic melanoma 1
22.5
KidneyNAT 1
11.8

Melanoma 2
2.6
Kidney cancer 2
91.4

Melanoma 3
5.3
Kidney NAT 2
18.4

metastatic melanoma 4
50.0
Kidney cancer 3
81.2

metastatic melanoma 5
41.5
Kidney NAT 3
7.7

Bladder cancer 1
5.0
Kidney cancer 4
10.2

Bladder cancer NAT 1
0.0
Kidney NAT 4
2.0

Bladder cancer 2
2.4

[0701] CNS_neurodegeneration_v1.0 Summary: Ag4442 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

[0702] General_screening_panel_v1.4 Summary: Ag4442 Highest expression of this gene is seen in fetal brain (CT=25.5). In addition, moderate levels of expression are seen throughout the CNS. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0703] Moderate levels of expression are also seen in all the cancer cell lines on this panel.

[0704] Among tissues with metabolic function, this gene is expressed at moderate levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle and heart. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

[0705] In addition, this gene is expressed at much higher levels in fetal heart and skeletal muscle tissue (CTs=28-29) when compared to expression in the adult counterpart (CTs=31-32). Thus, expression of this gene may be used to differentiate between the fetal and adult source of these tissues.

[0706] Panel 4.1D Summary: Ag4442 Highest expression of this gene is seen in thymus (CT=28.74). This gene is also expressed at moderate to low levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

[0707] general oncology screening panel_v—2.4 Summary: Ag4442 Highest expression of this gene is seen in lung cancer (CT=28.3). In addition, this gene is more highly expressed in lung and kidney cancer than in the corresponding normal adjacent tissue. Thus, expression of this gene could be used as a marker of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of lung and kidney cancer.

[0708] J. CG111464-01: ELKS Like Gene

[0709] Expression of gene CG111464-01 was assessed using the primer-probe set Ag4444, described in Table JA. Results of the RTQ-PCR runs are shown in Tables JB, JC, JD and JE.

223TABLE JAProbe Name Ag4444PrimersSequencesLengthStart PositionSEQ ID NoForward5′-caaatgtgtcccagtgaacag-3′215032145ProbeTET-5′-tggttctcactgcctcctacaaccag-3′-TAMRA265073146Reverse5′-gttgcagagttcaggtcaagac-3′225099147

[0710]

224

TABLE JB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4444,

(%) Ag4444,

Run

Run

Tissue Name
224535011
Tissue Name
224535011

AD 1 Hippo
30.4
Control (Path) 3
8.5

Temporal Ctx

AD 2 Hippo
45.1
Control (Path) 4
43.2

Temporal Ctx

AD 3 Hippo
16.2
AD 1 Occipital Ctx
25.5

AD 4 Hippo
22.8
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 Hippo
100.0
AD 3 Occipital Ctx
11.2

AD 6 Hippo
69.7
AD 4 Occipital Ctx
36.3

Control 2 Hippo
57.0
AD 5 Occipital Ctx
76.3

Control 4 Hippo
22.2
AD 6 Occipital Ctx
31.4

Control (Path) 3
12.8
Control 1 Occipital
7.3

Hippo

Ctx

AD 1 Temporal Ctx
20.9
Control 2 Occipital
90.8

Ctx

AD 2 Temporal Ctx
44.4
Control 3 Occipital
24.8

Ctx

AD 3 Temporal Ctx
9.3
Control 4 Occipital
11.8

Ctx

AD 4 Temporal Ctx
30.8
Control (Path) 1
87.1

Occipital Ctx

AD 5 Inf Temporal
99.3
Control (Path) 2
17.9

Ctx

Occipital Ctx

AD 5 Sup Temporal
70.7
Control (Path) 3
4.3

Ctx

Occipital Ctx

AD 6 Inf Temporal
43.2
Control (Path) 4
19.1

Ctx

Occipital Ctx

AD 6 Sup Temporal
42.0
Control 1 Parietal
13.0

Ctx

Ctx

Control 1 Temporal
11.0
Control 2 Parietal
59.5

Ctx

Ctx

Control 2 Temporal
75.8
Control 3 Parietal
35.8

Ctx

Ctx

Control 3 Temporal
30.6
Control (Path) 1
79.0

Ctx

Parietal Ctx

Control 3 Temporal
16.6
Control (Path) 2
27.4

Ctx

Parietal Ctx

Control (Path) 1
75.8
Control (Path) 3
7.3

Temporal Ctx

Parietal Ctx

Control (Path) 2
54.0
Control (Path) 4
50.0

Temporal Ctx

Parietal Ctx

[0711]

225

TABLE JC

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4444,

(%) Ag4444,

Run

Run

Tissue Name
220244251
Tissue Name
220244251

Adipose
0.3
Renal ca. TK-10
4.2

Melanoma*
0.1
Bladder
2.6

Hs688(A).T

Melanoma*
0.1
Gastric ca. (liver
0.3

Hs688(B).T

met.) NCI-N87

Melanoma* M14
0.0
Gastric ca. KATO III
0.0

Melanoma*
0.0
Colon ca. SW-948
0.0

LOXIMVI

Melanoma*
0.0
Colon ca. SW480
1.1

SK-MEL-5

Squamous cell
0.2
Colon ca.* (SW480
0.1

carcinoma SCC-4

met) SW620

Testis Pool
1.4
Colon ca. HT29
0.0

Prostate ca.* (bone
0.3
Colon ca. HCT-116
0.0

met) PC-3

Prostate Pool
1.5
Colon ca. CaCo-2
0.2

Placenta
0.4
Colon cancer tissue
0.2

Uterus Pool
0.0
Colon ca. SW1116
0.0

Ovarian ca.
3.2
Colon ca. Colo-205
0.0

OVCAR-3

Ovarian ca.
0.1
Colon ca. SW-48
0.0

SK-OV-3

Ovarian ca.
0.8
Colon Pool
0.5

OVCAR-4

Ovarian ca.
0.0
Small Intestine Pool
0.6

OVCAR-5

Ovarian ca.
1.3
Stomach Pool
1.2

IGROV-1

Ovarian ca.
5.6
Bone Marrow Pool
0.1

OVCAR-8

Ovary
5.3
Fetal Heart
5.2

Breast ca. MCF-7
15.3
Heart Pool
0.0

Breast ca. MDA-
0.1
Lymph Node Pool
0.6

MB-231

Breast ca. BT 549
0.0
Fetal Skeletal Muscle
1.0

Breast ca. T47D
0.0
Skeletal Muscle Pool
0.5

Breast ca. MDA-N
0.3
Spleen Pool
0.7

Breast Pool
1.5
Thymus Pool
1.6

Trachea
0.7
CNS cancer (glio/
3.8

astro) U87-MG

Lung
3.7
CNS cancer (glio/
1.1

astro) U-118-MG

Fetal Lung
2.2
CNS cancer (neuro;
0.3

met) SK-N-AS

Lung ca. NCI-N47
1.3
CNS cancer (astro)
0.0

SF-539

Lung ca. LX-1
0.0
CNS cancer (astro)
0.0

SNB-75

Lung ca. NCI-H146
4.5
CNS cancer (glio)
1.1

SNB-19

Lung ca. SHP-77
28.3
CNS cancer (glio)
39.2

SF-295

Lung ca. A549
0.0
Brain (Amygdala)
45.1

Pool

Lung ca. NCI-H526
1.3
Brain (cerebellum)
13.3

Lung ca. NCI-H23
0.3
Brain (fetal)
99.3

Lung ca. NCI-H460
1.0
Brain (Hippocampus)
54.7

Pool

Lung ca. HOP-62
4.1
Cerebral Cortex Pool
74.2

Lung ca. NCI-H522
0.3
Brain (Substantia
46.3

nigra) Pool

Liver
0.0
Brain (Thalamus) Pool
100.0

Fetal Liver
0.1
Brain (whole)
55.5

Liver ca. HepG2
0.1
Spinal Cord Pool
8.6

Kidney Pool
0.2
Adrenal Gland
0.3

Fetal Kidney
7.6
Pituitary gland Pool
8.1

Renal ca. 786-0
0.0
Salivary Gland
0.0

Renal ca A498
0.0
Thyroid (female)
0.1

Renal ca. ACHN
0.6
Pancreatic ca.
0.0

CAPAN2

Renal ca. UO-31
11.1
Pancreas Pool
1.4

[0712]

226

TABLE JD

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4444,

(%) Ag4444,

Run

Run

Tissue Name
190820186
Tissue Name
190820186

Secondary Th1 act
7.4
HUVEC IL-1beta
28.7

Sccondary Th2 act
0.0
HUVEC IFN gamma
100.0

Secondary Tr1 act
0.0
HUVEC TNF alpha +
16.4

IFN gamma

Secondary Th1 rest
0.0
HUVEC TNF alpha +
38.4

IL4

Secondary Th2 rest
0.0
HUVEC IL-11
53.2

Secondary Tr1 rest
0.0
Lung Microvascular
54.3

EC none

Primary Th1 act
0.0
Lung Microvascular
16.4

EC TNFalpha +

IL-1beta

Primary Th2 act
0.0
Microvascular Dermal
0.0

EC none

Primary Tr1 act
0.0
Microvascular Dermal
0.0

EC TNFalpha +

IL-1beta

Primary Th1 rest
9.1
Bronchial
0.0

epithelium

TNFalpha + IL1beta

Primary Th2 rest
0.0
Small airway
0.0

epithelium none

Primary Tr1 rest
0.0
Small airway
0.0

epithelium

TNFalpha + IL-1beta

CD45RA CD4
0.0
Coronery artery SMC
0.0

lymphocyte act

rest

CD45RO CD4
0.0
Coronery artery SMC
12.9

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
0.0
Astrocytes rest
39.0

Secondary CD8
0.0
Astrocytes
85.3

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
0.0
KU-812 (Basophil)
0.0

lymphocyte act

rest

CD4 lymphocyte
0.0
KU-812 (Basophil)
9.3

none

PMA/ionomycin

2ry Th1/Th2/
0.0
CCD1106
0.0

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
0.0
CCD1106
0.0

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
0.0
Liver cirrhosis
14.8

LAK cells IL-2 +
0.0
NCI-H292 none
0.0

IL-12

LAK cells IL-2 +
0.0
NCI-H292 IL-4
0.0

IFN gamma

LAK cells IL-2 +
0.0
NCI-H292 IL-9
0.0

IL-18

LAK cells
0.0
NCI-H292 IL-13
0.0

PMA/ionomycin

NK Cells IL-2 rest
0.0
NCI-H292 IFN gamma
0.0

Two Way MLR 3
0.0
HPAEC none
42.9

day

Two Way MLR 5
6.3
HPAEC TNF alpha +
9.9

day

IL-1 beta

Two Way MLR 7
0.0
Lung fibroblast none
10.4

day

PBMC rest
0.0
Lung fibroblast TNF
7.3

alpha + IL-1 beta

PBMC PWM
4.9
Lung fibroblast IL-4
10.3

PBMC PHA-L
0.0
Lung fibroblast IL-9
0.0

Ramos (B cell) none
0.0
Lung fibroblast IL-13
0.0

Ramos (B cell)
0.0
Lung fibroblast IFN
6.4

ionomycin

gamma

B lymphocytes
0.0
Dermal fibroblast
4.5

PWM

CCD1070 rest

B lymphocytes
0.0
Dermal fibroblast
0.0

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0

CCD1070 IL-1 beta

EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0

PMA/ionomycin

IFN gamma

Dendritic cells none
8.1
Dermal fibroblast IL-4
0.0

Dendritic cells LPS
18.6
Dermal fibroblasts rest
0.0

Dendritic cells
7.3
Neutrophils TNFa +
0.0

anti-CD40

LPS

Monocytes rest
0.0
Neutrophils rest
0.0

Monocytes LPS
15.6
Colon
7.0

Macrophages rest
0.0
Lung
7.9

Macrophages LPS
0.0
Thymus
6.5

HUVEC none
48.0
Kidney
56.6

HUVEC starved
40.1

[0713]

227

TABLE JE

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4444,

(%) Ag4444,

Run

Run

Tissue Name
268672042
Tissue Name
268672042

Colon cancer 1
4.4
Bladder cancer NAT
0.0

2

Colon cancer NAT 1
6.8
Bladder cancer NAT
0.0

3

Colon cancer 2
14.7
Bladder cancer NAT
0.0

4

Colon cancer NAT 2
0.0
Prostate
28.9

adenocarcinoma 1

Colon cancer 3
3.5
Prostate
0.0

adenocarcinoma 2

Colon NAT 3
0.0
Prostate
6.1

adenocarcinoma 3

Colon malignant
23.0
Prostate
0.0

cancer 4

adenocarcinoma 4

Colon normal
0.0
Prostate cancer
1.8

adjacent tissue 4

NAT 5

Lung cancer 1
14.6
Prostate
1.9

adenocarcinoma 6

Lung NAT 1
0.0
Prostate
3.3

adenocarcinoma 7

Lung cancer 2
100.0
Prostate
0.0

adenocarcinoma 8

Lung NAT 2
3.5
Prostate
10.9

adenocarcinoma 9

Squamous cell
54.0
Prostate cancer
0.0

carcinoma 3

NAT 10

Lung NAT 3
0.0
Kidney cancer 1
18.8

metastatic melanoma 1
57.8
KidneyNAT 1
7.3

Melanoma 2
1.7
Kidney cancer 2
11.6

Melanoma 3
0.0
Kidney NAT 2
28.5

metastatic melanoma 4
63.7
Kidney cancer 3
1.8

metastatic melanoma 5
92.0
Kidney NAT 3
3.6

Bladder cancer 1
0.0
Kidney cancer 4
0.0

Bladder cancer NAT 1
0.0
Kidney NAT 4
0.0

Bladder cancer 2
0.0

[0714] CNS_neurodegeneration_v1.0 Summary: Ag4444 This panel confirms the expression of this gene at low levels in the brain in an independent group of individuals. This gene appears to be slightly down-regulated in the temporal cortex of Alzheimer's disease patients. Therefore, up-regulation of this gene or its protein product, or treatment with specific agonists for this receptor may be of use in reversing the dementia, memory loss, and neuronal death associated with this disease.

[0715] General_screening_panel_v1.4 Summary: Ag4444 Highest expression of this gene is seen in the thalamus (CT=26). In addition, this gene shows high to moderate levels of expression throughout the CNS. Thus, expression of this gene could be used to differentiate between brain derived tissue and non-neuronal tissue. In addition, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurological disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0716] Low to moderate levels of expression are seen in cell lines derived from brain cancer, renal cancer, ovarian cancer, breast cancer, and lung cancer. In addition, higher levels of expression are detected in fetal heart and kidney (CTs=30) when compared to the corresponding adult tissue (CTs=35-40). Thus, expression of this gene could be used to differentiate between the fetal and adult sources of these tissues. In addition, this expression profile suggests a role for this protein product in cell proliferation and/or growth. Thus, therapeutic modulation of the expression or function of this gene may be useful in the treatment of cancer.

[0717] Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, fetal heart and adult and fetal skeletal muscle. This expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

[0718] Panel 4.1D Summary: Ag4444 Highest level of expression of this gene is seen in IFN gamma treated HUVECs (CT=32.8). Lower levels of expression are also seen in a cluster of samples derived from HUVECs, and lung-derived endothelial cells, as well as in atrocytes and kidney. Therefore, therapies designed with the protein encoded by this transcript could be important in regulating endothelium function including leukocyte extravasation, a major component of inflammation during asthma, IBD, and psoriasis.

[0719] general oncology screening panel_v—2.4 Summary: Ag4444 Highest level of expression of this gene is seen in lung cancer (CT=32.3), with low but significant levels of expression also seen in melanoma, colon and kidney cancer. This expression in cancer derived samples is in agreement with expression in Panel 1.4. Please see that panel for discussion of utility of this gene in cancer.

[0720] K. CG111512-01: ARNT-Like

[0721] Expression of gene CG111512-01 was assessed using the primer-probe set Ag4447, described in Table KA. Results of the RTQ-PCR runs are shown in Tables KB, KC, KD and KE.

228TABLE KAProbe Name Ag4447PrimersSequencesLengthStart PositionSEQ ID NoForward5′-cagcagttgaactctgaagaca-3′221510148ProbeTET-5′-cttatgtcctgggcactccgaccat-3′-TAMRA251541149Reverse5′-ctcttcctgggaaagaatgttt-3′221584150

[0722]

229

TABLE KB

CNS_neurodegeneration_v1.0

Rel. Exp. (%) Ag4447, Run

Rel. Exp. (%) Ag4447, Run

Tissue Name
224618519
Tissue Name
224618519

AD 1 Hippo
0.0
Control (Path) 3
0.0

Temporal Ctx

AD 2 Hippo
0.0
Control (Path) 4
0.1

Temporal Ctx

AD 3 Hippo
0.1
AD 1 Occipital Ctx
0.0

AD 4 Hippo
0.1
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 Hippo
0.2
AD 3 Occipital Ctx
0.0

AD 6 Hippo
0.7
AD 4 Occipital Ctx
0.1

Control 2 Hippo
1.8
AD 5 Occipital Ctx
1.0

Control 4 Hippo
0.0
AD 6 Occipital Ctx
100.0

Control (Path) 3 Hippo
0.0
Control 1 Occipital Ctx
0.0

AD 1 Temporal Ctx
0.0
Control 2 Occipital Ctx
0.4

AD 2 Temporal Ctx
0.0
Control 3 Occipital Ctx
0.0

AD 3 Temporal Ctx
0.0
Control 4 Occipital Ctx
0.0

AD 4 Temporal Ctx
0.0
Control (Path) 1
3.4

Occipital Ctx

AD 5 Inf Temporal Ctx
0.0
Control (Path) 2
0.2

Occipital Ctx

AD 5 Sup Temporal
0.0
Control (Path) 3
0.0

Ctx

Occipital Ctx

AD 6 Inf Temporal Ctx
1.3
Control (Path) 4
0.3

Occipital Ctx

AD 6 Sup Temporal
0.7
Control 1 Parietal Ctx
0.1

Ctx

Control 1 Temporal
0.0
Control 2 Parietal Ctx
0.0

Ctx

Control 2 Temporal
0.1
Control 3 Parietal Ctx
0.1

Ctx

Control 3 Temporal
0.1
Control (Path) 1
2.4

Ctx

Parietal Ctx

Control 3 Temporal
0.0
Control (Path) 2
0.2

Ctx

Parietal Ctx

Control (Path) 1
0.7
Control (Path) 3
0.0

Temporal Ctx

Parietal Ctx

Control (Path) 2
0.4
Control (Path) 4
1.1

Temporal Ctx

Perietal Ctx

[0723]

230

TABLE KC

General_screening_panel_v1.4

Rel. Exp. (%) Ag4447,

Rel. Exp. (%) Ag4447,

Tissue Name
Run 220264143
Tissue name
Run 220264143

Adipose
0.3
Renal ca 1 K-10
0.1

Melanoma*
5.4
Bladder
0.6

Hs688(A) T

Melanoma*
5.1
Gastric ca. (liver met)
0.0

Hs688(B) T

NCI-N87

Melanoma* M14
0.0
Gastric ca. KATO III
0.0

Melanoma* LOXIMVI
0.0
Colon ca. SW-948
0.0

Melanoma* SK-MEL-5
0.0
Colon ca. SW480
0.0

Squamous cell
0.0
Colon ca.* (SW480 met)
0.0

carcinoma SCC-4

SW620

Testis Pool
2.3
Colon ca. HT29
0.0

Prostate ca.* (bone met)
0.1
Colon ca. HCI-116
0.2

PC-3

Prostate Pool
1.7
Colon ca. CaCo-2
0.1

Placenta
0.4
Colon cancer tissue
0.3

Uterus Pool
3.3
Colon ca. SW1116
0.0

Ovarian ca. OVCAR-3
0.0
Colon ca. Colo-205
0.0

Ovarian ca SK-OV-3
0.1
Colon ca SW-48
0.0

Ovarian ca OVCAR-4
1.4
Colon Pool
47.3

Ovarian ca. OVCAR-5
0.0
Small Intestine Pool
10.0

Ovarian ca. IGROV-1
0.0
Stomach Pool
7.7

Ovarian ca. OVCAR-8
0.0
Bone Marrow Pool
11.8

Ovary
1.6
Fetal Heart
1.0

Breast ca. MCF-7
0.0
Heart Pool
11.4

Breast ca. MDA-MB-
0.0
Lymph Node Pool
33.9

231

Breast ca. BT 549
1.0
Fetal Skeletal Muscle
1.2

Breast ca. T47D
0.0
Skeletal Muscle Pool
0.5

Breast ca. MDA-N
0.4
Spleen Pool
0.0

Breast Pool
57.4
Thymus Pool
5.8

Trachea
1.2
CNS cancer (glio/astro)
0.4

U87-MG

Lung
1.5
CNS cancer (glio/astro)
0.8

U-118-MG

Fetal Lung
14.4
CNS cancer (neuro; met)
0.1

SK-N-AS

Lung ca. NCI-N417
0.8
CNS cancer (astro) SF-
0.2

539

Lung ca. LX-1
0.0
CNS cancer (astro) SNB-
4.9

75

Lung ca NCI-11146
2.2
CNS cancer (glio) SNB-
0.0

19

Lung ca SHP-77
2.0
CNS cancer (glio) SF-
0.0

295

Lung ca. A549
0.0
Brain (Amygdala) Pool
1.2

Lung ca NCI-H526
0.3
Brain (cerebellum)
100.0

Lung ca NCI-H23
0.0
Brain (fetal)
15.4

Lung ca NCI-H460
0.0
Brain (Hippocampus)
1.3

Pool

Lung ca HOP-62
0.1
Cerebral Cortex Pool
2.1

Lung ca. NCI-H522
0.0
Brain (Substantia nigra)
1.8

Pool

Liver
0.0
Brain (Thalamus) Pool
5.4

Fetal Liver
0.1
Brain (whole)
23.8

Liver ca. HepG2
0.0
Spinal Cord Pool
0.1

Kidney Pool
26.6
Adrenal Gland
4.2

Fetal Kidney
9.9
Pituitary gland Pool
13.1

Renal ca. 786-0
0.0
Salivary Gland
0.4

Renal ca. A498
0.0
Thyroid (female)
0.2

Renal ca. ACHN
0.0
Pancreatic ca. CAPAN2
0.0

Renal ca. UO-31
0.1
Pancreas Pool
26.6

[0724]

231

TABLE KD

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4447,

(%) Ag4447,

Run

Run

Tissue Name
190826622
Tissue Name
190826622

Secondary Th1 act
0.0
HUVEC IL-1beta
0.0

Secondary Th2 act
0.6
HUVEC IFN gamma
0.0

Secondary Tr1 act
0.0
HUVEC TNF alpha +
0.0

IFN gamma

Secondary Th1 rest
0.0
HUVEC TNF alpha +
0.0

IL4

Secondary Th2 rest
0.0
HUVEC IL-11
0.0

Secondary Tr1 rest
0.0
Lung Microvascular
0.0

EC none

Primary Th1 act
0.8
Lung Microvascular
0.0

EC TNFalpha +

IL-1beta

Primary Th2 act
0.7
Microvascular Dermal
0.0

EC none

Primary Tr1 act
0.4
Microsvasular Dermal
0.0

EC TNFalpha +

IL-1beta

Primary Th1 rest
0.0
Bronchial epithelium
0.0

TNFalpha + IL1beta

Primary Th2 rest
1.3
Small airway
0.0

epithelium none

Primary Tr1 rest
0.4
Small airway
0.0

epithelium

TNFalpha + IL-1beta

CD45RA CD4
3.1
Coronery artery SMC
0.0

lymphocyte act

rest

CD45RO CD4
0.5
Coronery artery SMC
1.2

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
0.0
Astrocytes rest
2.8

Secondary CD8
0.0
Astrocytes
1.1

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
0.0
KU-812 (Basophil)
0.4

lymphocyte act

rest

CD4 lymphocyte
0.0
KU-812 (Basophil)
0.4

none

PMA/ionomycin

2ry Th1/Th2/
0.0
CCD1106
0.0

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
0.0
CCD1106
0.0

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
0.8
Liver cirrhosis
0.0

LAK cells IL-2 +
0.9
NCI-H292 none
0.0

IL-12

LAK cells IL-2 +
0.4
NCI-H292 IL-4
0.0

IFN gamma

LAK cells IL-2 +
0.6
NCI-H292 IL-9
0.6

IL-18

LAK cells
0.0
NCI-H292 IL-13
0.0

PMA/ionomycin

NK Cells IL-2 rest
0.0
NCI-H292 IFN gamma
0.0

Two Way MLR 3
0.0
HPAEC none
0.0

day

Two Way MLR 5
0.0
HPAEC TNF alpha +
0.0

day

IL-1 beta

Two Way MLR 7
0.0
Lung fibroblast none
0.0

day

PBMC rest
0.0
Lung fibroblast TNF
0.4

alpha + IL-1 beta

PBMC PWM
0.0
Lung fibroblast IL-4
0.0

PBMC PHA-L
0.9
Lung fibroblast IL-9
0.5

Ramos (B cell) none
0.0
Lung fibroblast IL-13
0.4

Ramos (B cell)
0.0
Lung fibroblast IFN
0.0

ionomycin

gamma

B lymphocytes
0.0
Dermal fibroblast
2.6

PWM

CCD1070 rest

B lymphocytes
0.0
Dermal fibroblast
3.5

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
0.0
Dermal fibroblast
3.8

CCD1070 IL-1 beta

EOL-1 dbcAMP
1.2
Dermal fibroblast IFN
0.9

PMA/ionomycin

gamma

Dendritic cells none
0.0
Dermal fibroblast IL-4
1.1

Dendritic cells LPS
0.0
Dermal Fibroblasts
0.4

rest

Dendritic cells
0.0
Neutrophils TNFa +
1.1

anti CD40

LPS

Monocytes rest
0.0
Neutrophils rest
2.2

Monocytes LPS
0.0
Colon
2.5

Macrophages rest
0.4
Lung
1.2

Macrophages LPS
0.0
Thymus
5.3

HUVEC none
0.0
Kidney
100.0

HUVEC starved
0.0

[0725]

232

TABLE KE

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4447,

(%) Ag4447,

Run

Run

Tissue Name
268672043
Tissue Name
268672043

Colon cancer 1
2.7
Bladder NAT 2
0.7

Colon NAT 1
2.8
Bladder NAT 3
0.7

Colon cancer 2
5.3
Bladder NAT 4
39.2

Colon NAT 2
1.8
Prostate
100.0

adenocarcinoma 1

Colon cancer 3
1.2
Prostate
12.2

adenocarcinoma 2

Colon NAT 3
22.4
Prostate
6.3

adenocarcinoma 3

Colon malignant
0.7
Prostate
3.8

cancer 4

adenocarcinoma 4

Colon NAT 4
3.1
Prostate NAT 5
5.5

Lung cancer 1
3.8
Prostate
15.0

adenocarcinoma 6

Lung NAT 1
1.1
Prostate
33.9

adenocarcinoma 7

Lung cancer 2
5.7
Prostate
11.6

adenocarcinoma 8

Lung NAT 2
1.6
Prostate
50.0

adenocarcinoma 9

Squamous cell
0.5
Prostate NAT 10
6.6

carcinoma 3

Lung NAT 3
0.0
Kidney cancer 1
4.2

Metastatic melanoma 1
100.0
Kidney NAT 1
24.0

Melanoma 2
0.0
Kidney cancer 2
7.8

Melanoma 3
5.0
Kidney NAT 2
44.4

Metastatic melanoma 4
59.9
Kidney cancer 3
6.3

Metastatic melanoma 5
80.1
Kidney NAT 3
9.0

Bladder cancer 1
10.4
Kidney cancer 4
0.0

Bladder NAT 1
0.0
Kidney NAT 4
0.4

Bladder cancer 2
7.4

[0726] CNS_neurodegeneration_v1.0 Summary: Ag4447 This panel does not show differential expression of this genie in Alzheimer's disease. However, this expression profile confirms the presence of this genie in the brain. Please see Panel 1.5 for discussion of utility of this gene in the central nervous system.

[0727] General_screening_panel_v1.4 Summary: Ag4447 Highest expression of this gene is seen in the cerebellum (CT=26.4). This gene is also expressed at moderate to low levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0728] Moderate expression is also seen melanoma cancer cell lines. Thus, expression of this gene could be used to detect the presence of melanoma. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of this cancer.

[0729] Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, and adult and fetal skeletal muscle and heart. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

[0730] In addition, this gene is expressed at much higher levels in fetal heart tissue (CT=29.5) when compared to expression in the adult counterpart (CT=33). Thus, expression of this gene may be used to differentiate between the fetal and adult source of this tissue.

[0731] Panel 4.1D Summary: Ag4447 This gene is only expressed at detectable levels II the kidney (CT=31.3). Thus, expression of this gene could be used to differentiate the kidney derived sample from other samples on this panel and as a marker of kidney tissue. In addition, therapeutic targeting of the expression or function of this gene may modulate kidney function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney, including lupus and glomerulonephritis.

[0732] general oncology screening panel_v—2.4 Summary: Ag4447 Highest expression of this gene is seen in prostate cancer (CT=31.1). In addition, moderate levels of expression are seen in melanoma, in agreement with expression in panel 1.5. Conversely, expression of this gene is also detected at moderate levels in normal kidney and colon adjacent to tumors. Thus, modulation of the expression or function of this gene may be useful in the treatment of these cancers.

[0733] L. CG111646-01: RhoGAP

[0734] Expression of gene CG111646-01 was assessed using the primer-probe set Ag4451, described in Table LA. Results of the RTQ-PCR runs are shown in Tables LB, LC, LD and LE.

233TABLE LAProbe Name Ag4451PrimersSequencesLengthStart PositionSEQ ID NoForward5′-tctgcctatctgaggacctgta-3′221433151ProbeTET-5′-cccgatatcaatgtcatcactggcat-3′-TAMRA261456152Reverse5′-ggcaactctcgaagataatcct-3′221487153

[0735]

234

TABLE LB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4451,

(%) Ag4451,

Run

Run

Tissue Name
224618552
Tissue Name
224618552

AD 1 Hippo
36.1
Control (Path) 3
27.7

Temporal Ctx

AD 2 Hippo
50.0
Control (Path) 4
39.2

Temporal Ctx

AD 3 Hippo
19.8
AD 1 Occipital Ctx
37.4

AD 4 Hippo
27.2
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 hippo
97.9
AD 3 Occipital Ctx
30.8

AD 6 Hippo
100.0
AD 4 Occipital Ctx
42.0

Control 3 Hippo
29.9
AD 5 Occipital Ctx
33.7

Control 4 Hippo
51.4
AD 6 Occipital Ctx
32.1

Control (Path) 3
46.7
Control 1 Occipital
37.1

Hippo

Ctx

AD 1 Temporal Ctx
59.5
Control 2 Occipital
39.8

Ctx

AD 2 Temporal Ctx
51.4
Control 3 Occipital
28.9

Ctx

AD 3 Temporal Ctx
31.4
Control 4 Occipital
25.5

Ctx

AD 4 Temporal Ctx
59.5
Control (Path) 1
37.4

Occipital Ctx

AD 5 Inf Temporal
97.3
Control (Path) 2
21.8

Ctx

Occipital Ctx

AD 5 Sup Temporal
82.9
Control (Path) 3
24.0

Ctx

Occipital Ctx

AD 6 Inf Temporal
78.5
Control (Path) 4
42.9

Ctx

Occipital Ctx

AD 6 Sup Temporal
74.2
Control 1 Parietal
33.2

Ctx

Ctx

Control 1 Temporal
24.8
Control 2 Parietal
60.3

Ctx

Ctx

Control 2 Temporal
36.6
Control 3 Parietal
12.2

Ctx

Ctx

Control 3 Temporal
28.5
Control (Path) 1
31.4

Ctx

Parietal Ctx

Control 4 Temporal
10.0
Control (Path) 2
42.9

Ctx

Parietal Ctx

Control (Path) 1
57.4
Control (Path) 3
32.8

Temporal Ctx

Parietal Ctx

Control (Path) 2
30.1
Control (Path) 4
55.9

Temporal Ctx

Parietal Ctx

[0736]

235

TABLE LC

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4451,

(%) Ag4451,

Run

Run

Tissue Name
220264517
Tissue Name
220264517

Adipose
5.9
Renal ca TK-10
15.1

Melanoma*
54.3
Bladder
4.5

Hs688(A).T

Melanoma*
44.8
Gastric ca. (liver met.)
2.9

Hs688(B).T

NCI-N87

Melanoma* M14
31.6
Gastric ca. KATO III
0.0

Melanoma*
28.9
Colon ca. SW-948
0.0

LOXIMVI

Melanoma*
7.1
Colon ca. SW480
7.7

SK-MEL-5

Squamous cell
2.6
Colon ca.* (SW480
12.5

carcinoma SCC-4

met) SW620

Testis Pool
5.1
Colon ca. HT29
0.0

Prostate ca* (bone
27.9
Colon ca HCT-116
8.7

met) PC-3

Prostate Pool
3.6
Colon ca. CaCo-2
2.1

Placenta
59.0
Colon cancer tissue
9.2

Uterus Pool
6.2
Colon ca SW1116
0.0

Ovarian ca.
3.4
Colon ca. Colo-205
0.0

OVCAR-3

Ovarian ca
27.2
Colon ca. SW-48
0.0

SK-OV-3

Ovarian ca
2.1
Colon Pool
20.0

OVCAR-4

Ovarian ca
7.8
Small Intestine Pool
16.2

OVCAR-5

Ovarian ca
18.4
Stomach Pool
8.1

IGROV-1

Ovarian ca
15.6
Bone Marrow Pool
10.0

OVCAR-8

Ovary
14.5
Fetal Heart
17.7

Breast ca MCF-7
2.3
Heart Pool
8.8

Breast ca. MDA-
55.5
Lymph Node Pool
22.5

MB-231

Breast ca. BT 549
81.8
Fetal Skeletal Muscle
6.5

Breast ca. T47D
15.7
Skeletal Muscle Pool
3.0

Breast ca MDA-N
26.8
Spleen Pool
4.8

Breast Pool
21.3
Thymus Pool
7.5

Trachea
5.6
CNS cancer (glio/
29.3

astro) U87-MG

Lung
3.7
CNS cancer (glio/
100.0

astro) U-118-MG

Fetal Lung
26.8
CNS cancer (neuro;
27.7

met) SK-N-AS

Lung ca NCI-N417
0.7
CNS cancer (astro)
18.3

SF-539

Lung ca. LX-1
0.2
CNS cancer (astro)
68.8

SNB-75

Lung ca. NCI-H146
0.1
CNS cancer (glio)
15.3

SNB-19

Lung ca. SHP-77
0.0
CNS cancer (glio)
43.2

SF-295

Lung ca. A549
7.5
Brain (Amygdala)
1.0

Pool

Lung ca NCI-H526
0.0
Brain (cerebellum)
5.1

Lung ca NCI-H23
8.2
Brain (fetal)
2.7

Lung ca. NCI-H460
6.7
Brain (Hippocampus)
2.0

Pool

Lung ca. HOP-62
10.7
Cerebral Cortex Pool
1.6

Lung ca NCI-H522
25.3
Brain (Substantia
1.0

nigra) Pool

Liver
1.2
Brain (Thalamus) Pool
1.7

Fetal Liver
4.0
Brain (whole)
2.9

Liver ca. HepG2
2.8
Spinal Cord Pool
2.9

Kidney Pool
26.8
Adrenal Gland
7.8

Fetal Kidney
13.4
Pituitary gland Pool
0.8

Renal ca. 786-0
25.5
Salivary Gland
0.9

Renal ca. A498
12.3
Thyroid (female)
3.4

Renal ca. ACHN
13.7
Pancreatic ca.
23.0

CAPAN2

Renal ca. UO-31
16.4
Pancreas Pool
19.9

[0737]

236

TABLE LD

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4451,

(%) Ag4451,

Run

Run

Tissue Name
191391597
Tissue Name
191391597

Secondary Th1 act
0.1
HUVEC IL-1beta
20.4

Secondary Th2 act
0.3
HUVEC IFN gamma
15.7

Secondary Tr1 act
0.5
HUVEC TNF alpha +
19.9

IFN gamma

Secondary Th1 rest
0.4
HUVEC TNF alpha +
14.4

IL4

Secondary Th2 rest
0.0
HUVEC IL-11
9.8

Secondary Tr1 rest
0.0
Lung Microvascular
28.9

EC none

Primary Th1 act
0.0
Lung Microvascular
28.9

EC TNFalpha +

IL-1beta

Primary Th2 act
0.1
Microvascular Dermal
15.6

EC none

Primary Tr1 act
0.1
Microsvasular Dermal
22.7

EC TNFalpha +

IL-1beta

Primary Th1 rest
0.0
Bronchial epithelium
10.7

TNFalpha + IL1beta

Primary Th2 rest
0.0
Small airway
3.1

epithelium none

Primary Tr1 rest
0.0
Small airway
6.4

epithelium

TNFalpha + IL-1beta

CD45RA CD4
30.6
Coronery artery SMC
30.4

lymphocyte act

rest

CD45RO CD4
0.2
Coronery artery SMC
29.3

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
0.4
Astrocytes rest
21.3

Secondary CD8
0.9
Astrocytes
27.4

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
0.0
KU-812 (Basophil)
1.4

lymphocyte act

rest

CD4 lymphocyte
0.0
KU-812 (Basophil)
1.6

none

PMA/ionomycin

2ry Th1/Th2/
0.2
CCD1106
6.3

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
0.0
CCD1106
6.3

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
0.0
Liver cirrhosis
6.0

LAK cells IL-2 +
0.0
NCI-H292 none
1.8

IL-12

LAK cells IL-2 +
0.1
NCI-H292 IL-4
5.5

IFN gamma

LAK cells IL-2 +
0.0
NCI-H292 IL-9
4.7

IL-18

LAK cells
0.0
NCI-H292 IL-13
7.2

PMA/ionomycin

NK Cells IL-2 rest
0.0
NCI-H292 IFN gamma
3.7

Two Way MLR 3
0.0
HPAEC none
13.2

day

Two Way MLR 5
0.5
HPAEC TNF alpha +
21.8

day

IL-1 beta

Two Way MLR 7
0.0
Lung fibroblast none
39.8

day

PBMC rest
0.0
Lung fibroblast TNF
35.1

alpha + IL-1 beta

PBMC PWM
0.4
Lung fibroblast IL-4
51.4

PBMC PHA-L
1.7
Lung fibroblast IL-9
100.0

Ramos (B cell) none
0.0
Lung fibroblast IL-13
57.0

Ramos (B cell)
0.0
Lung fibroblast IFN
74.2

ionomycin

gamma

B lymphocytes
0.1
Dermal fibroblast
66.0

PWM

CCD1070 rest

B lymphocytes
0.2
Dermal fibroblast
60.3

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
0.0
Dermal fibroblast
48.3

CCD1070 IL-1 beta

EOL-1 dbcAMP
0.0
Dermal fibroblast IFN
27.9

PMA/ionornycin

gamma

Dendritic cells none
0.0
Dermal fibroblast IL-4
38.7

Dendritic cells LPS
1.1
Dermal Fibroblasts
25.4

rest

Dendritic cells
0.0
Neutrophils TNFa +
1.6

anti CD40

LPS

Monocytes rest
0.0
Neutrophils rest
2.7

Monocytes LPS
0.2
Colon
4.5

Macrophages rest
0.0
Lung
15.0

Macrophages LPS
0.1
Thymus
1.9

HUVEC none
10.1
Kidney
7.9

HUVEC starved
13.0

[0738]

237

TABLE LE

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4451,

(%) Ag4451,

Run

Run

Tissue Name
268672289
Tissue Name
268672289

Colon cancer 1
8.9
Bladder NAT 2
1.8

Colon NAT 1
11.5
Bladder NAT 3
0.9

Colon cancer 2
22.4
Bladder NAT 4
15.2

Colon NAT 2
5.8
Prostate
56.3

adenocarcinoma 1

Colon cancer 3
20.0
Prostate
6.5

adenocarcinoma 2

Colon NAT 3
15.4
Prostate
7.8

adenocarcinoma 3

Colon malignant
17.1
Prostate
14.7

cancer 4

adenocarcinoma 4

Colon NAT 4
5.6
Prostate NAT 5
7.4

Lung cancer 1
11.2
Prostate
5.3

adenocarcinoma 6

Lung NAT 1
2.0
Prostate
9.4

adenocarcinoma 7

Lung cancer 2
56.3
Prostate
2.9

adenocarcinoma 8

Lung NAT 2
3.8
Prostate
35.6

adenocarcinoma 9

Squamous cell
11.2
Prostate NAT 10
3.2

carcinoma 3

Lung NAT 3
2.6
Kidney cancer 1
39.8

Metastatic melanoma 1
47.6
Kidney NAT 1
11.7

Melanoma 2
6.0
Kidney cancer 2
83.5

Melanoma 3
4.9
Kidney NAT 2
31.6

Metastatic melanoma 4
100.0
Kidney cancer 3
25.7

Metastatic melanoma 5
95.9
Kidney NAT 3
6.8

Bladder cancer 1
6.0
Kidney cancer 4
23.7

Bladder NAT 1
0.0
Kidney NAT 4
9.4

Bladder cancer 2
13.3

[0739] CNS_neurodegeneration_v1.0 Summary: Ag4451 This panel confirms the expression of this gene at low to moderate levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

[0740] General_screening_panel_v1.4 Summary: Ag4451 Expression of the CG111646-01 gene is highest in a CNS cancer cell line (CT=25.3). Interestingly, this gene appears to be overexpressed in 7/7 CNS cancer cell lines (CTs=25-28), when compared to normal brain tissues (CTs=30-31). Expression of this gene is also high in a number of melanoma cell lines. Therefore, therapeutic modulation of the activity of this gene or its protein product may be of benefit in the treatment of melanoma or CNS cancers.

[0741] In addition, the moderate expression of this gene in amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord suggests that the CG111646-01 gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0742] Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0743] Panel 4.1D Summary: Ag4451 Expression of the CG111646-01 gene is highest in lung and dermal fibroblasts, independent of treatment (CTs=26-27). Therefore, expression of this gene could be used to distinguish lung and skin fibroblasts from the other samples on this panel. In addition, the expression of this gene in lung and skin fibroblasts suggests that this gene may play a role in inflammatory lung and skin disorders, including chronic obstructive pulmonary disease, asthma, allergy, emphysema, and psoriasis.

[0744] This gene is also expressed at lower levels in endothelial cells. Thus, therapeutic modulation of the activity of this gene or its protein product may be of benefit in the treatment of autoimmune and inflammatory diseases that involve endothelial cells, Such as lupus erythematosus, asthma, emphysema, Crohn's disease, ulcerative colitis, rheumatoid arthritis, osteoarthritis, and psoriasis.

[0745] general oncology screening panel_v—2.4 Summary: Ag4451 The CG111646-01 gene is expressed at high levels in three metastatic melanoma samples (CT-27-28) and at more moderate levels in two additional melanomas. These results are consistent with what was observed in Panel 1.4. Thus, the CG111646-01 gene may play a role in melanoma and metastasis. Therefore, therapeutic modulation of the activity of this gene or its protein product may be of benefit in the treatment of melanoma.

[0746] M. CG111744-01: Putative Phospholipase

[0747] Expression of gene CG111744-01 was assessed using, the primer-probe set Ag4454, described in Table MA. Results of the RTQ-PCR runs are shown in Tables MB, MC, MD and ME.

238TABLE MAProbe Name Ag4454StartPrimersSequencesLengthPositionSEQ ID NoForward5′-tcccaggatgataagcttgat-3′214231154ProbeTET-5′-tcatatattatttgcgctgcttcatttg-3′-TAMRA284269155Reverse5′-ttggtctagagattgcacatga-3′224299156

[0748]

239

TABLE MB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4454,

(%) Ag4454,

Run

Run

Tissue Name
224618594
Tissue Name
224618594

AD 1 Hippo
13.0
Control (Path) 3
5.2

Temporal Ctx

AD 2 Hippo
29.5
Control (Path) 4
46.3

Temporal Ctx

AD 3 Hippo
8.0
AD 1 Occipital Ctx
29.1

AD 4 Hippo
9.0
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 Hippo
95.9
AD 3 Occipital Ctx
4.8

AD 6 Hippo
49.3
AD 4 Occipital Ctx
34.6

Control 2 Hippo
37.9
AD 5 Occipital Ctx
69.3

Control 4 Hippo
8.2
AD 6 Occipital Ctx
27.4

Control (Path) 3
8.2
Control 1 Occipital
3.5

Hippo

Ctx

AD 1 Temporal Ctx
20.4
Control 2 Occipital
70.7

Ctx

AD 2 Temporal Ctx
32.3
Control 3 Occipital
31.0

Ctx

AD 3 Temporal Ctx
7.6
Control 4 Occipital
7.7

Ctx

AD 4 Temporal Ctx
34.2
Control (Path) 1
90.1

Occipital Ctx

AD 5 Inf Temporal
100.0
Control (Path) 2
19.8

Ctx

Occipital Ctx

AD 5 Sup Temporal
38.2
Control (Path) 3
5.4

Ctx

Occipital Ctx

AD 6 Inf Temporal
37.1
Control (Path) 4
18.6

Ctx

Occipital Ctx

AD 6 Sup Temporal
51.8
Control 1 Parietal
5.2

Ctx

Ctx

Control 1 Temporal
3.7
Control 2 Parietal
33.4

Ctx

Ctx

Control 2 Temporal
39.2
Control 3 Parietal
40.1

Ctx

Ctx

Control 3 Temporal
28.3
Control (Path) 1
90.1

Ctx

Parietal Ctx

Control 3 Temporal
7.2
Control (Path) 2
33.2

Ctx

Parietal Ctx

Control (Path) 1
61.6
Control (Path) 3
7.1

Temporal Ctx

Parietal Ctx

Control (Path) 2
57.4
Control (Path) 4
66.4

Temporal Ctx

Parietal Ctx

[0749]

240

TABLE MC

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4454,

(%) Ag4454,

Run

Run

Tissue Name
220264599
Tissue Name
220264599

Adipose
22.8
Renal ca. TK-10
71.2

Melanoma*
25.0
Bladder
31.0

Hs688(A).T

Melanoma*
25.5
Gastric ca. (liver
26.4

Hs688(B).T

met.) NCI-N87

Melanoma* M14
19.2
Gastric ca. KATO III
31.9

Melanoma*
18.6
Colon ca. SW-948
7.4

LOXIMVI

Melanoma*
33.2
Colon ca. SW480
40.6

SK-MEL-5

Squamous cell
9.2
Colon ca.* (SW480
49.3

carcinoma SCC-4

met) SW620

Testis Pool
12.3
Colon ca HT29
7.9

Prostate ca.* (bone
22.4
Colon ca. HCT-116
59.5

met) PC-3

Prostate Pool
21.0
Colon ca. CaCo-2
54.7

Placenta
2.2
Colon cancer tissue
18.4

Uterus Pool
8.3
Colon ca. SW1116
10.6

Ovarian ca
33.7
Colon ca. Colo-205
3.8

OVCAR-3

Ovarian ca.
75.3
Colon ca. SW-48
4.3

SK-OV-3

Ovarian ca
7.5
Colon Pool
36.6

OVCAR-4

Ovarian ca
59.5
Small Intestine Pool
30.6

OVCAR-5

Ovarian ca
28.3
Stomach Pool
19.2

IGROV-1

Ovarian ca
24.1
Bone Marrow Pool
13.2

OVCAR-8

Ovary
21.2
Fetal Heart
22.7

Breast ca MCF-7
16.6
Heart Pool
17.0

Breast ca. MDA-
51.1
Lymph Node Pool
30.6

MB-231

Breast ca. BT 549
100.0
Fetal Skeletal Muscle
15.8

Breast ca. T47D
90.8
Skeletal Muscle Pool
11.6

Breast ca. MDA-N
22.7
Spleen Pool
12.0

Breast Pool
31.4
Thymus Pool
20.6

Trachea
21.0
CNS cancer (glio/
53.6

astro) U87-MG

Lung
18.7
CNS cancer (glio/
63.3

astro) U-118-MG

Fetal Lung
56.6
CNS cancer (neuro;
38.7

met) SK-N-AS

Lung ca. NCI-N47
6.3
CNS cancer (astro)
28.1

SF-539

Lung ca LX-1
40.6
CNS cancer (astro)
86.5

SNB-75

Lung ca NCI-H146
7.6
CNS cancer (glio)
35.6

SNB-19

Lung ca SHP-77
61.1
CNS cancer (glio)
59.0

SF-295

Lung ca A549
46.7
Brain (Amygdala)
35.1

Pool

Lung ca NCI-H526
9.9
Brain (cerebellum)
29.1

Lung ca NCI-H23
48.0
Brain (fetal)
39.0

Lung ca. NCI-H460
11.5
Brain (Hippocampus)
31.2

Pool

Lung ca. HOP-62
21.3
Cerebral Cortex Pool
55.9

Lung ca. NCI-H522
62.0
Brain (Substantia
44.4

nigra) Pool

Liver
0.5
Brain (Thalamus) Pool
59.9

Fetal Liver
15.3
Brain (whole)
28.7

Liver ca HepG2
26.2
Spinal Cord Pool
38.2

Kidney Pool
51.8
Adrenal Gland
13.0

Fetal Kidney
43.2
Pituitary gland Pool
11.3

Renal ca. 786-0
29.1
Salivary Gland
4.5

Renal ca. A498
5.2
Thyroid (female)
7.4

Renal ca. ACHN
16.4
Pancreatic ca.
26.2

CAPAN2

Renal ca. UO-31
3.1
Pancreas Pool
28.3

[0750]

241

TABLE MD

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4454,

(%) Ag4454,

Run

Run

Tissue Name
191391793
Tissue Name
191391793

Secondary Th1 act
54.0
HUVEC IL-1beta
61.6

Secondary Th2 act
47.3
HUVEC IFN gamma
55.5

Secondary Tr1 act
42.9
HUVEC TNF alpha +
35.8

IFN gamma

Secondary Th1 rest
28.1
HUVEC TNF alpha +
35.4

IL4

Secondary Th2 rest
32.5
HUVEC IL-11
33.9

Secondary Tr1 rest
33.0
Lung Microvascular
100.0

EC none

Primary Th1 act
46.0
Lung Microvascular
68.8

EC TNFalpha +

IL-1beta

Primary Th2 act
47.3
Microvascular Dermal
54.7

EC none

Primary Tr1 act
52.5
Microvascular Dermal
49.3

EC TNFalpha +

IL-1beta

Primary Th1 rest
17.8
Bronchial
52.9

epithelium

TNFalpha + IL1beta

Primary Th2 rest
28.1
Small airway
13.3

epithelium none

Primary Tr1 rest
52.9
Small airway
52.9

epithelium

TNFalpha + IL-1beta

CD45RA CD4
49.7
Coronery artery SMC
30.8

lymphocyte act

rest

CD45RO CD4
72.2
Coronery artery SMC
33.9

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
46.0
Astrocytes rest
37.9

Secondary CD8
52.1
Astrocytes
25.0

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
26.4
KU-812 (Basophil)
55.1

lymphocyte act

rest

CD4 lymphocyte
37.1
KU-812 (Basophil)
57.8

none

PMA/ionomycin

2ry Th1/Th2/
47.6
CCD1106
40.1

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
29.5
CCD1106
30.4

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
42.6
Liver cirrhosis
18.8

LAK cells IL-2 +
44.1
NCI-H292 none
56.6

IL-12

LAK cells IL-2 +
36.3
NCI-H292 IL-4
60.7

IFN gamma

LAK IL-2 +
44.4
NCI-H292 IL-9
82.4

IL-18

LAK cells
25.2
NCI-H292 IL-13
60.7

PMA/ionomycin

NK Cells IL-2 rest
71.2
NCI-H292 IFN gamma
39.8

Two Way MLR 3
47.0
HPAEC none
35.1

day

Two Way MLR 5
32.1
HPAEC TNF alpha +
62.0

day

IL-1 beta

Two Way MLR 7
38.7
Lung fibroblast none
31.6

day

PBMC rest
16.8
Lung fibroblast TNF
24.3

alpha + IL-1 beta

PBMC PWM
33.2
Lung fibroblast IL-4
33.2

PBMC PHA-L
43.2
Lung fibroblast IL-9
56.6

Ramos (B cell) none
41.2
Lung fibroblast IL-13
29.9

Ramos (B cell)
47.6
Lung fibroblast IFN
36.3

ionomycin

gamma

B lymphocytes
31.4
Dermal fibroblast
49.3

PWM

CCD1070 rest

B lymphocytes
58.6
Dermal fibroblast
79.6

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
54.3
Dermal fibroblast
25.2

CCD1070 IL-1 beta

EOL-1 dbcAMP
27.2
Dermal fibroblast
35.1

PMA/ionomycin

IFN gamma

Dendritic cells none
35.1
Dermal fibroblast IL-4
59.9

Dendritic cells LPS
24.0
Dermal Fibroblasts
27.2

rest

Dendritic cells
30.6
Neutrophils TNFa +
3.8

anti-CD40

LPS

Monocytes rest
12.9
Neutrophils rest
8.6

Monocytes LPS
25.0
Colon
26.4

Macrophages rest
29.3
Lung
18.6

Macrophages LPS
8.1
Thymus
60.3

HUVEC none
50.7
Kidney
72.2

HUVEC starved
58.2

[0751]

242

TABLE ME

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4454,

(%) Ag4454,

Run

Run

Tissue Name
268672044
Tissue Name
268672044

Colon cancer 1
7.7
Bladder cancer NAT
1.2

2

Colon cancer NAT 1
1.5
Bladder cancer NAT
0.0

3

Colon cancer 2
9.5
Bladder cancer NAT
8.3

4

Colon cancer NAT 2
3.5
Prostate
36.6

adenocarcinoma 1

Colon cancer 3
38.2
Prostate
0.2

adenocarcinoma 2

Colon NAT 3
12.2
Prostate
9.1

adenocarcinoma 3

Colon malignant
26.2
Prostate
10.9

cancer 4

denocarcinoma 4

Colon normal
1.1
Prostate cancer
4.5

adjacent tissue 4

NAT 5

Lung cancer 1
8.2
Prostate
2.7

adenocarcinoma 6

Lung NAT 1
0.1
Prostate
0.2

adenocarcinoma 7

Lung cancer 2
59.9
Prostate
1.9

adenocarcinoma 8

Lung NAT 2
2.0
Prostate
48.3

adenocarcinoma 9

Squamous cell
10.7
Prostate cancer
0.4

carcinoma 3

NAT 10

Lung cancer NAT 3
0.5
Kidney cancer 1
29.3

metastatic melanoma 1
21.0
Kidney NAT 1
8.2

Melanoma 2
0.7
Kidney cancer 2
85.3

Melanoma 3
1.9
KidneyNAT 2
29.3

metastatic melanoma 4
100.0
Kidney cancer 3
26.1

metastatic melanoma 5
95.3
Kidney NAT 3
4.0

Bladder cancer 1
1.2
Kidney cancer 4
10.4

Bladder cancer NAT 1
0.0
Kidney NAT 4
3.2

Bladder cancer 2
6.8

[0752] CNS_neurodegeneration_v1.0 Summary: Ag4454 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

[0753] General_screening_panel_v1.4 Summary: Ag4454 Expression of the CG111744-01 gene is highest in a breast cancer cell line (CT=27.3). This gene is expressed at moderate levels in the majority of tissues examined.

[0754] Specifically, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0755] In addition, among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0756] Panel 4.1D Summary: Ag4454 Expression of the CG111744-01 gene is highest in lung microvascular endothelial cells (CT=29.6). This gene is expressed at moderate to low levels in a wide range of cell types of significance in the immune response in health and disease. These cells include T-cells, B-cells, endothelial cells, macrophages, monocytes, eosinophils, basophils, neutrophils, peripheral blood mononuclear cells, lung and skin epithelial cells, lung and skin fibroblast cells, as well as normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

[0757] general oncology screening panel_v—2.4 Summary: Ag4454 Expression of this gene is highest in a metastatic melanoma sample (CT=29). In general, expression of this gene appears to be upregulated in tumors when compared to normal tissues. Specifically, expression of the CG111744-01 gene appears to be significantly upregulated in lung tumor samples when compared to normal adjacent tissue. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of lung cancer and melanoma.

[0758] N. CG111815-01: Scavenger Receptor Domain Containing Protein

[0759] Expression of gene CG111815-01 was assessed using the primer-probe set Ag4456, described in Table NA. Results of the RTQ-PCR runs are shown in Tables NB, NC and ND.

243TABLE NAProbe Name Ag4456PrimersSequencesLengthStart PositionSEQ ID NoForward5′-gctgtcctgtgtgatgaattct-3′29493157ProbeTET-5′-ccccaacaaggaagatgttaaccag-3′-TAMRA25527158Reverse5′-cagtgtcgtaggaggtgctcta-3′22552159

[0760]

244

TABLE NB

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4456,

(%) Ag4456,

Run

Run

Tissue Name
220264167
Tissue Name
220264167

Adipose
0.7
Renal ca. TK-10
6.2

Melanoma*
0.0
Bladder
0.8

Hs688(A).T

Melanoma*
0.0
Gastric ca. (liver met.)
0.0

Hs688(B).T

NCI-N87

Melanoma* M14
0.0
Gastric ca. KATO III
0.0

Melanoma*
0.0
Colon ca SW-948
0.0

LOXIMVI

Melanoma*
0.0
Colon ca SW480
2.8

SK-MEL-5

Squamous cell
0.0
Colon ca.* (SW480
0.5

carcinoma SCC-4

met) SW620

Testis Pool
0.0
Colon ca HT29
0.0

Prostate ca.* (bone
0.4
Colon ca. HCT-116
0.6

met) PC-3

Prostate Pool
0.5
Colon ca. CaCo-2
5.4

Placenta
1.0
Colon cancer tissue
0.0

Uterus Pool
0.0
Colon ca. SW1116
0.0

Ovarian ca
45.7
Colon ca. Colo-205
0.0

OVCAR-3

Ovarian ca.
1.1
Colon ca. SW-48
0.0

SK-OV-3

Ovarian ca.
100.0
Colon Pool
0.0

OVCAR-4

Ovarian ca.
7.7
Small Intestine Pool
0.4

OVCAR-5

Ovarian ca.
2.1
Stomach Pool
1.3

IGROV-1

Ovarian ca.
2.6
Bone Marrow Pool
0.5

OVCAR-8

Ovary
0.6
Fetal Heart
0.0

Breast ca. MCF-7
0.1
Heart Pool
0.0

Breast ca. MDA-
0.3
Lymph Node Pool
0.0

MB-231

Breast ca. BT 549
0.0
Fetal Skeletal Muscle
0.0

Breast ca. T47D
39.5
Skeletal Muscle Pool
0.0

Breast ca. MDA-N
0.0
Spleen Pool
0.3

Breast Pool
0.0
Thymus Pool
1.4

Trachea
0.3
CNS cancer (glio/
0.0

astro) U87-MG

Lung
0.0
CNS cancer (glio/
0.0

astro) U-118-MG

Fetal Lung
0.0
CNS cancer (neuro;
1.4

met) SK-N-AS

Lung ca. NCI-N417
0.0
CNS cancer (astro)
0.0

SF-539

Lung ca. LX-1
6.9
CNS cancer (astro)
0.0

SNB-75

Lung ca. NCI-H146
0.0
CNS cancer (glio)
0.9

SNB-19

Lung ca. SHP-77
0.0
CNS cancer (glio)
0.0

SF-295

Lung ca. A549
0.0
Brain (Amygdala)
0.0

Pool

Lung ca NCI-H526
0.0
Brain (cerebellum)
0.0

Lung ca. NCI-H23
0.0
Brain (fetal)
0.3

Lung ca. NCI-H460
0.0
Brain (Hippocampus)
0.0

Pool

Lung ca. HOP-62
28.9
Cerebral Cortex Pool
0.0

Lung ca. NCI-H522
0.0
Brain (Substantia
0.0

nigra) Pool

Liver
0.0
Brain (Thalamus) Pool
0.0

Fetal Liver
10.5
Brain (whole)
0.0

Liver ca. HepG2
20.6
Spinal Cord Pool
0.0

Kidney Pool
0.0
Adrenal Gland
0.2

Fetal Kidney
3.4
Pituitary gland Pool
2.2

Renal ca 786-0
0.8
Salivary Gland
2.3

Renal ca. A498
0.0
Thyroid (female)
5.3

Renal ca. ACHN
5.3
Pancreatic ca.
0.0

CAPAN2

Renal ca. UO-31
32.3
Pancreas Pool
1.3

[0761]

245

TABLE NC

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4456,

(%) Ag4456,

Run

Run

Tissue Name
191391800
Tissue Name
191391800

Secondary Th1 act
0.0
HUVEC IL-1beta
0.0

Secondary Th2 act
0.0
HUVEC IFN gamma
0.0

Secondary Tr1 act
0.0
HUVEC TNF alpha +
0.0

IFN gamma

Secondary Th1 rest
0.0
HUVEC TNF alpha +
0.0

IL4

Secondary Th2 rest
0.0
HUVEC IL-11
0.0

Secondary Tr1 rest
0.0
Lung Microvascular
0.0

EC none

Primary Th1 act
0.0
Lung Microvascular
0.0

EC TNFalpha +

IL-1beta

Primary Th2 act
0.0
Microvascular Dermal
0.0

EC none

Primary Tr1 act
0.0
Microsvasular Dermal
0.0

EC TNFalpha +

IL-1beta

Primary Th1 rest
0.0
Bronchial epithelium
100.0

TNFalpha + IL1beta

Primary Th2 rest
0.0
Small airway
1.1

epithelium none

Primary Tr1 rest
0.0
Small airway
5.5

epithelium

TNFalpha + IL-1beta

CD45RA CD4
0.0
Coronery artery SMC
0.0

lymphocyte act

rest

CD45RO CD4
0.0
Coronery artery SMC
0.0

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
0.0
Astrocytes rest
0.0

Secondary CD8
0.0
Astrocytes
0.0

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
0.0
KU-812 (Basophil)
0.0

lymphocyte act

rest

CD4 lymphocyte
0.0
KU-812 (Basophil)
0.0

none

PMA/ionomycin

2ry Th1/Th2/
0.0
CCD1106
20.0

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
5.4
CCD1106
19.6

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
0.0
Liver cirrhosis
0.0

LAK cells IL-2 +
0.0
NCI-H292 none
2.0

IL-12

LAK cells IL-2 +
0.0
NCI-H292 IL-4
0.0

IFN gamma

LAK cells IL-2 +
0.0
NCI-H292 IL-9
0.0

IL-18

LAK cells
0.0
NCI-H292 IL-13
0.0

PMA/ionomycin

NK Cells IL-2 rest
0.0
NCI-H292 IFN gamma
0.0

Two Way MLR 3
4.5
HPAEC none
0.0

day

Two Way MLR 5
0.0
HPAEC TNF alpha +
0.0

day

IL-1 beta

Two Way MLR 7
0.0
Lung fibroblast none
0.0

day

PBMC rest
0.0
Lung fibroblast TNF
0.0

alpha + IL-1 beta

PBMC PWM
0.0
Lung fibroblast IL-4
0.0

PBMC PHA-L
0.0
Lung fibroblast IL-9
0.0

Ramos (B cell) none
0.0
Lung fibroblast IL-13
0.0

Ramos (B cell)
0.0
Lung fibroblast IFN
0.0

ionomycin

gamma

B lymphocytes
0.0
Dermal fibroblast
0.0

PWM

CCD1070 rest

B lymphocytes
0.0
Dermal fibroblast
0.0

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0

CCD1070 IL-1 beta

EOL-1 dbcAMP
0.0
Dermal fibroblast IFN
0.0

PMA/ionomycin

gamma

Dendritic cells none
1.1
Dermal fibroblast IL-4
0.0

Dendritic cells LPS
0.0
Dermal Fibroblasts
0.0

rest

Dendritic cells
5.0
Neutrophils TNFa +
0.0

anti-CD40

LPS

Monocytes rest
0.0
Neutrophils rest
0.0

Monocytes LPS
0.0
Colon
0.0

Macrophages rest
0.0
Lung
0.0

Macrophages LPS
0.0
Thymus
0.0

HUVEC none
0.0
Kidney
5.6

HUVEC starved
0.0

[0762]

246

TABLE ND

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4456,

(%) Ag4456,

Run

Run

Tissue Name
268672296
Tissue Name
268672296

Colon cancer 1
0.0
Bladder cancer NAT
0.0

2

Colon cancer NAT 1
0.0
Bladder cancer NAT
0.0

3

Colon cancer 2
0.0
Bladder cancer NAT
0.0

4

Colon cancer NAT 2
0.0
Prostate
0.0

adenocarcinoma 1

Colon cancer 3
0.0
Prostate
0.0

adenocarcinoma 2

Colon cancer NAT 3
0.0
Prostate
0.0

adenocarcinoma 3

Colon malignant
0.0
Prostate
0.0

cancer 4

adenocarcinoma 4

Colon normal
0.0
Prostate cancer
0.0

adjacent tissue 4

NAT 5

Lung cancer 1
0.0
Prostate
0.0

adenocarcinoma 6

Lung NAT 1
0.0
Prostate
0.0

adenocarcinoma 7

Lung cancer 2
29.5
Prostate
0.0

adenocarcinoma 8

Lung NAT 2
0.0
Prostate
0.0

adenocarcinoma 9

Squamous cell
0.0
Prostate cancer
0.0

carcinoma 3

NAT 10

Lung NAT 3
0.0
Kidney cancer 1
100.0

metastatic melanoma 1
10.0
Kidney NAT 1
5.3

Melanoma 2
0.0
Kidney cancer 2
12.1

Melanoma 3
0.0
Kidney NAT 2
54.0

metastatic melanoma 4
0.0
Kidney cancer 3
0.0

metastatic melanoma 5
0.0
Kidney NAT 3
26.2

Bladder cancer 1
0.0
Kidney cancer 4
5.5

Bladder cancer NAT 1
0.0
Kidney NAT 4
21.0

Bladder cancer 2
0.0

[0763] CNS_neurodegeneration_v1.0 Summary: Ag4456 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0764] General_screening_panel_v1.4 Summary: Ag4456 Expression of the CG111815-01 gene is highest in an ovarian cancer cell line (CT=29.9). In general, expression of this gene is limited to a few ovarian, lung and renal cancer cell lines. Interestingly, expression of this gene is also higher in fetal liver (CT=33.1) and a liver cancer cell line (CT=32.1) when compared to adult liver (CT=40). Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of ovarian, lung, renal, and liver cancer. Furthermore, expression of this gene can be used to distinguish fetal liver from adult liver.

[0765] Panel 4.1D Summary Ag4456 Significant expression of the CG111815-01 gene is limited to bronchial epithelial cells treated with TNF-alpha and IL1-beta (CT=32.7). Therefore, expression of this gene may be used as a marker for activated bronchial epithelial cells. Furthermore, therapeutic modulation of the activity of this gene or its protein product may reduce or eliminate symptoms caused by inflammation in chronic obstructive pulmonary disease, asthma, allergy, and emphysema.

[0766] general oncology screening panel_v—2.4 Summary: Ag4456 Significant expression of this gene is limited to a normal kidney sample and a kidney cancer sample. Therefore, expression of this gene may be used to distinguish kidney-derived tissue from the other samples on this panel.

[0767] O. CG112475-01: NOGO Receptor Like

[0768] Expression of gene CG112475-01 was assessed using the primer-probe set Ag6799, described in Table OA.

247TABLE OAProbe Name Ag6799PrimersSequencesLengthStart PositionSEQ ID NoForward5′-aaatgtcaccacctcaaggaa-3′211362160ProbeTET-5′-actgctcacccagaagcaatctctcc-3′-TAMRA261393161Reverse5′-caggaggtacaaaagactgttgag-3′241431162

[0769] CNS_neurodegeneration_v1.0 Summary: Ag6799 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

[0770] General_screening_panel_v1.6 Summary: Ag6799 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

[0771] Panel 4.1D Summary: Ag6799 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

[0772] P. CG112713-01: FYVE-Protein

[0773] Expression of gene CG112713-01 was assessed using the primer-probe sets Ag1550 and Ag4457, described in Tables PA and PB. Results of the RTQ-PCR runs are shown in Tables PC, PD and PE.

248TABLE PAProbe Name Ag1550StartPrimersSequencesLengthPositionSEQ ID NoForward5′-tggaaatactggtgatggaaag-3′22939163ProbeTET-5′-tcaaccacactttcttttatggtcgtg-3′-TAMRA27971164Reverse5′-tcggggaggttttaaagactt-3′21998165

[0774]

249

TABLE PB

Probe Name Ag4457

Primers
Sequences
Length
Start Position
SEQ ID No

Forward
5′-atttcagaagctctcccagaag-3′
22
298
166

Probe
TET-5′-ccaggatctccaggaacctgaattga-3′-TAMRA
26
336
167

Reverse
5′-atactcacgtttggcgtatgac-3′
22
362
168

[0775]

250

TABLE PC

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4457,

(%) Ag4457,

Run

Run

Tissue Name
224618633
Tissue Name
224618633

AD 1 Hippo
0.3
Control (Path) 3
0.0

Temporal Ctx

AD 2 Hippo
1.8
Control (Path) 4
1.2

Temporal Ctx

AD 3 Hippo
0.2
AD 1 Occipital Ctx
0.4

AD 4 Hippo
0.0
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 hippo
1.7
AD 3 Occipital Ctx
0.0

AD 6 Hippo
100.0
AD 4 Occipital Ctx
0.0

Control 2 Hippo
0.8
AD 5 Occipital Ctx
0.0

Control 4 Hippo
1.3
AD 6 Occipital Ctx
0.0

Control (Path) 3 Hippo
0.0
Control 1 Occipital
0.0

Ctx

AD 1 Temporal Ctx
0.8
Control 2 Occipital
0.4

Ctx

AD 2 Temporal Ctx
0.0
Control 3 Occipital
0.7

Ctx

AD 3 Temporal Ctx
0.0
Control 4 Occipital
0.0

Ctx

AD 4 Temporal Ctx
0.8
Control (Path) 1
0.4

Occipital Ctx

AD 5 Inf Temporal
5.8
Control (Path) 2
0.0

Ctx

Occipital Ctx

AD 5 Sup Temporal
0.9
Control (Path) 3
0.0

Ctx

Occipital Ctx

AD 6 Inf Temporal
0.7
Control (Path) 4
0.0

Ctx

Occipital Ctx

AD 6 Sup Temporal
3.3
Control 1 Parietal
0.4

Ctx

Ctx

Control 1 Temporal
0.0
Control 2 Parietal
2.4

Ctx

Ctx

Control 2 Temporal
0.7
Control 3 Parietal
0.0

Ctx

Ctx

Control 3 Temporal
0.3
Control (Path) 1
0.7

Ctx

Parietal Ctx

Control 4 Temporal
0.3
Control (Path) 2
0.6

Ctx

Parietal Ctx

Control (Path) 1
0.3
Control (Path) 3
0.0

Temporal Ctx

Parietal Ctx

Control (Path) 2
0.6
Control (Path) 4
0.8

Temporal Ctx

Parietal Ctx

[0776]

251

TABLE PD

Panel 1.3D

Rel. Exp.

Rel. Exp.

(%) Ag1550,

(%) Ag1550,

Run

Run

Tissue Name
146287527
Tissue Name
146287527

Liver adenocarcinoma
20.2
Kidney (fetal)
10.9

Pancreas
4.7
Renal ca. 786-0
12.9

Pancreatic ca.
4.7
Renal ca. A498
24.0

CAPAN 2

Adrenal gland
15.1
Renal ca. RXF 393
10.4

Thyroid
11.4
Renal ca. ACHN
21.9

Salivary gland
4.5
Renal ca. UO-31
9.6

Pituitary gland
8.0
Renal ca. TK-10
4.8

Brain (fetal)
9.5
Liver
3.2

Brain (whole)
15.0
Liver (fetal)
12.8

Brain (amygdala)
15.8
Liver ca.
12.7

(hepatoblast) HepG2

Brain (cerebellum)
6.7
Lung
10.3

Brain (hippocampus)
30.6
Lung (fetal)
12.8

Brain (substantia
6.8
Lung ca. (small
5.7

nigra)

cell) LX-1

Brain (thalamus)
14.1
Lung ca. (small
9.2

cell) NCI-H69

Cerebral Cortex
45.1
Lung ca. (s. cell
12.6

var) SHP-77

Spinal cord
8.4
Lung ca (large
2.2

cell) NCI-H460

glio/astro U87-MG
30.4
Lung ca. (non-sm.
4.6

cell) A549

glio/astro U-118-MG
42.9
Lung ca. (non-s
11.5

cell) NCI-H23

astrocytoma SW1783
16.8
Lung ca. (non-s.
11.2

HOP-62

neuro*; met SK-N-AS
23.2
Lung ca. (non-s
11.5

cl) NCI-H522

astrocytoma SF-539
15.5
Lung ca. (squam.)
17.1

SW 900

astrocytoma SNB-75
55.1
Lung ca. (squam)
4.0

NCI-H596

glioma SNB-19
1.5
Mammary gland
27.0

glioma U251
12.8
Breast ca* (pl ef)
34.4

MCF-7

glioma SF-295
9.2
Breast ca* (pl ef)
24.8

MDA-MB-231

Heart (fetal)
33.7
Breast ca* (pl ef)
31.4

T47D

Heart
3.3
Breast ca. BT549
33.0

Skeletal muscle (fetal)
100.0
Breast ca. MDA-N
21.2

Skeletal muscle
7.7
Ovary
36.1

Bone marrow
11.8
Ovarian ca
19.8

OVCAR-3

Thymus
12.1
Ovarian ca.
5.3

OVCAR-4

Spleen
10.4
Ovarian ca.
12.9

OVCAR-5

Lymph node
8.1
Ovarian ca.
11.2

OVCAR-8

Colorectal
11.3
Ovarian ca.
2.5

IGROV-1

Stomach
17.3
Ovarian ca.*
10.6

(ascites) SK-OV-3

Small intestine
9.1
Uterus
11.0

Colon ca SW480
14.9
Placenta
14.8

Colon ca.* SW620
6.3
Prostate
6.4

(SW480 met)

Colon ca. HT29
2.5
Prostate ca.* (bone
41.8

met) PC-3

Colon ca. HCT-116
5.2
Testis
15.2

Colon ca. CaCo-2
9.2
Melanoma
45.7

Hs688(A).T

Colon ca. tissue
11.3
Melanoma* (met)
44.1

(ODO3866)

Hs688(B).T

Colon ca. HCC-2998
5.6
Melanoma
12.5

UACC-62

Gastric ca.* (liver
32.8
Melanoma M14
7.6

met) NCI-N87

Bladder
6.9
Melanoma LOX
3.7

IMVI

Trachea
14.2
Melanoma* (met)
26.4

SK-MEL-5

Kidney
7.1
Adipose
5.8

[0777]

252

TABLE PE

Panel 4.1D

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag4457, Run
Ag4457, Run

Ag4457, Run
Ag4457, Run

Tissue Name
191579119
195509494
Tissue Name
191579119
195509494

Secondary Th1 act
0.0
0.7
HUVEC IL-1beta
0.0
0.0

Secondary Th2 act
0.0
0.0
HUVEC IFN gamma
0.0
0.7

Secondary Tr1 act
100.0
0.0
HUVEC TNF alpha +
0.0
0.0

IFN gamma

Secondary Th1 rest
0.0
0.0
HUVEC TNF alpha +
0.0
0.0

IL4

Secondary Th2 rest
0.0
1.0
HUVEC IL-11
0.0
0.0

Secondary Tr1 rest
0.0
0.0
Lung Microvascular
0.0
0.0

EC none

Primary Th1 act
0.0
0.0
Long Microvascular
0.0
0.0

EC TNFalpha + IL-

1beta

Primary Th2 act
0.0
0.0
Microvascular
0.0
00

Dermal EC none

Primary Tr1 act
0.0
0.0
Microsvasular
0.0
0.0

Dermal EC

TNFalpha + IL-1beta

Primary Th1 rest
0.0
0.0
Bronchial epithelium
0.0
0.0

TNFalpha + IL.1beta

Primary Th2 rest
0.0
0.0
Small airway
0.0
0.0

epithelium none

Primary Tr1 rest
0.0
0.0
Small airway
0.0
0.0

epithelium TNFalpha +

IL-1beta

CD45RA CD4
0.0
0.0
Coronery artery SMC
0.0
0.0

lymphocyte act

rest

CD45RO CD4
0.0
0.0
Coronery artery SMC
0.0
0.0

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
0.0
0.0
Astrocytes rest
0.0
1.8

Secondary CD8
0.0
0.0
Astrocytes TNFalpha +
0.0
0.0

lymphocyte rest

IL-1beta

Secondary CD8
0.0
0.0
KU-812 (Basophil)
0.0
0.0

lymphocyte act

rest

CD4 lymphocyte
0.0
0.0
KU-812 (Basophil)
0.0
0.0

none

PMA/ionomycin

2ry
0.0
0.0
CCD1106
0.0
0.0

Th1/Th2/Tr1_anti

(Keratinocytes) none

CD95 CH11

LAK cells rest
0.0
0.0
CCD1106
0.0
0.0

(Kelatinocytcs)

TNFalpha + IL-1beta

LAK cells IL-2
0.5
0.0
Liver cirrhosis
0.0
0.0

LAK cells IL-2 + IL-
0.0
0.0
NCl-H292 none
0.0
1.8

12

LAK cells IL-2 +
0.0
2.4
NCl-H292 IL-4
0.0
0.0

IFN gamma

LAK cells IL-2 + IL-
1.0
0.0
NCl-h292 IL-9
0.0
0.0

18

LAK cells
0.0
0.0
NCl-H292 IL-13
0.0
0.0

PMA/ionomycin -

NK Cells IL-2 rest
0.0
0.0
NCl-H292 IFN
0.0
0.0

gamma

Two way MLR 3
0.0
0.0
HPAEC none
0.0
0.0

day

Two Way MLR 5
0.0
0.0
HPAEC TNF alpha +
0.0
0.0

day

0.0
0.0
IL-1beta

Two Way MLR 7
0.0
0.0
Lung fibroblast none
0.0
0.0

day

PBMC rest
0.0
0.0
Lung fibroblast TNF
0.0
00

alpha + IL-1beta

PBMC PWM
2.9
1.7
Lung fibroblast IL-4
0.0
0.0

PBMC PHA-L
0.0
0.0
Lung fibroblast IL-9
0.0
0.0

Ramos (B cell) none
0.0
0.0
Lung fibroblast IL-13
0.0
0.0

Ramos (B cell)
0.0
0.0
Lung fibroblast IFN
0.0
0.0

ionomycin

gamma

B lymphocytes
0.0
0.0
Dermal fibroblast
0.0
0.0

PWM

CCD1070 rest

B lymphocytes
0.0
0.0
Dermal fibroblast
0.0
0.0

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
0.0
0.0

CCD1070 IL-1 beta

EOL-1 dbcAMP
0.0
0.0
Dermal fibroblast
0.0
0.0

PMA/ionomycin

IFN gamma

Dendrite cells none
0.0
0.0
Dermal fibroblast IL-4
0.0
0.0

Dendrite cells LPS
0.0
0.0
Dermal fibroblasts
0.0
0.0

rest

Dentrite cells anti-
0.0
0.0
Neutrophils
0.0
0.0

CD40

TNFa + LPS

Monocytes rest
0.0
0.0
Neutrophils rest
0.0
0.0

Monocytes LPS
0.0
0.0
Colon
0.0
4.5

Macrophages rest
0.0
0.0
Lung
0.0
4.8

Macrophages LPS
0.0
0.0
Thymus
0.0
11.0

HUVEC none
0.0
0.0
Kidney
2.9
100.0

HUVEC starved
0.0
0.0

[0778] CNS_neurodegeneration_v1.0 Summary: Ag4457 Highest expression of this gene is found in hippocampus sample derived from Alzheimer's disease patients (CTF=30.8). Therefore, therapeutic modulation of this gene may be useful in the treatment of Alzheimer's diseases, schizophrenia, forgetfulness, and siezure.

[0779] General_screening_panel_v1.4 Summary: Ag4457 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0780] Panel 1.3D Summary: Ag1550 The CG112713-01 gene, a variant of double FYVE-containing protein 1 (DFCP1), is ubiquitously expressed in this panel, with highest expression seen in fetal skeletal muscle (CT=29). Expression of this gene appears to be much higher in fetal skeletal muscle and heart (CT=30.5) as compared to the adult tissues (CTs=32.6-33.9). Therefore, expression of this gene could be used to distinguish between adult and fetal sources of heart and skeletal muscle. In addition, the higher levels of expression of this genie in fetal heart and skeletal muscle when compared to the levels of expression in adult tissue, suggests that the protein encoded by this gene may be involved in the development of these tissues. Therefore, therapeutic modulation of this gene or its protein product may be effective in the treatment of diseases that affect the heart, such as atherosclerosis, hypertension, or aortic stenosis. Furthermore, the therapeutic modulation of this gene or gene product, through replacement therapy, could be used as a regenerative therapy for muscle disease.

[0781] Moderate levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, renal, breast, ovarian, prostate, liver, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.

[0782] Among, tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in pancreas, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0783] This gene is expressed at moderate levels in all the regions of brain examined, including including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0784] Panel 4.1D Summary: Ag4457 Highest expression of this gene is found in activated secondary Tr1 cells and kidney (CTs=32). Therefore, therapeutic modulation of this gene may be useful in the treatment of T cell-mediated diseases such as asthma, arthritis, psoriasis, IBD, and lupus.

[0785] general oncology screening panel_v—2.4 Summary: Ag4457 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0786] Q. CG112731-01: NOELIN Like Protein

[0787] Expression of gene CG112731-01 was assessed using the primer-probe set Ag4459, described in Table QA. Results of the RTQ-PCR runs are shown in Tables QB, QC, QD, QE and QF.

253TABLE QAProbe Name Ag4459StartPrimersSequencesLengthPositionSEQ ID NoForward5′-tgttaggagggaaacagatcaa-3′221098169ProbeTET-5′-tgcaaactttgatttaagaacttccca-3′-TAMRA271120170Reverse5′-ttgtatgctaacatggcaagaa-3′221152171

[0788]

254

TABLE QB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4459,

(%) Ag4459,

Run

Run

Tissue Name
224621301
Tissue Name
224621301

AD 1 Hippo
4.5
Control (Path) 3
1.2

Temporal Ctx

AD 2 Hippo
17.3
Control (Path) 4
12.9

Temporal Ctx

AD 3 Hippo
1.5
AD 1 Occipital Ctx
7.8

AD 4 Hippo
4.0
AD 2 Occipital Ctx
0.1

(Missing)

AD 5 hippo
37.1
AD 3 Occipital Ctx
2.1

AD 6 Hippo
39.0
AD 4 Occipital Ctx
16.5

Control 2 Hippo
29.5
AD 5 Occipital Ctx
17.7

Control 4 Hippo
7.6
AD 6 Occipital Ctx
33.2

Control (Path) 3 Hippo
2.6
Control 1 Occipital
1.7

Ctx

AD 1 Temporal Ctx
8.2
Control 2 Occipital
62.0

Ctx

AD 2 Temporal Ctx
20.4
Control 3 Occipital
11.9

Ctx

AD 3 Temporal Ctx
1.0
Control 4 Occipital
8.4

Ctx

AD 4 Temporal Ctx
23.7
Control (Path) 1
100.0

Occipital Ctx

AD 5 Inf Temporal
76.8
Control (Path) 2
10.8

Ctx

Occipital Ctx

AD 5 Sup Temporal
30.1
Control (Path) 3
2.7

Ctx

Occipital Ctx

AD 6 Inf Temporal
55.5
Control (Path) 4
10.9

Ctx

Occipital Ctx

AD 6 Sup Temporal
31.9
Control 1 Parietal
3.5

Ctx

Ctx

Control 1 Temporal
0.8
Control 2 Parietal
26.2

Ctx

Ctx

Control 2 Temporal
36.3
Control 3 Parietal
14.0

Ctx

Ctx

Control 3 Temporal
10.5
Control (Path) 1
34.6

Ctx

Parietal Ctx

Control 4 Temporal
4.0
Control (Path) 2
17.4

Ctx

Parietal Ctx

Control (Path) 1
30.1
Control (Path) 3
1.8

Temporal Ctx

Parietal Ctx

Control (Path) 2
17.0
Control (Path) 4
27.5

Temporal Ctx

Parietal Ctx

[0789]

255

TABLE QC

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4459,

(%) Ag4459,

Run

Run

Tissue Name
222523505
Tissue Name
222523505

Adipose
1.7
Renal ca. TK-10
0.1

Melanoma*
0.0
Bladder
3.7

Hs688(A).T

Melanoma*
0.0
Gastric ca. (liver
2.4

Hs688(B).T

met.) NCI-N87

Melanoma* M14
0.0
Gastric ca. KATO III
0.1

Melanoma*
0.0
Colon ca. SW-948
0.0

LOXIMVI

Melanoma*
0.0
Colon ca. SW480
0.1

SK-MEL-5

Squamous cell
0.1
Colon ca.* (SW480
0.4

carcinoma SCC-4

met) SW620

Testis Pool
0.5
Colon ca HT29
0.5

Prostate ca.* (bone
0.1
Colon ca. HCT-116
0.6

met) PC-3

Prostate Pool
0.5
Colon ca CaCo-2
0.6

Placenta
29.1
Colon canecr tissue
0.8

Uterus Pool
0.1
Colon ca. SW1116
0.2

Ovarian ca.
0.0
Colon ca. Colo-205
0.0

OVCAR-3

Ovarian ca.
0.0
Colon ca. SW-48
0.0

SK-OV-3

Ovarian ca.
0.0
Colon Pool
0.1

OVCAR-4

Ovarian ca.
2.8
Small Intestine Pool
0.4

OVCAR-5

Ovarian ca.
0.2
Stomach Pool
0.1

IGROV-1

Ovarian ca.
0.2
Bone Marrow Pool
0.1

OVCAR-8

Ovary
0.1
Fetal Heart
0.0

Breast ca. MCF-7
3.1
Heart Pool
0.6

Breast ca. MDA-
0.3
Lymph Node Pool
0.1

MB-231

Breast ca. BT 549
0.0
Fetal Skeletal Muscle
0.8

Breast ca. T47D
2.3
Skeletal Muscle Pool
0.1

Breast ca. MDA-N
0.0
Spleen Pool
0.5

Breast Pool
0.1
Thymus Pool
0.2

Trachea
1.1
CNS cancer (glio/
0.0

astro) U87-MG

Lung
0.4
CNS cancer (glio/
0.1

astro) U-118-MG

Fetal Lung
0.4
CNS cancer (neuro;
0.0

met) SK-N-AS

Lung ca. NCI-N47
0.2
CNS cancer (astro)
0.1

SF-539

Lung ca LX-1
1.8
CNS cancer (astro)
10.0

SNB-75

Lung ca. NCI-H146
0.8
CNS cancer (glio)
0.3

SNB-19

Lung ca. SHP-77
1.7
CNS cancer (glio)
100.0

SF-295

Lung ca. A549
0.1
Brain (Amygdala)
16.3

Pool

Lung ca. NCI-H526
0.4
Brain (cerebellum)
3.0

Lung ca. NCI-H23
0.0
Brain (fetal)
0.3

Lung ca. NCI-H460
4.0
Brain (Hippocampus)
10.2

Pool

Lung ca. HOP-62
0.5
Cerebral Cortex Pool
10.4

Lung ca. NCI-H522
0.0
Brain (Substantia
9.6

nigra) Pool

Liver
0.0
Brain (Thalamus) Pool
19.3

Fetal Liver
0.3
Brain (whole)
11.7

Liver ca. HepG2
0.2
Spinal Cord Pool
12.2

Kidney Pool
1.2
Adrenal Gland
1.6

Fetal Kidney
0.0
Pituitary gland Pool
0.0

Renal ca. 786-0
0.0
Salivary Gland
0.1

Renal ca A498
0.0
Thyroid (female)
0.1

Renal ca. ACHN
0.0
Pancreatic ca.
0.4

CAPAN2

Renal ca. UO-31
0.0
Pancreas Pool
0.3

[0790]

256

TABLE QD

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4459,

(%) Ag4459,

Run

Run

Tissue Name
191579098
Tissue Name
191579098

Secondary Th1 act
0.0
HUVEC IL-1beta
0.0

Sccondary Th2 act
0.0
HUVEC IFN gamma
0.0

Secondary Tr1 act
0.0
HUVEC TNF alpha +
0.0

IFN gamma

Secondary Th1 rest
0.0
HUVEC TNF alpha +
0.0

IL4

Secondary Th2 rest
0.0
HUVEC IL-11
0.0

Secondary Tr1 rest
0.0
Lung Microvascular
0.3

EC none

Primary Th1 act
0.3
Lung Microvascular
0.4

EC TNFalpha +

IL-1beta

Primary Th2 act
0.0
Microvascular Dermal
0.5

EC none

Primary Tr1 act
0.0
Microvascular Dermal
0.0

EC TNFalpha +

IL-1beta

Primary Th1 rest
0.0
Bronchial
1.0

epithelium

TNFalpha + IL1beta

Primary Th2 rest
0.0
Small airway
0.0

epithelium none

Primary Tr1 rest
0.0
Small airway
0.0

epithelium

TNFalpha + IL-1beta

CD45RA CD4
2.4
Coronery artery SMC
0.0

lymphocyte act

rest

CD45RO CD4
0.0
Coronery artery SMC
0.0

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
0.0
Astrocytes rest
0.5

Secondary CD8
0.0
Astrocytes
0.0

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
0.0
KU-812 (Basophil)
0.0

lymphocyte act

rest

CD4 lymphocyte
0.0
KU-812 (Basophil)
0.0

none

PMA/ionomycin

2ry Th1/Th2/
0.0
CCD1106
0.0

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
10.5
CCD1106
0.0

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
0.0
Liver cirrhosis
2.1

LAK cells IL-2 +
0.5
NCI-H292 none
6.2

IL-12

LAK cells IL-2 +
0.0
NCI-H292 IL-4
3.3

IFN gamma

LAK IL-2 +
0.6
NCI-H292 IL-9
4.2

IL-18

LAK cells
1.9
NCI-H292 IL-13
9.9

PMA/ionomycin

NK Cells IL-2 rest
0.0
NCI-H292 IFN gamma
1.1

Two Way MLR 3
2.0
HPAEC none
0.0

day

Two Way MLR 5
7.9
HPAEC TNF alpha +
0.0

day

IL-1 beta

Two Way MLR 7
1.6
Lung fibroblast none
5.1

day

PBMC rest
0.0
Lung fibroblast TNF
0.0

alpha + IL-1 beta

PBMC PWM
0.0
Lung fibroblast IL-4
2.6

PBMC PHA-L
0.0
Lung fibroblast IL-9
0.3

Ramos (B cell) none
0.0
Lung fibroblast IL-13
3.4

Ramos (B cell)
0.0
Lung fibroblast IFN
5.0

ionomycin

gamma

B lymphocytes
0.0
Dermal fibroblast
6.6

PWM

CCD1070 rest

B lymphocytes
0.0
Dermal fibroblast
2.1

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
0.0
Dermal fibroblast
9.6

CCD1070 IL-1 beta

EOL-1 dbcAMP
0.0
Dermal fibroblast
9.5

PMA/ionomycin

IFN gamma

Dendritic cells none
5.7
Dermal fibroblast IL-4
85.9

Dendritic cells LPS
100.0
Dermal fibroblasts rest
5.4

Dendritic cells
13.0
Neutrophils TNFa +
0.5

anti-CD40

LPS

Monocytes rest
0.0
Neutrophils rest
0.7

Monocytes LPS
4.6
Colon
0.0

Macrophages rest
5.2
Lung
8.1

Macrophages LPS
8.1
Thymus
2.1

HUVEC none
0.0
Kidney
4.6

HUVEC starved
0.0

[0791]

257

TABLE QE

Panel CNS_1.1

Rel. Exp.

Rel. Exp.

(%) Ag4459,

(%) Ag4459,

Run

Run

Tissue Name
195308647
Tissue Name
195308647

Cing Gyr
11.3
BA17 PSP2
5.8

Depression2

Cing Gyr
6.1
BA17 PSP
26.4

Depression

Cing Gyr PSP2
2.7
BA17 Huntington's2
6.0

Cing Gyr PSP
55.5
BA17 Huntington's
5.4

Cing Gyr
26.4
BA17 Parkinson's2
13.6

Huntington's2

Cing Gyr
55.1
BA17 Parkinson's
47.6

Huntington's

Cing Gyr
40.3
BA17 Alzheimer's2
5.3

Parkinson's2

Cing Gyr
69.7
BA17 Control2
43.8

Parkinson's

Cing Gyr
8.2
BA17 Control
21.8

Alzheimer's2

Cing Gyr
13.2
BA9 Depression2
0.0

Alzheimer's

Cing Gyr Control2
29.7
BA9 Depression
4.6

Cing Gyr Control
28.1
BA9 PSP2
4.5

Temp Pole
0.0
BA9 PSP
14.8

Depression2

Temp Pole PSP2
1.2
BA9 Huntington's2
5.1

Temp Pole PSP
0.0
BA9 Huntington's
26.2

Temp Pole
5.9
BA9 Parkinson's2
14.2

Huntington's

Temp Pole
6.7
BA9 Parkinson's
16.8

Parkinson's2

Temp Pole
12.1
BA9 Alzheimer's2
1.4

Parkinson's

Temp Pole
0.0
BA9 Alzheimer's
0.0

Alzheimer's2

Temp Pole
0.0
BA9 Control2
100.0

Alzheimer's

Temp Pole Control2
19.6
BA9 Control
6.0

Temp Pole Control
1.4
BA7 Depression
8.5

Glob Palladus
13.0
BA7 PSP2
10.0

Depression

Glob Palladus PSP2
2.3
BA7 PSP
18.7

Glob Palladus PSP
11.2
BA7 Huntington's2
15.7

Glob Palladus
7.1
BA7 Huntington's
14.7

Parkinson's2

Glob Palladus
71.2
BA7 Parkinson's2
10.6

Parkinson's

Glob Palladus
10.1
BA7 Parkinson's
5.5

Alzheimer's2

Glob Palladus
14.0
BA7 Alzheimer's2
0.0

Alzheimer's

Glob Palladus
15.0
BA7 Control2
21.8

Control2

Glob Palladus
28.3
BA7 Control
15.1

Control

Sub Nigia
4.3
BA4 Depression2
3.3

Depression2

Sub Nigra
26.6
BA4 Depression
8.7

Depression

Sub Nigra PSP2
16.2
BA4 PSP2
18.0

Sub Nigra
25.0
BA4 PSP
7.9

Huntington's2

Sub Nigra
75.3
BA4 Huntington's2
0.0

Huntington's

Sub Nigra
59.5
BA4 Huntington's
10.3

Parkinson's2

Sub Nigia
29.1
BA4 Parkinson's2
28.1

Alzheimer's2

Sub Nigra Control2
80.7
BA4 Parkinson's
28.5

Sub Nigia Control
100.0
BA4 Alzheimer's2
2.1

BA17 Depression2
11.5
BA4 Control2
30.6

BA17 Depression
4.0
BA4 Control
8.9

[0792]

258

TABLE QF

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4459,

(%) Ag4459,

Run

Run

Tissue Name
268672301
Tissue Name
268672301

Colon cancer 1
1.0
Bladder NAT 2
0.0

Colon NAT 1
4.8
Bladder NAT 3
1.3

Colon cancer 2
5.8
Bladder NAT 4
6.8

Colon NAT 2
1.2
Prostate
52.5

adenocarcinoma 1

Colon cancer 3
24.3
Prostate
0.0

adenocarcinoma 2

Colon NAT 3
100.0
Prostate
6.5

adenocarcinoma 3

Colon malignant
18.3
Prostate
43.2

cancer 4

adenocarcinoma 4

Colon NAT 4
4.0
Prostate NAT 5
6.0

Lung cancer 1
1.9
Prostate
0.0

adenocarcinoma 6

Lung NAT 1
4.7
Prostate
11.0

adenocarcinoma 7

Lung cancer 2
7.2
Prostate
3.2

adenocarcinoma 8

Lung NAT 2
21.3
Prostate
66.9

adenocarcinoma 9

Squamous cell
16.2
Prostate NAT 10
1.1

carcinoma 3

Lung NAT 3
2.2
Kidney cancer 1
1.6

Metastatic melanoma 1
6.9
Kidney NAT 1
5.3

Melanoma 2
34.9
Kidney cancer 2
3.5

Melanoma 3
14.7
Kidney NAT 2
3.2

Metastatic melanoma 4
7.6
Kidney cancer 3
3.6

Metastatic melanoma 5
23.0
Kidney NAT 3
2.5

Bladder cancer 1
6.4
Kidney cancer 4
2.1

Bladder NAT 1
0.0
Kidney NAT 4
1.5

Bladder cancer 2
13.6

[0793] CNS_neurodegeneration_v1.0 Summary: Ag4459 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

[0794] General_screening_panel_v1.4 Summary: Ag4459 Expression of the CG112731-01 gene is highest in a CNS cancer cell line (CT=25). In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0795] The CG112731-01 gene encodes a protein containing an olfactomedin-like domain and two collagen triple helix repeat motifs. It is similar to noelin [NEURONAL OLFACTOMEDIN-RELATED ER LOCALIZED PROTEIN) (PANCORTIN) (1B426B)]. The vertebrate neural crest arises at the border of the neural plate during early stages of nervous system development; however, little is known about the molecular mechanisms underlying neural crest formation. Barembaum et al. (1) identified a secreted protein, Noelin-1, which has the ability to prolong neural crest production. Noelin-1 messenger RNA is expressed in a graded pattern in the closing neural tube. It subsequently becomes restricted to the dorsal neural folds and migrating neural crest. Over expression of Noelin-1 using, recombinant retroviruses causes an excess of neural crest emigration and extends the time that the neural tube is competent to generate as well as regenerate neural crest cells. These results support an important role for Noelin-1 in regulating the production of neural crest cells by the neural tube (1).

[0796] Among tissues with metabolic or endocrine function, this gene is expressed at low levels in pancreas, adipose, adrenal gland, fetal skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

REFERENCES

[0797] 1. Barembaum M, Moreno T A, LaBonne C, Sechrist J, Bronner-Fraser M. Noelin-1 is a secreted glycoprotein involved in generation of the neural crest. Nat Cell Biol. April 2000;2(4):219-25. PMID: 10783240

[0798] Panel 4. D Summary: Ag4459 Expression of this gene is upregulated in dendritic cells treated with LPS or CD40 (CT=30). Therefore, therapeutic modulation of the activity of this gene or its protein product may be important in immune modulation, organ/bone marrow transplantation, and the treatment of diseases where antigen presentation, a function of mature dendritic cells, plays an important role including such diseases as asthma, rheumatoid arthritis, IBD, and psoriasis. In addition, expression in IL-4 treated dermal fibroblasts suggests that this gene product may be involved in skin disorders, including psoriasis.

[0799] Panel CNS—1.1 Summary: Ag4459 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

[0800] general oncology screening panel_v—2.4 Summary: Ag4459 Expression of this gene is highest in a normal colon sample (CT=33.2). Expression of this gene appears to be upregulated in a number of prostate tumors when compared to normal prostate tissue. Thus, expression of this gene could be used to distinguish prostate tumors from normal prostate. Furthermore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of prostate cancer.

[0801] R. CG112749-01: Cyclin

[0802] Expression of gene CG112749-01 was assessed using the primer-probe set Ag6807, described in Table RA. Results of the RTQ-PCR runs are shown in Tables RB and RC.

259TABLE RAProbe Name Ag6807PrimersSequencesLengthStart PositionSEQ ID NoForward5′-gcaagggtcggtgctt-3′16116172ProbeTET-5′-cctcgcccgcaacaccctcct-3′-TAMRA21134173Reverse5′-gagggaggcagcgaga-3′16168174

[0803]

260

TABLE RB

General_screening_panel_v1.6

Rel. Exp.

Rel. Exp.

(%) Ag6807,

(%) Ag6807,

Run

Run

Tissue Name
278017591
Tissue Name
278017591

Adipose
0.0
Renal ca. TK-10
7.1

Melanoma*
3.1
Bladder
5.4

Hs688(A).T

Melanoma*
0.0
Gastric ca. (liver met.)
8.4

Hs688(B).T

NCI-N87

Melanoma* M14
0.0
Gastric ca. KATO III
45.4

Melanoma*
0.0
Colon ca. SW-948
0.0

LOXIMVI

Melanoma*
0.0
Colon ca. SW480
0.0

SK-MEL-5

Squamous cell
0.0
Colon ca.* (SW480
2.6

carcinoma SCC-4

met) SW620

Testis Pool
4.8
Colon ca. HT29
0.0

Prostate ca.* (bone
0.0
Colon ca. HCT-116
5.1

met) PC-3

Prostate Pool
0.4
Colon ca. CaCo-2
12.5

Placenta
0.0
Colon cancer tissue
2.5

Uterus Pool
0.0
Colon ca. SW1116
0.0

Ovarian ca.
8.9
Colon ca. Colo-205
0.0

OVCAR-3

Ovarian ca.
2.9
Colon ca. SW-48
9.3

SK-OV-3

Ovarian ca
0.9
Colon Pool
2.3

OVCAR-4

Ovarian ca
60.7
Small Intestine Pool
3.3

OVCAR-5

Ovarian ca
8.6
Stomach Pool
3.0

IGROV-1

Ovarian ca
2.7
Bone Marrow Pool
0.0

OVCAR-8

Ovary
0.0
Fetal Heart
0.0

Breast ca MCF-7
25.2
Heart Pool
0.0

Breast ca. MDA-
8.5
Lymph Node Pool
5.3

MB-231

Breast ca. BT 549
0.0
Fetal Skeletal Muscle
2.0

Breast ca T47D
0.6
Skeletal Muscle Pool
2.1

Breast ca. MDA-N
0.0
Spleen Pool
0.0

Breast Pool
0.0
Thymus Pool
3.0

Trachea
0.0
CNS cancer (glio/
0.0

astro) U87-MG

Lung
0.0
CNS cancer (glio/
8.5

astro) U-118-MG

Fetal Lung
0.0
CNS cancer (neuro,
0.0

met) SK-N-AS

Lung ca. NCI-N417
0.0
CNS cancer (astro)
3.2

SF-539

Lung ca. LX-1
0.8
CNS cancer (astro)
0.0

SNB-75

Lung ca NCI-H146
62.4
CNS cancer (glio)
14.8

SNB-19

Lung ca SHP-77
14.7
CNS cancer (glio)
2.6

SF-295

Lung ca. A549
4.8
Brain (Amygdala)
2.1

Pool

Lung ca. NCI-H526
100.0
Brain (cerebellum)
7.9

Lung c. NCI-H23
0.0
Brain (fetal)
4.5

Lung ca. NCI-H460
2.5
Brain (Hippocampus)
2.0

Pool

Lung ca. HOP-62
6.4
Cerebral Cortex Pool
3.1

Lung ca NCI-H522
0.7
Brain (Substantia
3.0

nigra) Pool

Liver
0.0
Brain (Thalamus) Pool
4.2

Fetal Liver
7.1
Brain (whole)
1.7

Liver ca HepG2
10.1
Spinal Cord Pool
2.1

Kidney Pool
11.3
Adrenal Gland
0.0

Fetal Kidney
4.4
Pituitary gland Pool
3.1

Renal ca. 786-0
0.0
Salivary Gland
0.0

Renal ca. A498
5.1
Thyroid (female)
11.3

Renal ca. ACHN
0.0
Pancreatic ca.
0.0

CAPAN2

Renal ca. UO-31
0.0
Pancreas Pool
0.0

[0804]

261

TABLE RC

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag6807,

(%) Ag6807,

Run

Run

Tissue Name
278020699
Tissue Name
278020699

Secondary Th1 act
0.0
HUVEC IL-1beta
0.0

Secondary Th2 act
0.0
HUVEC IFN gamma
0.0

Secondary Tr1 act
0.0
HUVEC TNF alpha +
0.0

IFN gamma

Secondary Th1 rest
0.0
HUVEC TNF alpha +
0.0

IL4

Secondary Th2 rest
0.0
HUVEC IL-11
0.0

Secondary Tr1 rest
0.0
Lung Microvascular
5.0

EC none

Primary Th1 act
0.0
Lung Microvascular
0.0

EC TNFalpha +

IL-1beta

Primary Th2 act
0.0
Microvascular Dermal
0.0

EC none

Primary Tr1 act
0.0
Microsvasular Dermal
36.3

EC TNFalpha +

IL-1beta

Primary Th1 rest
0.0
Bronchial epithelium
0.0

TNFalpha + IL1beta

Primary Th2 rest
15.4
Small airway
30.8

epithelium none

Primary Tr1 rest
0.0
Small airway
0.0

epithelium

TNFalpha + IL-1beta

CD45RA CD4
0.0
Coronery artery SMC
0.0

lymphocyte act

rest

CD45RO CD4
0.0
Coronery artery SMC
0.0

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
0.0
Astrocytes rest
0.0

Secondary CD8
0.0
Astrocytes
0.0

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
0.0
KU-812 (Basophil)
0.0

lymphocyte act

rest

CD4 lymphocyte
16.3
KU-812 (Basophil)
12.0

none

PMA/ionomycin

2ry Th1/Th2/
0.0
CCD1106
0.0

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
0.0
CCD1106
100.0

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
0.0
Liver cirrhosis
0.0

LAK cells IL-2 +
0.0
NCI-H292 none
0.0

IL-12

LAK cells IL-2 +
0.0
NCI-H292 IL-4
9.9

IFN gamma

LAK cells IL-2 +
11.7
NCI-H292 IL-9
9.8

IL-18

LAK cells
14.9
NCI-H292 IL-13
0.0

PMA/ionomycin

NK Cells IL-2 rest
0.0
NCI-H292 IFN gamma
27.5

Two Way MLR 3
6.7
HPAEC none
0.0

day

Two Way MLR 5
0.0
HPAEC TNF alpha +
0.0

day

IL-1 beta

Two Way MLR 7
0.0
Lung fibroblast none
0.0

day

PBMC rest
0.0
Lung fibroblast TNF
0.0

alpha + IL-1 beta

PBMC PWM
0.0
Lung fibroblast IL-4
0.0

PBMC PHA-L
0.0
Lung fibroblast IL-9
0.0

Ramos (B cell) none
0.0
Lung fibroblast IL-13
0.0

Ramos (B cell)
0.0
Lung fibroblast IFN
0.0

ionomycin

gamma

B lymphocytes
0.0
Dermal fibroblast
0.0

PWM

CCD1070 rest

B lymphocytes
0.0
Dermal fibroblast
0.0

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
12.0
Dermal fibroblast
0.0

CCD1070 IL-1 beta

EOL-1 dbcAMP
0.0
Dermal fibroblast IFN
0.0

PMA/ionornycin

gamma

Dendritic cells none
19.3
Dermal fibroblast IL-4
16.4

Dendritic cells LPS
0.0
Dermal Fibroblasts
0.0

rest

Dendritic cells
0.0
Neutrophils TNFa +
0.0

anti CD40

LPS

Monocytes rest
0.0
Neutrophils rest
0.0

Monocytes LPS
6.0
Colon
0.0

Macrophages rest
0.0
Lung
0.0

Macrophages LPS
0.0
Thymus
0.0

HUVEC none
0.0
Kidney
0.0

HUVEC starved
0.0

[0805] CNS_neurodegeneration_v1.0 Summary: Ag6807 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0806] General_screening_panel_v1.6 Summary: Ag6807 Expression of the CG112749-01 gene is highest in a lung cancer cell line (CT=32). This gene is also expressed at low but significant levels in an ovarian cancer cell line, a breast cancer cell line, a gastric cell line, as well as in two additional lung cancer cell lines. Thus, the expression of this gene could be used to distinguish these samples from the other samples in the panel. Furthermore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of lung, ovarian, breast, and gastric cancer.

[0807] Panel 4.1D Summary: Ag6807 Expression of the CG112749-01 gene is limited to keratinocytes treated with the inflammatory cytokines TNF-a and IL-1b (CT=34.4). Therefore, therapeutic modulation of the activity of this gene or its protein product through the application of small molecule therapeutics may be useful in the treatment of psoriasis and wound healing.

[0808] S. CG112749-02: Cyclin

[0809] Expression of full length physical clone CG112749-02, a variant of CG112749-01 above, was assessed using the primer-probe set Ag6781, described in Table SA. Results of the RTQ-PCR runs are shown in Tables SB, SC and SD.

262TABLE SAProbe Name Ag6781PrimersSequencesLengthStart PositionSEQ ID No.Forward5′-tgagtgcacgtccatgtca-3′1916175ProbeTET-5′-aggcacgcacaggagtcccaca-3′-TAMRA2239176Reverse5′-gcggcacacccacgt-3′1592177

[0810]

263

TABLE SB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag6781,

(%) Ag6781,

Run

Run

Tissue Name
277731700
Tissue Name
277731700

AD 1 Hippo
27.4
Control (Path) 3
6.0

Temporal Ctx

AD 2 Hippo
35.6
Control (Path) 4
33.9

Temporal Ctx

AD 3 Hippo
10.7
AD 1 Occipital Ctx
35.8

AD 4 Hippo
9.6
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 hippo
100.0
AD 3 Occipital Ctx
16.6

AD 6 Hippo
65.5
AD 4 Occipital Ctx
14.4

Control 3 Hippo
22.4
AD 5 Occipital Ctx
26.1

Control 4 Hippo
37.4
AD 6 Occipital Ctx
45.7

Control (Path) 3
9.0
Control 1 Occipital
5.8

Hippo

Ctx

AD 1 Temporal Ctx
27.2
Control 2 Occipital
49.0

Ctx

AD 2 Temporal Ctx
38.4
Control 3 Occipital
34.2

Ctx

AD 3 Temporal Ctx
11.2
Control 4 Occipital
15.6

Ctx

AD 4 Temporal Ctx
21.0
Control (Path) 1
80.7

Occipital Ctx

AD 5 Inf Temporal
89.5
Control (Path) 2
16.7

Ctx

Occipital Ctx

AD 5 SupTemporal
62.0
Control (Path) 3
6.1

Ctx

Occipital Ctx

AD 6 Inf Temporal
99.3
Control (Path) 4
32.1

Ctx

Occipital Ctx

AD 6 Sup Temporal
81.8
Control 1 Parietal
22.2

Ctx

Ctx

Control 1 Temporal
19.6
Control 2 Parietal
75.8

Ctx

Ctx

Control 2 Temporal
41.5
Control 3 Parietal
24.3

Ctx

Ctx

Control 3 Temporal
0.0
Control (Path) 1
64.6

Ctx

Parietal Ctx

Control 4 Temporal
24.5
Control (Path) 2
35.8

Ctx

Parietal Ctx

Control (Path) 1
57.0
Control (Path) 3
5.6

Temporal Ctx

Parietal Ctx

Control (Path) 2
45.1
Control (Path) 4
35.6

Temporal Ctx

Parietal Ctx

[0811]

264

TABLE SC

General_screening_panel_v1.6

Rel. Exp.

Rel. Exp.

(%) Ag6781,

(%) Ag6781,

Run

Run

Tissue Name
278015359
Tissue Name
278015359

Adipose
1.1
Renal ca TK-10
4.6

Melanoma*
5.9
Bladder
4.0

Hs688(A).T

Melanoma*
4.9
Gastric ca. (liver met.)
19.8

Hs688(B).T

NCI-N87

Melanoma* M14
9.7
Gastric ca KATO III
14.1

Melanoma*
5.3
Colon ca. SW-948
3.1

LOXIMVI

Melanoma*
4.5
Colon ca. SW480
13.0

SK-MEL-5

Squamous cell
3.3
Colon ca.* (SW480
7.1

carcinoma SCC-4

met) SW620

Testis Pool
2.0
Colon ca. HT29
7.6

Prostate ca.* (bone
6.1
Colon ca. HCT-116
8.2

met) PC-3

Prostate Pool
1.8
Colon ca. CaCo-2
11.2

Placenta
1.4
Colon cancer tissue
1.8

Uterus Pool
0.0
Colon ca. SW1116
2.1

Ovarian ca.
100.0
Colon ca. Colo-205
4.4

OVCAR-3

Ovarian ca.
8.3
Colon ca. SW-48
1.2

SK-OV-3

Ovarian ca.
6.2
Colon Pool
2.2

OVCAR-4

Ovarian ca.
8.8
Small Intestine Pool
2.0

OVCAR-5

Ovarian ca.
4.7
Stomach Pool
2.4

IGROV-1

Ovarian ca.
2.6
Bone Marrow Pool
0.6

OVCAR-8

Ovary
1.5
Fetal Heart
1.1

Breast ca. MCF-7
8.4
Heart Pool
1.2

Breast ca. MDA-
11.5
Lymph Node Pool
3.1

MB-231

Breast ca BT 549
8.5
Fetal Skeletal Muscle
1.7

Breast ca. T47D
1.5
Skeletal Muscle Pool
1.0

Breast ca. MDA-N
4.1
Spleen Pool
2.5

Breast Pool
2.2
Thymus Pool
3.3

Trachea
1.5
CNS cancer (glio/
8.1

astro) U87-MG

Lung
1.5
CNS cancer (glio/
11.2

astro) U-118-MG

Fetal Lung
4.2
CNS cancer (neuro;
12.9

met) SK-N-AS

Lung ca. NCI-N417
1.8
CNS cancer (astro)
9.2

SF-539

Lung ca. LX-1
5.6
CNS cancer (astro)
15.9

SNB-75

Lung ca NCI-H146
2.9
CNS cancer (glio)
5.0

SNB-19

Lung ca SHP-77
10.5
CNS cancer (glio)
11.2

SF-295

Lung ca A549
13.8
Brain (Amygdala)
2.0

Pool

Lung ca. NCI-H526
4.5
Brain (cerebellum)
8.1

Lung ca. NCI-H23
7.9
Brain (fetal)
2.9

Lung ca. NCI-H460
5.2
Brain (Hippocampus)
1.9

Pool

Lung ca. HOP-62
2.9
Cerebral Cortex Pool
1.8

Lung ca. NCI-H522
4.1
Brain (Substantia
2.0

nigra) Pool

Liver
0.6
Brain (Thalamus) Pool
3.1

Fetal Liver
2.1
Brain (whole)
1.3

Liver ca. HepG2
1.7
Spinal Cord Pool
2.2

Kidney Pool
3.7
Adrenal Gland
2.3

Fetal Kidney
2.8
Pituitary gland Pool
0.4

Renal ca. 786-0
4.9
Salivary Gland
0.8

Renal ca. A498
4.4
Thyroid (female)
3.4

Renal ca. ACHN
3.9
Pancreatic ca.
7.2

CAPAN2

Renal ca. UO-31
1.7
Pancreas Pool
1.9

[0812]

265

TABLE SD

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag6781,

(%) Ag6781,

Run

Run

Tissue Name
277641307
Tissue Name
277641307

Secondary Th1 act
37.9
HUVEC IL-1beta
19.3

Secondary Th2 act
83.5
HUVEC IFN gamma
15.5

Secondary Tr1 act
17.2
HUVEC TNF alpha +
18.2

IFN gamma

Secondary Th1 rest
0.0
HUVEC TNF alpha +
0.0

IL4

Secondary Th2 rest
11.8
HUVEC IL-11
0.0

Secondary Tr1 rest
13.2
Lung Microvascular
15.1

EC none

Primary Th1 act
23.3
Lung Microvascular
0.0

EC TNFalpha +

IL-1beta

Primary Th2 act
48.6
Microvascular Dermal
0.0

EC none

Primary Tr1 act
61.6
Microsvasular Dermal
0.0

EC TNFalpha +

IL-1beta

Primary Th1 rest
0.0
Bronchial epithelium
12.2

TNFalpha + IL1beta

Primary Th2 rest
0.0
Small airway
13.2

epithelium none

Primary Tr1 rest
0.0
Small airway
37.1

epithelium

TNFalpha + IL-1beta

CD45RA CD4
44.1
Coronery artery SMC
35.8

lymphocyte act

rest

CD45RO CD4
66.0
Coronery artery SMC
33.2

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
20.7
Astrocytes rest
12.9

Secondary CD8
28.5
Astrocytes
24.8

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
15.6
KU-812 (Basophil)
27.9

lymphocyte act

rest

CD4 lymphocyte
12.9
KU-812 (Basophil)
23.0

none

PMA/ionomycin

2ry Th1/Th2/
15.0
CCD1106
40.6

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
25.7
CCD1106
51.4

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
24.1
Liver cirrhosis
0.0

LAK cells IL-2 +
0.0
NCI-H292 none
52.1

IL-12

LAK cells IL-2 +
0.0
NCI-H292 IL-4
75.3

IFN gamma

LAK cells IL-2 +
0.0
NCI-H292 IL-9
57.4

IL-18

LAK cells
26.6
NCI-H292 IL-13
57.8

PMA/ionomycin

NK Cells IL-2 rest
68.8
NCI-H292 IFN gamma
37.6

Two Way MLR 3
16.6
HPAEC none
15.6

day

Two Way MLR 5
0.0
HPAEC TNF alpha +
28.3

day

IL-1 beta

Two Way MLR 7
36.6
Lung fibroblast none
57.4

day

PBMC rest
0.0
Lung fibroblast TNF
70.2

alpha + IL-1b eta

PBMC PWM
21.5
Lung fibroblast IL-4
27.7

PBMC PHA-L
39.0
Lung fibroblast IL-9
21.8

Ramos (B cell) none
30.8
Lung fibroblast IL-13
49.7

Ramos (B cell)
55.5
Lung fibroblast IFN
34.9

ionomycin

gamma

B lymphocytes
24.7
Dermal fibroblast
67.8

PWM

CCD1070 rest

B lymphocytes
54.0
Dermal fibroblast
52.5

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
100.0
Dermal fibroblast
57.0

CCD1070 IL-1beta

EOL-1 dbcAMP
11.1
Dermal fibroblast IFN
47.3

PMA/ionomycin

gamma

Dendritic cells none
0.0
Dermal fibroblast IL-4
36.6

Dendritic cells LPS
0.0
Dermal Fibroblasts
33.2

rest

Dendritic cells
24.7
Neutrophils TNFa +
0.0

anti CD40

LPS

Monocytes rest
0.0
Neutrophils rest
26.6

Monocytes LPS
0.0
Colon
0.0

Macrophages rest
0.0
Lung
0.0

Macrophages LPS
0.0
Thymus
0.0

HUVEC none
14.1
Kidney
30.6

HUVEC starved
14.7

[0813] CNS_neurodegeneration_v1.0 Summary: Ag678 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. This gene is expressed at low levels in the CNS suggesting that therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0814] General_screening_panel_v1.6 Summary: Ag678 Highest expression of this gene is seen in an ovarian cancer cell line (CT=30.5). This gene is widely expressed among the cell lines on this panel, with low but significant expression seen in brain, colon, gastric, lung, breast, ovarian, and melanoma cancer cell lines. This expression profile suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer.

[0815] Panel 4.1D Summary: Ag6781 Expression is low/undetectable in all samples on this panel (CTs>35).

[0816] T. CG112758-03: TPR-Domain Protein

[0817] Expression of gene CG112758-01 was assessed using the primer-probe set Ag4460, described in Table TA. Results of the RTQ-PCR runs are shown in Tables TB, TC, TD and TE.

266TABLE TAProbe Name Ag4460PrimersSequencesLengthStart PositionSEQ ID No.-hz,1/49 Forward5′-atccagctgactcagctgaag-3′21781178ProbeTET-5′-atgaatcgttgcagcctccagcg-3′-TAMRA23802179Reverse5′-agccaattacatcccgagtct-3′21848180

[0818]

267

TABLE TB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4460,

(%) Ag4460,

Run

Run

Tissue Name
224621595
Tissue Name
224621595

AD 1 Hippo
12.4
Control (Path) 3
8.5

Temporal Ctx

AD 2 Hippo
30.4
Control (Path) 4
34.6

Temporal Ctx

AD 3 Hippo
12.9
AD 1 Occipital
20.7

Ctx

AD 4 Hippo
15.1
AD 2 Occipital
0.0

Ctx (Missing)

AD 5 Hippo
100.0
AD 3 Occipital
8.7

Ctx

AD 6 Hippo
28.9
AD 4 Occipital
22.2

Control 2 Hippo
42.0
AD 5 Occipital
51.1

Ctx

Control 4 Hippo
6.9
AD 6 Occipital
16.3

Ctx

Control (Path) 3 Hippo
9.1
Control 1
5.7

Occipital Ctx

AD 1 Temporal Ctx
19.3
Control 2
85.9

Occipital Ctx

AD 2 Temporal Ctx
26.6
Control 3
27.7

Occipital Ctx

AD 3 Temporal Ctx
11.6
Control 4
6.7

Occipital Ctx

AD 4 Temporal Ctx
22.7
Control (Path) 1
92.0

Occipital Ctx

AD 5 Inf Temporal Ctx
79.6
Control (Path) 2
18.6

Occipital Ctx

AD 5 Sup Temporal
35.4
Control (Path) 3
4.0

Ctx

Occipital Ctx

AD 6 Inf Temporal Ctx
29.9
Control (Path) 4
19.3

Occipital Ctx

AD 6 Sup Temporal
33.2
Control 1 Parietal
7.2

Ctx

Ctx

Control 1 Temporal
7.7
Control 2 Parietal
43.2

Ctx

Ctx

Control 2 Temporal
60.3
Control 3 Parietal
17.8

Ctx

Ctx

Control 3 Temporal
23.0
Control (Path) 1
81.8

Ctx

Parietal Ctx

Control 3 Temporal
12.7
Control (Path) 2
23.2

Ctx

Parietal Ctx

Control (Path) 1
80.1
Control (Path) 3
6.3

Temporal Ctx

Parietal Ctx

Control (Path) 2
53.2
Control (Path) 4
49.3

Temporal Ctx

Parietal Ctx

[0819]

268

TABLE TC

General_screening_panel_v1.

Rel. Exp.

Rel. Exp.

(%) Ag4460,

(%) Ag4460,

Run

Run

Tissue Name
222523506
Tissue Name
222523506

Adipose
0.8
Renal ca. TK-10
3.6

Melanoma*
1.1
Bladder
1.2

Hs688(A).T

Melanoma*
1.6
Gastric ca. (liver met.)
3.6

Hs688(B).T

NCI-N87

Melanoma* M14
2.8
Gastric ca. KATO III
2.1

Melanoma* LOXIMVI
0.3
Colon ca. SW-948
0.6

Melanoma* SK-MEL-5
0.6
Colon ca. SW480
3.1

Squamous cell
0.0
Colon ca.* (SW480 met)
1.4

carcinoma SCC-4

SW620

Testis Pool
1.5
Colon ca. HT29
0.6

Prostate ca.* (bone met)
0.6
Colon ca. HCT-116
3.3

PC-3

Prostate Pool
0.6
Colon ca. CaCo-2
0.8

Placenta
0.3
Colon cancer tissue
1.9

Uterus Pool
0.3
Colon ca. SW1116
1.1

Ovarian ca. OVCAR-3
5.6
Colon ca. Colo-205
0.6

Ovarian ca. SK-OV-3
1.9
Colon ca. SW-48
1.0

Ovarian ca. OVCAR-4
0.6
Colon Pool
1.5

Ovarian ca. OVCAR-5
3.8
Small Intestine Pool
2.9

Ovarian ca. IGROV-1
3.6
Stomach Pool
1.0

Ovarian ca. OVCAR-8
2.4
Bone Marrow Pool
1.2

Ovary
1.1
Fetal Heart
0.5

Breast ca. MCF-7
2.4
Heart Pool
1.1

Breast ca. MDA-MB-
1.7
Lymph Node Pool
1.9

231

Breast ca. BT 549
1.7
Fetal Skeletal Muscle
0.8

Breast ca. T47D
3.0
Skeletal Muscle Pool
0.4

Breast ca. MDA-N
2.2
Spleen Pool
0.7

Breast Pool
1.7
Thymus Pool
1.3

Trachea
0.5
CNS cancer (glio/astro)
4.8

U87-MG

Lung
1.2
CNS cancer (glio/astro)
3.2

U-118-MG

Fetal Lung
2.2
CNS cancer (neuro, met)
4.7

SK-N-AS

Lung ca. NCI-N417
0.5
CNS cancer (astro)
0.7

SF-539

Lung ca. LX-1
2.7
CNS cancer (astro) SNB-
4.0

75

Lung ca. NCI-H146
5.6
CNS cancer (glio)
2.1

SNB-19

Lung ca. SHP-77
7.4
CNS cancer (glio)
6.1

SF-295

Lung ca. A549
1.8
Brain (Amygdala) Pool
34.2

Lung ca. NCI-H526
0.7
Brain (cerebellum)
100.0

Lung ca. NCI-H23
1.0
Brain (fetal)
82.9

Lung ca. NCI-H460
1.6
Brain (Hippocampus)
23.7

Pool

Lung ca. HOP-62
0.5
Cerebral Cortex Pool
41.5

Lung ca. NCI-H522
1.4
Brain (Substantia nigra)
48.6

Pool

Liver
0.0
Brain (Thalamus) Pool
55.9

Fetal Liver
0.3
Brain (whole)
55.1

Liver ca. HepG2
1.4
Spinal Cord Pool
5.8

Kidney Pool
3.6
Adrenal Gland
1.9

Fetal Kidney
1.6
Pituitary gland Pool
0.7

Renal ca. 786-0
0.6
Salivary Gland
0.8

Renal ca. A498
1.3
Thyroid (female)
0.7

Renal ca. ACHN
1.2
Pancreatic ca. CAPAN2
0.4

Renal ca. UO-31
0.9
Pancreas Pool
1.5

[0820]

269

TABLE TD

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4460,

(%) Ag4460,

Run

Run

Tissue Name
191579099
Tissue Name
191579099

Secondary Th1 act
0.0
HUVEC IL-1beta
37.1

Sccondary Th2 act
34.4
HUVEC IFN gamma
46.7

Secondary Tr1 act
8.4
HUVEC TNF alpha +
0.0

IFN gamma

Secondary Th1 rest
23.2
HUVEC TNF alpha +
0.0

IL4

Secondary Th2 rest
39.5
HUVEC IL-11
30.1

Secondary Tr1 rest
43.2
Lung Microvascular
9.6

EC none

Primary Th1 act
27.7
Lung Microvascular
19.3

EC TNFalpha +

IL-1beta

Primary Th2 act
33.4
Microvascular Dermal
18.4

EC none

Primary Tr1 act
36.3
Microvascular Dermal
7.2

EC TNFalpha +

IL-1beta

Primary Th1 rest
40.3
Bronchial
46.3

epithelium

TNFalpha + IL1beta

Primary Th2 rest
0.0
Small airway
0.0

epithelium none

Primary Tr1 rest
25.7
Small airway
9.3

epithelium

TNFalpha + IL-1beta

CD45RA CD4
17.7
Coronery artery SMC
8.1

lymphocyte act

rest

CD45RO CD4
87.1
Coronery artery SMC
0.0

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
0.0
Astrocytes rest
19.9

Secondary CD8
0.0
Astrocytes
0.0

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
16.2
KU-812 (Basophil)
37.9

lymphocyte act

rest

CD4 lymphocyte
68.3
KU-812 (Basophil)
8.2

none

PMA/ionomycin

2ry Th1/Th2/
68.8
CCD1106
13.9

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
22.2
CCD1106
36.6

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
6.7
Liver ciirhosis
0.0

LAK cells IL-2 +
0.0
NCI-H292 none
37.4

IL-12

LAK cells IL-2 +
9.5
NCI-H292 IL-4
0.0

IFN gamma

LAK cells IL-2 +
9.3
NCI-H292 IL-9
18.0

IL-18

LAK cells
9.1
NCI-H292 IL-13
36.3

PMA/ionomycin

NK Cells IL-2 rest
58.2
NCI-H292 IFN gamma
30.8

Two Way MLR 3
100.0
HPAEC none
10.6

day

Two Way MLR 5
34.4
HPAEC TNF alpha +
37.4

day

IL-1 beta

Two Way MLR 7
69.3
Lung fibroblast none
7.0

day

PBMC rest
60.3
Lung fibroblast TNF
76.3

alpha + IL-1 beta

PBMC PWM
7.9
Lung fibroblast IL-4
37.4

PBMC PHA-L
57.0
Lung fibroblast IL-9
28.9

Ramos (B cell) none
0.0
Lung fibroblast IL-13
20.6

Ramos (B cell)
9.6
Lung fibroblast IFN
71.2

ionomycin

gamma

B lymphocytes
27.0
Dermal fibroblast
0.0

PWM

CCD1070 rest

B lymphocytes
66.4
Dermal fibroblast
41.8

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
19.2
Dermal fibroblast
13.7

CCD1070 IL-1 beta

EOL-1 dbcAMP
9.4
Dermal fibroblast
28.9

PMA/ionomycin

IFN gamma

Dendritic cells none
10.2
Dermal fibroblast IL-4
24.0

Dendritic cells LPS
33.2
Dermal fibroblasts rest
24.7

Dendritic cells
9.7
Neutrophils TNFa +
0.0

anti-CD40

LPS

Monocytes rest
92.7
Neutrophils rest
10.7

Monocytes LPS
33.4
Colon
9.1

Macrophages rest
0.0
Lung
17.6

Macrophages LPS
19.2
Thymus
56.6

HUVEC none
0.0
Kidney
38.2

HUVEC starved
40.3

[0821]

270

TABLE TE

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4460,

(%) Ag4460,

Run

Run

Tissue Name
268672302
Tissue Name
268672302

Colon cancer 1
6.6
Bladder cancer NAT
0.0

2

Colon cancer NAT 1
11.3
Bladder cancer NAT
0.0

3

Colon cancer 2
12.6
Bladder cancer NAT
5.4

4

Colon cancer NAT 2
12.7
Prostate
11.0

adenocarcinoma 1

Colon cancer 3
29.7
Prostate
5.7

adenocarcinoma 2

Colon cancer NAT 3
8.2
Prostate
12.9

adenocarcinoma 3

Colon malignant
11.0
Prostate
9.1

cancer 4

adenocarcinoma 4

Colon normal
0.0
Prostate cancer
9.2

adjacent tissue 4

NAT 5

Lung cancer 1
20.4
Prostate
17.4

adenocarcinoma 6

Lung NAT 1
0.0
Prostate
27.2

adenocarcinoma 7

Lung cancer 2
10.1
Prostate
0.0

adenocarcinoma 8

Lung NAT 2
4.6
Prostate
26.6

adenocarcinoma 9

Squamous cell
10.7
Prostate cancer
0.0

carcinoma 3

NAT 10

Lung NAT 3
0.0
Kidney cancer 1
24.1

metastatic melanoma 1
33.0
Kidney NAT 1
15.3

Melanoma 2
2.4
Kidney cancer 2
45.4

Melanoma 3
8.8
Kidney NAT 2
24.7

metastatic melanoma 4
100.0
Kidney cancer 3
11.6

Metastatic melanoma 5
51.4
Kidney NAT 3
12.0

Bladder cancer 1
0.0
Kidney cancer 4
15.8

Bladder cancer NAT 1
0.0
Kidney NAT 4
10.1

Bladder cancer 2
10.4

[0822] CNS_neurodegeneration_v1.0 Summary: Ag4460 This panel confirms the expression of this gene at high levels in the brain in an independent group of individuals. This gene is found to be down-regulated in the temporal cortex of Alzheimer's disease patients. Therefore, up-regulation of this gene or its protein product, or treatment with specific agonists for this receptor may be of use in reversing the dementia, memory loss, and neuronal death associated with this disease.

[0823] General_screening_panel_v1.4 Summary: Ag4460 This gene is also expressed at low but significant levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0824] Overall, this gene is expressed widely on this panel, with moderate expression seen in brain, colon, gastric, lung, breast, ovarian, and melanoma cancer cell lines. This expression profile suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer.

[0825] Among tissues with metabolic function, this gene is expressed at low but significant levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle and heart. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

[0826] Panel 4.1 D Summary: Ag4460 Low but significant levels of expression are seen in resting monocytes, activated CD4 lymphocytes and in a sample from a 3 day 2 way MLR (CTs=34.5-35).

[0827] general oncology screening panel_v—2.4 Summary: Ag4460 Expression of this gene is restricted to a sample derived from a melanoma (CT=34.2). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker to detect the presence of colon cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of colon cancer.

[0828] U. CG112892-01: Immunoglobulin Domain Containing Gene

[0829] Expression of gene CG112892-01 was assessed using the primer-probe set Ag4466, described in Table UA.

271TABLE UAProbe Name Ag4466StartPrimersSequencesLengthPositionSEQ ID No.Forward5′-tgatagaaaagcagcatgatga-3′22354181ProbeTET-5′-caccaaatgaaataaagacccttaggga-3′-28381182TAMRAReverse5′-tttgtgctctgttgctagttca-3′22415183

[0830] CNS_neurodegeneration_v1.0 Summary: Ag4466 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

[0831] General_screening_panel_v1.4 Summary: Ag4466 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

[0832] Panel 4.1D Summary: Ag4466 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

[0833] general oncology screening panel_v—2.4 Summary: Ag4466 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

[0834] V. CG113794-01: PA Domain Containing Protein

[0835] Expression of gene CG113794-01 was assessed using the primer-probe set Ag5065, described in Table VA. Results of the RTQ-PCR runs are shown in Tables VB and VC.

272TABLE VAProbe Name Ag5065PrimersSequencesLengthStart PositionSEQ ID No.Forward5′-tgagcagattcaccttgtcc-3′20183184ProbeTET-5′-aactcagcgcaggtttcttcatccag-3′-TAMRA26230185Reverse5′-actctccaccagagcgatct-3′20260186

[0836]

273

TABLE VB

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag5065,

(%) Ag5065,

Run

Run

Tissue Name
222653540
Tissue Name
222653540

Adipose
2.7
Renal ca. TK-10
29.9

Melanoma*
3.7
Bladder
14.4

Hs688(A).T

Melanoma*
2.0
Gastric ca. (liver met.)
10.7

Hs688(B).T

NCI-N87

Melanoma* M14
5.6
Gastric ca. KATO III
7.8

Melanoma*
3.9
Colon ca. SW-948
19.5

LOXIMVI

Melanoma*
8.0
Colon ca. SW480
0.0

SK-MEL-5

Squamous cell
5.9
Colon ca.* (SW480
0.0

carcinoma SCC-4

met) SW620

Testis Pool
1.9
Colon ca HT29
0.0

Prostate ca.* (bone
15.1
Colon ca HCT-116
0.0

met) PC-3

Prostate Pool
2.5
Colon ca. CaCo-2
9.5

Placenta
0.0
Colon cancer tissue
3.4

Uterus Pool
0.0
Colon ca. SW1116
0.0

Ovarian ca.
20.4
Colon ca. Colo-205
1.9

OVCAR-3

Ovarian ca.
100.0
Colon ca. SW-48
3.3

SK-OV-3

Ovarian ca.
0.0
Colon Pool
20.0

OVCAR-4

Ovarian ca
8.4
Small Intestine Pool
39.5

OVCAR-5

Ovarian ca
2.2
Stomach Pool
17.0

IGROV-1

Ovarian ca.
14.9
Bone Marrow Pool
0.0

OVCAR-8

Ovary
5.0
Fetal Heart
5.6

Breast ca MCF-7
7.5
Heart Pool
4.9

Breast ca. MDA-
36.9
Lymph Node Pool
40.6

MB-231

Breast ca. BT 549
5.0
Fetal Skeletal Muscle
6.6

Breast ca. T47D
67.4
Skeletal Muscle Pool
4.0

Breast ca. MBA-N
5.4
Spleen Pool
9.2

Breast Pool
25.7
Thymus Pool
9.8

Trachea
2.0
CNS cancer (glio/
0.0

astro) U87-MG

Lung
20.0
CNS cancer (glio/
17.7

astro) U-118-MG

Fetal Lung
68.3
CNS cancer (neuro;
8.9

met) SK-N-AS

Lung ca. NCI-N417
2.7
CNS cancer (astro)
0.0

SF-539

Lung ca. LX-1
4.6
CNS cancer (astro)
24.3

SNB-75

Lung ca. NCI-H146
2.5
CNS cancer (glio)
9.0

SNB-19

Lung ca. SHP-77
3.3
CNS cancer (glio)
11.5

SF-295

Lung ca. A549
0.0
Brain (Amygdala)
0.0

Pool

Lung ca. NCI-H526
7.4
Brain (cerebellum)
5.9

Lung ca. NCI-H23
24.0
Brain (fetal)
9.5

Lung ca. NCI-H460
5.6
Brain (Hippocampus)
2.4

Pool

Lung ca. HOP-62
0.0
Cerebral Cortex Pool
0.0

Lung ca. NCI-H522
3.5
Brain (Substantia
4.0

nigra) Pool

Liver
0.0
Brain (Thalamus) Pool
18.2

Fetal Liver
0.0
Brain (whole)
0.0

Liver ca. HepG2
7.4
Spinal Cord Pool
17.4

Kidney Pool
60.3
Adrenal Gland
2.6

Fetal Kidney
16.4
Pituitary gland Pool
0.0

Renal ca. 786-0
11.5
Salivary Gland
0.0

Renal ca. A498
0.0
Thyroid (female)
0.0

Renal ca. ACHN
0.0
Pancreatic ca
0.0

CAPAN2

Renal ca. UO-31
0.0
Pancreas Pool
24.3

[0837]

274

TABLE VC

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag5065,

(%) Ag5065,

Run

Run

Tissue Name
223785444
Tissue Name
223785444

Secondary Th1 act
21.5
HUVEC IL-1beta
42.6

Secondary Th2 act
0.0
HUVEC IFN gamma
54.0

Secondary Tr1 act
10.8
HUVEC TNF alpha +
5.3

IFN gamma

Secondary Th1 rest
0.0
HUVEC TNF alpha +
7.5

IL4

Secondary Th2 rest
24.3
HUVEC IL-11
20.0

Secondary Tr1 rest
14.0
Lung Microvascular
64.6

EC none

Primary Th1 act
5.2
Lung Microvascular
14.8

EC TNFalpha +

IL-1beta

Primary Th2 act
75.8
Microvascular Dermal
13.2

EC none

Primary Tr1 act
2.3
Microsvasular Dermal
3.4

EC TNFalpha +

IL-1beta

Primary Th1 rest
45.5
Bronchial epithelium
27.2

TNFalpha + IL1beta

Primary Th2 rest
21.2
Small airway
7.4

epithelium none

Primary Tr1 rest
71.2
Small airway
26.6

epithelium

TNFalpha + IL-1beta

CD45RA CD4
36.3
Coronery artery SMC
26.1

lymphocyte act

rest

CD45RO CD4
62.4
Coronery artery SMC
19.5

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
42.6
Astrocytes rest
8.1

Secondary CD8
53.6
Astrocytes
18.8

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
18.2
KU-812 (Basophil)
42.3

lymphocyte act

rest

CD4 lymphocyte
17.1
KU-812 (Basophil)
97.9

none

PMA/ionomycin

2ry Th1/Th2/
70.2
CCD1106
45.1

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
36.6
CCD1106
24.0

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
89.5
Liver cirrhosis
4.9

LAK cells IL-2 +
39.5
NCI-H292 none
8.7

IL-12

LAK cells IL-2 +
39.0
NCI-H292 IL-4
11.8

IFN gamma

LAK cells IL-2 +
60.3
NCI-H292 IL-9
15.6

IL-18

LAK cells
47.6
NCI-H292 IL-13
11.3

PMA/ionomycin

NK Cells IL-2 rest
68.8
NCI-H292 IFN gamma
18.7

Two Way MLR 3
51.8
HPAEC none
15.5

day

Two Way MLR 5
64.2
HPAEC TNF alpha +
16.0

day

IL-1 beta

Two Way MLR 7
41.8
Lung fibroblast none
29.5

day

PBMC rest
12.6
Lung fibroblast TNF
19.2

alpha + IL- 1beta

PBMC PWM
16.8
Lung fibroblast IL-4
18.8

PBMC PHA-L
43.5
Lung fibroblast IL-9
22.4

Ramos (B cell) none
37.6
Lung fibroblast IL-13
18.9

Ramos (B cell)
27.9
Lung fibroblast IFN
22.1

ionomycin

gamma

B lymphocytes
29.3
Dermal fibroblast
28.1

PWM

CCD1070 rest

B lymphocytes
89.5
Dermal fibroblast
100.0

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
37.1
Dermal fibroblast
21.9

CCD1070 IL-1 beta

EOL-1 dbcAMP
17.8
Dermal fibroblast IFN
30.4

PMA/ionomycin

gamma

Dendritic cells none
40.6
Dermal fibroblast IL-4
27.0

Dendritic cells LPS
22.2
Dermal Fibroblasts
20.3

rest

Dendritic cells
15.4
Neutrophils TNFa +
41.2

anti CD40

LPS

Monocytes rest
58.2
Neutrophils rest
40.6

Monocytes LPS
92.0
Colon
16.2

Macrophages rest
54.3
Lung
23.3

Macrophages LPS
14.7
Thymus
48.6

HUVEC none
10.9
Kidney
20.9

HUVEC starved
34.4

[0838] General_screening_panel_v1.4 Summary: Ag5065 Expression of this gene is limited to an ovarian cancer cell line (CT=34.2), a breast cancer cell line, kidney and fetal lung. Therefore, expression of this gene may be used to differentiate these samples from other samples in this panel and as diagnostic marker to detect presence of ovarian and breast cancer. In addition, therapeutic modulation of this gene product may be useful in the treatment of ovarian and breast cancer and also diseases that affect kidney and lung.

[0839] Panel 4.1D Summary: Ag5065 Highest expression is seen in TNF-a stimulated dermal fibroblasts. This gene is also expressed at low but significant levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from skin. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

[0840] W. CG114814-01: Novel Gene Containing, Phenylalanine and Histidine Ammonia-Lyase Domain Protein

[0841] Expression of gene CG114814-01 was assessed using the primer-probe set Ag4478, described in Table WA.

275TABLE WAProbe Name Ag4478StartPrimersSequencesLengthPositionSEQ ID No.Forward5′-gtccatgccaagaactctca-3′20954187ProbeTET-5′-tcaaacctactattggccatacaaatca-3′-28975188TAMRAReverse5′-cttgtggagaccattttaacca-3′221008189

[0842] CNS_neurodegeneration_v1.0 Summary: Ag4478 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0843] General_screening_panel_v1.4 Summary: Ag4478 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0844] Panel 4.11D Summary: Ag4478 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0845] general oncology screening panel_v—2.4 Summary: Ag4478 Expression of this gene is low/undetectable (CT's>35) across all of the samples on this panel.

[0846] X. CG116840-01 and CG116840-02: Cellular Retinaldehyde-Binding Protein

[0847] Expression of gene CG116840-01 and full length physical clone CG116840-02 was assessed using the primer-probe set Ag4487, described in Table XA. Results of the RTQ-PCR runs are shown in Tables XB, XC, XD, XE and XF. Please note that CG116840-02 represents a full-length physical clone of the CG116840-01 gene, validating the prediction of the gene sequence.

276TABLE XAProbe Name Ag4487PrimersSequencesLengthStart PositionSEQ ID No.Forward5′-ggaactccttcacagacatcct-3′22515190ProbeTET-5′-ccatcctgctgtcattggaagtccta-3′-TAMRA26542191Reverse5′-tttatctgaagctccggatctt-3′22572192

[0848]

277

TABLE XB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4487,

(%) Ag4487,

Run

Run

Tissue Name
224621606
Tissue Name
224621606

AD 1 Hippo
11.0
Control (Path) 3
2.8

Temporal Ctx

AD 2 Hippo
26.2
Control (Path) 4
34.6

Temporal Ctx

AD 3 Hippo
6.6
AD 1 Occipital Ctx
12.1

AD 4 Hippo
4.5
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 hippo
100.0
AD 3 Occipital Ctx
3.4

AD 6 Hippo
8.4
AD 4 Occipital Ctx
20.6

Control 2 Hippo
26.2
AD 5 Occipital Ctx
52.5

Control 4 Hippo
3.6
AD 6 Occipital Ctx
15.0

Control (Path) 3 Hippo
2.8
Control 1 Occipital
0.5

Ctx

AD 1 Temporal Ctx
0.3
Control 2 Occipital
64.2

Ctx

AD 2 Temporal Ctx
30.4
Control 3 Occipital
13.0

Ctx

AD 3 Temporal Ctx
3.5
Control 4 Occipital
1.6

Ctx

AD 4 Temporal Ctx
19.1
Control (Path) 1
79.0

Occipital Ctx

AD 5 Inf Temporal
76.8
Control (Path) 2
10.6

Ctx

Occipital Ctx

AD 5 Sup Temporal
33.2
Control (Path) 3
0.4

Ctx

Occipital Ctx

AD 6 Inf Temporal
36.1
Control (Path) 4
17.0

Ctx

Occipital Ctx

AD 6 Sup Temporal
36.1
Control 1 Parietal
3.6

Ctx

Ctx

Control 1 Temporal
2.8
Control 2 Parietal
28.5

Ctx

Ctx

Control 2 Temporal
33.4
Control 3 Parietal
13.7

Ctx

Ctx

Control 3 Temporal
15.7
Control (Path) 1
84.7

Ctx

Parietal Ctx

Control 3 Temporal
3.7
Control (Path) 2
14.1

Ctx

Parietal Ctx

Control (Path) 1
67.4
Control (Path) 3
2.1

Temporal Ctx

Parietal Ctx

Control (Path) 2
38.4
Control (Path) 4
49.0

Temporal Ctx

Parietal Ctx

[0849]

278

TABLE XC

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4487,

(%) Ag4487,

Run

Run

Tissue Name
222665741
Tissue Name
222665741

Adipose
0.9
Renal ca. TK-10
0.1

Melanoma*
0.0
Bladder
37.1

Hs688(A).T

Melanoma*
0.0
Gastric ca (liver met.)
0.1

Hs688(B).T

NCI-N87

Melanoma* M14
0.0
Gastric ca KATO III
0.0

Melanoma*
0.0
Colon ca SW-948
0.0

LOXIMVI

Melanoma*
0.0
Colon ca. SW480
0.0

SK-MEL-5

Squamous cell
0.0
Colon ca* (SW480
0.0

carcinoma SCC-4

met)

Testis Pool
0.9
Colon ca. HT29
0.0

Prostate ca* (bone
0.1
Colon ca HCT-116
0.0

met) PC-3

Prostate Pool
0.0
Colon ca. CaCo-2
0.1

Placenta
0.0
Colon cancer tissue
0.0

Uterus Pool
0.1
Colon ca. SW1116
0.0

Ovarian ca.
0.2
Colon ca. Colo-205
0.0

OVCAR-3

Ovarian ca
0.0
Colon ca. SW-48
0.0

SK-OV-3

Ovarian ca.
0.0
Colon Pool
0.2

OVCAR-4

Ovarian ca
0.1
Small Intestine Pool
0.3

OVCAR-5

Ovarian ca
0.0
Stomach Pool
0.1

IGROV-1

Ovarian ca.
0.0
Bone Marrow Pool
0.2

OVCAR-8

Ovary
0.0
Fetal Heart
3.6

Breast ca MCF-7
0.0
Heart Pool
0.1

Breast ca MDA-
0.0
Lymph Node Pool
0.1

MB-231

Breast ca. BT 549
0.0
Fetal Skeletal Muscle
1.6

Breast ca. T47D
0.1
Skeletal Muscle Pool
0.1

Breast ca. MDA-N
0.0
Spleen Pool
0.2

Breast Pool
0.1
Thymus Pool
0.6

Trachea
0.4
CNS cancer (glio/
0.3

astro) U87-MG

Lung
0.0
CNS cancer (glio/
0.0

astro) U-118-MG

Fetal Lung
0.6
CNS cancer (neuro;
0.1

met) SK-N-AS

Lung ca NCI-N417
65.1
CNS cancer (astro)
0.0

SF-539

Lung ca. LX-1
0.0
CNS cancer (astro)
0.1

SNB-75

Lung ca NCI-H146
6.9
CNS cancer (glio)
0.0

SNB-19

Lung ca. SHP-77
33.2
CNS cancer (glio)
0.1

SF-295

Lung ca. A549
0.0
Brain (Amygdala)
20.3

Pool

Lung ca.NCI-H526
0.1
Brain (cerebellum)
31.4

Lung ca. NCI-H23
0.9
Brain (fetal)
100.0

Lung ca. NCI-H460
0.0
Brain (Hippocampus)
20.2

Pool

Lung ca. HOP-62
0.0
Cerebral Cortex Pool
37.4

Lung ca. NCI-H522
0.0
Brain (Substantia
20.4

nigra) Pool

Liver
0.0
Brain (Thalamus) Pool
50.3

Fetal Liver
0.2
Brain (whole)
48.6

Liver ca. HepG2
0.0
Spinal Cord Pool
6.9

Kidney Pool
0.1
Adrenal Gland
0.2

Fetal Kidney
0.8
Pituitary gland Pool
5.4

Renal ca 786-0
0.0
Salivary Gland
0.4

Renal ca. A498
0.0
Thyroid (female)
0.7

Renal ca ACHN
0.0
Pancreatic ca.
0.0

CAPAN2

Renal ca UO-31
0.0
Pancreas Pool
0.1

[0850]

279

TABLE XD

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4487,

(%) Ag4487,

Run

Run

Tissue Name
195476590
Tissue Name
195476590

Secondary Th1 act
0.0
HUVEC IL-1beta
1.6

Secondary Th2 act
0.0
HUVEC IFN gamma
0.0

Secondary Tr1 act
0.0
HUVEC TNF alpha +
0.0

IFN gamma

Secondary Th1 rest
2.6
HUVEC TNF alpha +
0.0

IL4

Secondary Th2 rest
0.0
HUVEC IL-11
0.0

Secondary Tr1 rest
0.0
Lung Microvascular
0.0

EC none

Primary Th1 act
0.7
Lung Microvascular
0.0

EC TNFalpha +

IL-1beta

Primary Th2 act
0.0
Microvascular Dermal
0.0

EC none

Primary Tr1 act
4.7
Microsvasular Dermal
0.0

EC TNFalpha +

IL-1beta

Primary Th1 rest
2.8
Bronchial epithelium
0.0

TNFalpha + IL1beta

Primary Th2 rest
0.0
Small airway
0.0

epithelium none

Primary Tr1 rest
0.0
Small airway
0.0

epithelium

TNFalpha + IL-1beta

CD45RA CD4
0.0
Coronery artery SMC
0.0

lymphocyte act

rest

CD45RO CD4
0.0
Coronery artery SMC
0.0

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
0.0
Astrocytes rest
0.0

Secondary CD8
0.0
Astrocytes
0.0

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
0.0
KU-812 (Basophil)
0.0

lymphocyte act

rest

CD4 lymphocyte
0.0
KU-812 (Basophil)
0.0

none

PMA/ionomycin

2ry Th1/Th2/
1.2
CCD1106
0.0

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
0.0
CCD1106
0.0

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
0.0
Liver cirrhosis
0.0

LAK cells IL-2 +
1.5
NCI-H292 none
0.0

IL-12

LAK cells IL-2 +
1.4
NCI-H292 IL-4
0.0

IFN gamma

LAK cells IL-2 +
0.0
NCI-H292 IL-9
0.0

IL-18

LAK cells
0.0
NCI-H292 IL-13
0.0

PMA/ionomycin

NK Cells IL-2 rest
0.0
NCI-H292 IFN gamma
0.0

Two Way MLR 3
0.0
HPAEC none
0.0

day

Two Way MLR 5
0.0
HPAEC TNF alpha +
0.0

day

IL-1 beta

Two Way MLR 7
1.6
Lung fibroblast none
0.0

day

PBMC rest
0.0
Lung fibroblast TNF
0.0

alpha + IL-1 beta

PBMC PWM
0.0
Lung fibroblast IL-4
0.0

PBMC PHA-L
0.0
Lung fibroblast IL-9
0.0

Ramos (B cell) none
0.0
Lung fibroblast IL-13
0.0

Ramos (B cell)
0.0
Lung fibroblast IFN
1.3

ionomycin

gamma

B lymphocytes
0.0
Dermal fibroblast
0.0

PWM

CCD1070 rest

B lymphocytes
2.6
Dermal fibroblast
0.0

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
0.0
Dermal fibroblast
0.0

CCD1070 IL-1 beta

EOL-1 dbcAMP
0.0
Dermal fibroblast IFN
0.0

PMA/ionomycin

gamma

Dendritic cells none
0.0
Dermal fibroblast IL-4
0.0

Dendritic cells LPS
0.0
Dermal Fibroblasts
2.8

rest

Dendritic cells
0.0
Neutrophils TNFa +
0.0

anti CD40

LPS

Monocytes rest
0.0
Neutrophils rest
1.4

Monocytes LPS
0.0
Colon
4.9

Macrophages rest
6.4
Lung
3.6

Macrophages LPS
1.5
Thymus
12.9

HUVEC none
0.0
Kidney
100.0

HUVEC starved
0.0

[0851]

280

TABLE XE

Panel CNS_1.1

Rel. Exp.

Rel. Exp.

(%) Ag4487,

(%) Ag4487,

Run

Run

Tissue Name
198360930
Tissue Name
198360930

Cing Gyr
16.8
BA17 PSP2
8.4

Depression2

Cing Gyr
2.6
BA17 PSP
48.0

Depression

Cing Gyr PSP2
8.5
BA17 Huntington's2
15.1

Cing Gyr PSP
18.8
BA17 Huntington's
48.6

Cing Gyr
6.0
BA17 Parkinson's2
61.1

Huntington's2

Cing Gyr
68.8
BA17 Parkinson's
44.8

Huntington's

Cing Gyr
47.3
BA17 Alzheimer's2
10.5

Parkinson's2

Cing Gyr
32.8
BA17 Control2
78.5

Parkinson's

Cing Gyr
9.0
BA17 Control
56.6

Alzheimer's2

Cing Gyr
26.1
BA9 Depression2
3.4

Alzheimer's

Cing Gyr Control2
34.9
BA9 Depression
11.4

Cing Gyr Control
58.6
BA9 PSP2
6.1

Temp Pole
2.2
BA9 PSP
19.1

Depression2

Temp Pole PSP2
6.1
BA9 Huntington's2
4.0

Temp Pole PSP
7.6
BA9 Huntington's
48.0

Temp Pole
28.7
BA9 Parkinson's2
63.7

Huntington's

Temp Pole
25.7
BA9 Parkinson's
31.9

Parkinson's2

Temp Pole
30.1
BA9 Alzheimer's2
3.8

Parkinson's

Temp Pole
9.9
BA9 Alzheimer's
3.7

Alzheimer's2

Temp Pole
3.3
BA9 Control2
95.9

Alzheimer's

Temp Pole Control2
100.0
BA9 Control
24.1

Temp Pole Control
30.4
BA7 Depression
8.1

Glob Palladus
4.6
BA7 PSP2
33.2

Depression

Glob Palladus PSP2
14.3
BA7 PSP
71.2

Glob Palladus PSP
12.8
BA7 Huntington's2
38.4

Glob Palladus
2.2
BA7 Huntington's
55.9

Parkinson's2

Glob Palladus
62.0
BA7 Parkinson's2
40.9

Parkinson's

Glob Palladus
6.2
BA7 Parkinson's
28.1

Alzheimer's2

Glob Palladus
10.5
BA7 Alzheimer's2
6.5

Alzhiemer's

Glob Palladus
6.0
BA7 Control2
31.2

Control2

Glob Palladus
20.0
BA7 Control
50.0

Control

Sub Nigra
13.1
BA4 Depression2
9.7

Depression2

Sub Nigra
0.0
BA4 Depression
20.4

Depression

Sub Nigra PSP2
4.2
BA4 PSP2
37.4

Sub Nigra
18.4
BA4 PSP
2.8

Huntington's2

Sub Nigra
33.0
BA4 Huntington's2
5.5

Huntington's

Sub Nigra
33.0
BA4 Huntington's
62.9

Parkinson's2

Sub Nigra
10.0
BA4 Parkinson's2
94.6

Alzheimer's2

Sub Nigra Control2
13.2
BA4 Parkinson's
54.0

Sub Nigra Control
25.0
BA4 Alzheimer's2
9.9

BA17 Depression2
26.4
BA4 Control2
97.3

BA17 Depression
7.6
BA4 Control
28.9

[0852]

281

TABLE XF

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4487,

(%) Ag4487,

Run

Run

Tissue Name
268690023
Tissue Name
268690023

Colon cancer 1
0.0
Bladder cancer NAT
4.6

2

Colon cancer NAT 1
4.6
Bladder cancer NAT
0.0

3

Colon cancer 2
17.4
Bladder cancer NAT
0.0

4

Colon cancer NAT 2
4.7
Prostate
100.0

adenocarcinoma 1

Colon cancer 3
35.4
Prostate
5.4

adenocarcinoma 2

Colon cancer NAT 3
22.5
Prostate
5.5

adenocarcinoma 3

Colon malignant
5.9
Prostate
0.0

cancer 4

adenocarcinoma 4

Colon normal
6.4
Prostate cancer
12.2

adjacent tissue 4

NAT 5

Lung cancer 1
0.0
Prostate
0.0

adenocarcinoma 6

Lung NAT 1
4.5
Prostate
5.8

adenocarcinoma 7

Lung cancer 2
39.0
Prostate
0.0

adenocarcinoma 8

Lung NAT 2
0.0
Prostate
15.7

adenocarcinoma 9

Squamous cell
4.7
Prostate cancer
0.0

carcinoma 3

NAT 10

Lung NAT 3
4.3
Kidney cancer 1
5.6

metastatic melanoma 1
6.0
Kidney NAT 1
5.6

Melanoma 2
5.6
Kidney cancer 2
34.2

Melanoma 3
19.2
Kidney NAT 2
0.0

metastatic melanoma 4
0.0
Kidney cancer 3
0.0

metastatic melanoma 5
4.9
Kidney NAT 3
5.4

Bladder cancer 1
0.0
Kidney cancer 4
5.8

Bladder cancer NAT 1
0.0
Kidney NAT 4
0.0

Bladder cancer 2
0.0

[0853] CNS_neurodegeneration_v1.0 Summary: Ag4487 This panel confirms the expression of this gene at low to moderate levels in the brains of an independent group of individuals. However, no differential expression of-this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

[0854] General_screening_panel_v1.4 Summary: Ag4487 Expression of the CG116840-01 gene is highest in fetal brain (CT=27.2). In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0855] The CG116840-01 gene encodes a protein with homology to cellular retinaldehyde binding protein. Cellular retinaldehyde-binding protein (CRALBP) is a 36-kD water-soluble protein which is found only in retina and pineal gland and which carries 11-cis-retinaldehyde or 11-cis-retinal as physiologic ligands. Several of its properties suggest that it is involved in the visual process and, therefore, potentially with retinal diseases.

[0856] Among tissues with metabolic or endocrine function, this gene is expressed at low levels in adipose, thyroid, pituitary gland, fetal skeletal muscle, and fetal heart. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0857] Panel 4.1D Summary: Ag4487 Significant expression of this gene is limited to kidney (CT=32.1). Thus, expression of this gene could be used to differentiate the kidney-derived sample from the other samples on this panel and as a marker of kidney tissue. In addition, therapeutic targeting of the expression or function of this gene may modulate kidney function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney, including lupus and glomerulonephritis.

[0858] Panel CNS—1.1 Summary: Ag4487 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

[0859] general oncology screening panel_v—2.4 Summary: Ag4487 Significant expression of this gene is limited to a single prostate cancer sample (CT=34.1). Therefore, expression of this gene can potentially be used as a marker to identify prostate cancers.

[0860] Y. CG116903-01: Glutamine Repeat Containing Protein

[0861] Expression of gene CG116903-01 was assessed using the primer-probe set Ag4488, described in Table YA. Results of the RTQ-PCR runs are shown in Tables YB, YC and YD.

282TABLE YAProbe Name Ag4488StartPrimersSequencesLengthPositionSEQ ID No.Forward5′-aaaactcgggacgattttaaaa-3′221252193ProbeTET-5′-tgaagatgtttcatttctatcagtcaatca-3′-301281194TAMRAReverse5′-aagactgtgttgggtttcttga-3′221321195

[0862]

283

TABLE YB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4488,

(%) Ag4488,

Run

Run

Tissue Name
224621607
Tissue Name
224621607

AD 1 Hippo
13.3
Control (Path) 3
14.9

Temporal Ctx

AD 2 Hippo
48.3
Control (Path) 4
40.1

Temporal Ctx

AD 3 Hippo
16.4
AD 1 Occipital Ctx
25.0

AD 4 Hippo
10.4
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 hippo
74.7
AD 3 Occipital Ctx
14.4

AD 6 Hippo
76.8
AD 4 Occipital Ctx
31.4

Control 2 Hippo
50.0
AD 5 Occipital Ctx
21.0

Control 4 Hippo
10.2
AD 6 Occipital Ctx
48.6

Control (Path) 3 Hippo
10.3
Control 1 Occipital
5.3

Ctx

AD 1 Temporal Ctx
26.4
Control 2 Occipital
47.0

Ctx

AD 2 Temporal Ctx
44.4
Control 3 Occipital
22.5

Ctx

AD 3 Temporal Ctx
15.7
Control 4 Occipital
9.5

Ctx

AD 4 Temporal Ctx
27.2
Control (Path) 1
100.0

Occipital Ctx

AD 5 Inf Temporal
74.7
Control (Path) 2
10.4

Ctx

Occipital Ctx

AD 5 Sup Temporal
52.9
Control (Path) 3
4.4

Ctx

Occipital Ctx

AD 6 Inf Temporal
85.3
Control (Path) 4
13.4

Ctx

Occipital Ctx

AD 6 Sup Temporal
70.7
Control 1 Parietal
10.0

Ctx

Ctx

Control 1 Temporal
15.3
Control 2 Parietal
70.2

Ctx

Ctx

Control 2 Temporal
44.4
Control 3 Parietal
6.6

Ctx

Ctx

Control 3 Temporal
33.4
Control (Path) 1
92.7

Ctx

Parietal Ctx

Control 4 Temporal
9.9
Control (Path) 2
32.3

Ctx

Parietal Ctx

Control (Path) 1
82.9
Control (Path) 3
8.5

Temporal Ctx

Parietal Ctx

Control (Path) 2
54.0
Control (Path) 4
45.4

Temporal Ctx

Parietal Ctx

[0863]

284

TABLE YC

General—13 screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4488,

(%) Ag4488,

Run

Run

Tissue Name
222666070
Tissue Name
222666070

Adipose
1.2
Renal ca. TK-10
2.4

Melanoma*
10.7
Bladder
1.3

Hs688(A).T

Melanoma*
13.7
Gastric ca. (liver
14.1

Hs688(B).T

met.) NCI-N87

Melanoma* M14
11.8
Gastric ca. KATO III
0.0

Melanoma*
3.0
Colon ca. SW-948
0.2

LOXIMVI

Melanoma*
8.4
Colon ca. SW480
12.6

SK-MEL-5

Squamous cell
0.4
Colon ca.* (SW480
0.4

carcinoma SCC-4

met) SW620

Testis Pool
1.0
Colon ca. HT29
0.1

Prostate ca.* (bone
4.2
Colon ca. HCT-116
10.2

met) PC-3

Prostate Pool
2.0
Colon ca. CaCo-2
4.2

Placenta
2.6
Colon canecr tissue
1.6

Uterus Pool
2.3
Colon ca. SW1116
0.7

Ovarian ca.
6.4
Colon ca Colo-205
0.0

OVCAR-3

Ovarian ca.
4.1
Colon ca. SW-48
0.1

SK-OV-3

Ovarian ca.
0.6
Colon Pool
4.8

OVCAR-4

Ovarian ca
10.1
Small Intestine Pool
7.7

OVCAR-5

Ovarian ca.
5.3
Stomach Pool
2.9

IGROV-1

Ovarian ca.
2.0
Bone Marrow Pool
2.8

OVCAR-8

Ovary
2.5
Fetal Heart
2.2

Breast ca. MCF-7
10.7
Heart Pool
2.1

Breast ca. MDA-
4.9
Lymph Node Pool
4.0

MB-231

Breast ca BT 549
7.3
Fetal Skeletal Muscle
2.8

Breast ca. T47D
14.1
Skeletal Muscle Pool
0.7

Breast ca. MDA-N
2.1
Spleen Pool
1.9

Breast Pool
4.5
Thymus Pool
3.1

Trachea
3.3
CNS cancer (glio/
11.8

astro) U87-MG

Lung
1.8
CNS cancer (glio/
9.7

astro) U-118-MG

Fetal Lung
5.8
CNS cancer (neuro;
14.8

met) SK-N-AS

Lung ca NCI-N47
4.0
CNS cancer (astro)
2.9

SF-539

Lung ca. LX-1
0.2
CNS cancer (astro)
1.7

SNB-75

Lung ca. NCI-H146
18.2
CNS cancer (glio)
5.1

SNB-19

Lung ca. SHP-77
14.3
CNS cancer (glio)
11.9

SF-295

Lune ca. A549
3.6
Brain (Amygdala)
26.1

Pool

Lung ca. NCI-H526
1.4
Brain (cerebellum)
9.3

Lung ca. NCI-H23
9.0
Brain (fetal)
27.9

Lung ca. NCI-H460
2.5
Brain (Hippocampus)
42.9

Pool

Lung ca. HOP-62
3.1
Cerebral Cortex Pool
51.1

Lung ca. NCI-H522
100.0
Brain (Substantia
37.1

nigra) Pool

Liver
0.0
Brain (Thalamus) Pool
58.6

Fetal Liver
0.8
Brain (whole)
35.1

Liver ca HepG2
0.1
Spinal Cord Pool
17.1

Kidney Pool
8.8
Adrenal Gland
4.9

Fetal Kidney
8.6
Pituitary gland Pool
12.1

Renal ca 786-0
3.2
Salivary Gland
1.3

Renal ca A498
2.3
Thyroid (female)
0.7

Renal ca. ACHN
2.3
Pancreatic ca.
15.8

CAPAN2

Renal ca. UO-31
1.9
Pancreas Pool
4.0

[0864]

285

TABLE UY

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4488,

(%) Ag4488,

Run

Run

Tissue Name
195476591
Tissue Name
195476591

Secondary Th1 act
3.4
HUVEC IL-1beta
37.4

Sccondary Th2 act
5.4
HUVEC IFN gamma
62.4

Secondary Tr1 act
5.6
HUVEC TNF alpha +
13.7

IFN gamma

Secondary Th1 rest
3.5
HUVEC TNF alpha +
15.8

IL4

Secondary Th2 rest
1.8
HUVEC IL-11
28.3

Secondary Tr1 rest
3.2
Lung Microvascular
58.6

EC none

Primary Th1 act
2.3
Lung Microsvasular
65.1

EC TNFalpha +

IL-1beta

Primary Th2 act
3.6
Microvascular Dermal
43.5

EC none

Primary Tr1 act
2.1
Microvascular Dermal
39.0

EC TNFalpha +

IL-1beta

Primary Th1 rest
2.4
Bronchial
6.1

epithelium

TNFalpha + IL1beta

Primary Th2 rest
0.2
Small airway
6.1

epithelium none

Primary Tr1 rest
2.4
Small airway
8.6

epithelium

TNFalpha + IL-1beta

CD45RA CD4
16.3
Coronery artery SMC
18.0

lymphocyte act

rest

CD45RO CD4
1.0
Coronery artery SMC
18.9

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
1.7
Astrocytes rest
19.2

Secondary CDS
0.2
Astrocytes
15.9

lymphocyte rest

TNFalpha + IL-1beta

Secondary CDS
0.8
KU-812 (Basophil)
2.4

lymphocyte act

rest

CD4 lymphocyte
1.0
KU-812 (Basophil)
5.5

none

PMA/ionomycin

2ry Th1/Th2/
8.2
CCD1106
4.0

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
0.5
CCD1106
1.4

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
3.8
Liver cirrhosis
3.9

LAK cells IL-2 +
0.0
NCI-H292 none
49.0

IL-12

LAK cells IL-2 +
1.3
NCI-H292 IL-4
52.5

IFN gamma

LAK cells IL-2 +
1.1
NCI-H292 IL-9
98.6

IL-18

LAK cells
2.6
NCI-H292 IL-13
49.7

PMA/ionomycin

NK Cells IL-2 rest
2.5
NCI-H292 IFN gamma
41.5

Two Way MLR 3
1.0
HPAEC none
26.4

day

Two Way MLR 5
0.7
HPAEC TNF alpha +
32.1

day

IL-1 beta

Two Way MLR 7
1.1
Lung fibroblast none
82.4

day

PBMC rest
0.5
Lung fibroblast TNF
23.2

alpha + IL-1beta

PBMC PWM
1.6
Lung fibroblast IL-4
70.2

PBMC PHA-L
2.4
Lung fibroblast IL-9
60.7

Ramos (B cell) none
0.0
Lung fibroblast IL-13
55.5

Ramos (B cell)
0.0
Lung fibroblast IFN
100.0

ionomycin

gamma

B lymphocytes
0.5
Dermal fibroblast
37.1

PWM

CCD1070 rest

B lymphocytes
2.6
Dermal fibroblast
29.5

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
1.1
Dermal fibroblast
14.6

CCD1070 IL-1beta

EOL-1 dbcAMP
2.6
Dermal fibroblast
13.8

PMA/ionomycin

IFN gamma

Dendritic cells none
0.6
Dermal fibroblast IL-4
21.8

Dendritic cells LPS
1.9
Dermal Fibroblasts
42.6

rest

Dendritic cells
1.0
Neutrophils TNFa +
4.2

anti-CD40

LPS

Monocytes rest
0.6
Neutrophils rest
2.6

Monocytes LPS
2.0
Colon
3.5

Macrophages rest
1.0
Lung
13.2

Macrophages LPS
0.0
Thymus
22.5

HUVEC none
19.9
Kidney
21.9

HUVEC starved
24.3

[0865] CNS_neurodegeneration_v1.0 Summary: Ag4488 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

[0866] General_screening_panel_v1.4 Summary: Ag4488 Highest expression of this gene is seen in a lung cancer cell line (CT=25.8), with widespread expression seen throughout this panel. Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker of lung cancer. In addition, therapeutic modulation of the expression or function of this gene may be useful in the treatment of lung cancer.

[0867] This gene also shows high to moderate levels of expression in all regions of the CNS examined. This prominent expression suggests that this gene may be involved in CNS function and that therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0868] Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

[0869] Panel 4.1D Summary: Ag4488 This gene is widely expressed in this panel, with highest expression in IFN gamma treated lung fibroblasts (CT=30.7). In addition, prominent levels of expression are seen in treated and treated endothelial cells and fibroblasts derived from the lung and skin. Thus, expression of this gene could be used as a marker of these cell types. Furthermore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of psoriasis, asthma, emphysema, allergy and COPD.

[0870] general oncology screening panel_v—2.4 Summary: Ag4488 Results from one experiment with this gene are not included. The amp plot indicates that there were experimental difficulties with this run.

[0871] Z. CG118634-01: TNF Receptor Associated Factor 2

[0872] Expression of gene CG118634-01 was assessed using the primer-probe set Ag4499, described in Table ZA.

286TABLE ZAProbe Name Ag4499PrimersSequencesLengthStart PositionSEQ ID No.Forward5′-catgcagccacascttctg-3′19121196ProbeTET-5′-aaaagtgcatccaaaagacctgtccg-3′-TAMRA26142197Reverse5′-ttttccttttcacctctttcct-3′22174198

[0873] CNS_neurodegeneration_v1.0 Summary: Ag4499 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

[0874] General_screening_panel_v1.4 Summary: Ag4499 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

[0875] Panel 4.1D Summary: Ag4499 Expression of this gene is low/undetectable in all samples on this panel (CTs>35).

[0876] AA. CG119215-01: Vacuolar Protein Sorting Homolog

[0877] Expression of gene CG119215-01 was assessed using the primer-probe set Ag4502, described in Table AAA. Results of the RTQ-PCR runs are shown in Tables AAB, AAC and AAD.

287TABLE AAAProbe Name Ag4502StartPrimersSequencesLengthPositionSEQ ID No.Forward5′-aagtggccaatatgatgatcag-3′22662199ProbeTET-5′-caggaagccagaattcaatatttcctg-3′-27701200TAMRAReverse5′-ccgatcaagcaacaagagatta-3′22735201

[0878]

288

TABLE AAB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4502,

(%) Ag4502,

Run

Run

Tissue Name
2246704538
Tissue Name
224704538

AD 1 Hippo
10.7
Control (Path) 3
3.1

Temporal Ctx

AD 2 Hippo
24.7
Control (Path) 4
31.9

Temporal Ctx

AD 3 Hippo
4.7
AD 1 Occipital Ctx
10.7

AD 4 Hippo
3.3
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 Hippo
88.3
AD 3 Occipital Ctx
3.3

AD 6 Hippo
60.3
AD 4 Occipital Ctx
19.1

Control 2 Hippo
28.5
AD 5 Occipital Ctx
54.7

Control 4 Hippo
9.9
AD 6 Occipital Ctx
22.2

Control (Path) 3 Hippo
4.9
Control 1 Occipital
2.3

Ctx

AD 1 Temporal Ctx
11.5
Control 2 Occipital
80.7

Ctx

AD 2 Temporal Ctx
40.6
Control 3 Occipital
9.6

Ctx

AD 3 Temporal Ctx
3.6
Control 4 Occipital
3.0

Ctx

AD 4 Temporal Ctx
19.1
Control (Path) 1
76.8

Occipital Ctx

AD 5 Inf Temporal
100.0
Control (Path) 2
10.2

Ctx

Occipital Ctx

AD 5 Sup Temporal
41.8
Control (Path) 3
1.1

Ctx

Occipital Ctx

AD 6 Inf Temporal
52.1
Control (Path) 4
14.0

Ctx

Occipital Ctx

AD 6 Sup Temporal
60.7
Control 1 Parietal
3.6

Ctx

Ctx

Control 1 Temporal
5.9
Control 2 Parietal
30.6

Ctx

Ctx

Control 2 Temporal
48.3
Control 3 Parietal
24.7

Ctx

Ctx

Control 3 Temporal
11.5
Control (Path) 1
83.5

Ctx

Parietal Ctx

Control 3 Temporal
5.1
Control (Path) 2
18.3

Ctx

Parietal Ctx

Control (Path) 1
65.1
Control (Path) 3
1.7

Temporal Ctx

Parietal Ctx

Control (Path) 2
37.9
Control (Path) 4
42.3

Temporal Ctx

Parietal Ctx

[0879]

289

TABLE AAC

General_screening_panel_v1.4

Rel. Exp. (%) Ag4502,

Rel. Exp. (%) Ag4502,

Tissue Name
Run 222695220
Tissue Name
Run 222695220

Adipose
6.9
Renal Ca. TK-10
29.9

Melanoma*
21.5
Bladder
15.0

Hs688(A) T

Melanoma*
22.1
Gastric ca (liver met.)
34.4

Hs688(B) T

NCI-N87

Melanoma* M14
35.6
Gastric ca. KATO III
58.6

Melanoma* LOXIMVI
49.3
Colon ca SW-948
13.4

Melanoma* SK-MEL-5
62.4
Colon ca. SW480
66.4

Squamous cell
11.6
Colon ca.* (SW480 met)
38.7

carcinoma SCC-4

SW620

Testis Pool
15.2
Colon ca. HT29
13.1

Prostate ca.* (bone met)
56.6
Colon ca. HCT-116
46.3

PC-3

Prostate Pool
4.5
Colon ca. CaCo-2
47.3

Placenta
10.9
Colon cancer tissue
28.3

Uterus Pool
3.6
Colon ca. SW1116
3.5

Ovarian ca. OVCAR-3
33.4
Colon ca. Colo-205
17.6

Ovarian ca. SK-OV-3
38.2
Colon ca. SW-48
9.3

Ovarian ca OVCAR-4
14.8
Colon Pool
10.7

Ovarian ca. OVCAR-5
36.6
Small Intestine Pool
11.7

Ovarian ca. IGROV-1
15.1
Stomach Pool
6.0

Ovarian ca OVCAR-8
17.0
Bone Marrow Pool
3.7

Ovary
8.2
Fetal Heart
5.6

Breast ca MCF-7
33.9
Heart Pool
5.8

Breast ca. MDA-MB-
39.2
Lymph Node Pool
11.0

231

Breast ca. BT 549
36.1
Fetal Skeletal Musclc
3.3

Breast ca. T47D
100.0
Skeletal Muscle Pool
10.7

Breast ca. MDA-N
12.6
Spleen Pool
10.4

Breast Pool
11.0
Thymus Pool
11.8

Trachea
10.2
CNS cancer (glio/astro)
55.9

U87-MG

Lung
2.6
CNS cancer (glio/astro)
49.0

U-118-MG

Fetal Lung
10.2
CNS cancer (neuro, met)
56.6

SK-N-AS

Lung ca. NCI-N417
6.6
CNS cancer (astro)
13.4

SF-539

Lung ca LX-1
26.6
CNS cancer (astro) SNB-
40.9

75

Lung ca NCI-H146
16.5
CNS cancer (glio)
14.6

SNB-19

Lung ca SHP-77
59.9
CNS cancer (glio)
38.7

SF-295

Lung ca. A549
57.0
Brain (Amygdala) Pool
10.9

Lung ca. NCI-H526
10.9
Brain (cerebellum)
14.6

Lung ca. NCI-H23
47.6
Brain (fetal)
16.7

Lung ca. NCI-H460
25.9
Brain (Hippocampus)
12.2

Pool

Lung ca HOP-62
15.1
Cerebral Cortex Pool
17.2

Lung ca NCI-H522
34.9
Brain (Substantia nigra)
13.3

Pool

Liver
1.4
Brain (Thalamus) Pool
20.4

Fetal Liver
19.2
Brain (whole)
15.5

Liver ca HepG2
24.1
Spinal Cord Pool
8.4

Kidney Pool
15.1
Adrenal Gland
17.1

Fetal Kidney
8.7
Pituitary gland Pool
7.4

Renal ca 786-0
24.8
Salrvary Gland
4.3

Renal ca A498
9.1
Thyroid (female)
6.7

Renal ca. ACHN
35.4
Pancreatic ca CAPAN2
14.5

Renal ca UO-31
26.1
Pancreas Pool
13.0

[0880]

290

TABLE AAD

Panel 4.1D

Ret. Exp. (%) Ag4502,

Ret Exp. (%) Ag4502,

Tissue Name
Run 197089618
Tissue Name
Run 197089618

Secondary Th1 act
69.3
HUVEC IL-1beta
45.1

Secondary Th2 act
100.0
HUVEC IFN gamma
51.1

Secondary Tr1 act
76.3
HUVEC TNF alpha + IFN
30.1

gamma

Secondary Th1 rest
30.6
HUVEC TNF alpha + IL4
38.7

Secondary Th2 rest
49.7
HUVEC IL-11
19.1

Secondary Tr1 rest
34.4
Lung Microvascular EC none
75.8

Primary Th1 act
42.3
Lung Microvascular EC
39.2

TNFalpha + IL-1beta

Primary Th2 act
71.7
Microvascular Dermal EC
34.4

none

Primary Tr1 act
66.4
Microsvasular Dermal EC
32.5

TNFalpha + IL-1beta

Primary Th1 rest
18.9
Bronchial epithelium
40.1

TNFalpha + IL1beta

Primary Th2 rest
13.7
Small airway epithelium none
17.6

Primary Tr1 rest
56.6
Small airway epithelium
40.1

TNFalpha + IL-1beta

CD45RA CD4
54.0
Coronery artery SMC rest
19.2

lymphocyte act

CD45RO CD4
77.4
Coronery artery SMC
18.9

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
61.1
Astrocytes rest
15.8

Secondary CD8
73.2
Astrocytes TNFalpha + IL-
14.4

lymphocyte rest

1beta

Secondary CD8
25.7
KU-812 (Basophil) rest
20.3

lymphocyte act

CD4 lymphocyte none
26.1
KU-812 (Basophil)
35.6

PMA/ionomycin

2ry Th1/Th2/Tr1_anti-
55.1
CCD1106 (Keratinocytes)
60.3

CD95 CH11

none

LAK cells rest
62.9
CCD1106 (Keratinocytes)
39.5

TNFalpha + IL-1beta

LAK cells IL-2
49.0
Liver cirrhosis
6.6

LAK cells IL-2 + IL-12
28.7
NCI-H292 none
31.0

LAK cells IL-2 + IFN
27.5
NCI-H292 IL-4
38.2

gamma

LAK cells IL-2 + IL-18
37.9
NCI-H292 IL-9
60.7

LAK cells
13.6
NCI-H292 IL-13
55.5

PMA/ionomycin

NK Cells IL-2 rest
69.3
NCI-H292 IFN gamma
36.6

Two Way MLR 3 day
60.3
HPAEC none
20.2

Two Way MLR 5 day
52.9
HPAEC TNF alpha + IL-1beta
57.0

Two Way MLR 7 day
39.5
Lung fibroblast none
43.8

PBMC rest
17.0
Lung fibroblast TNF alpha +
19.6

IL-1beta

PBMC PWM
47.3
Lung fibroblast IL-4
32.1

PBMC PHA-L
44.4
Lung fibroblast IL-9
39.0

Ramos (B cell) none
47.6
Lung fibroblast IL-13
32.8

Ramos (B cell)
57.0
Lung fibroblast IFN gamma
50.3

ionomycin

B lymphocytes PWM
44.4
Dermal fibroblast CCD1070
52.1

rest

B lymphocytes CD40L
74.7
Dermal fibroblast CCD1070
82.9

and IL-4

TNF alpha

EOL-1 dbcAMP
61.1
Dermal fibroblast CCD1070
30.8

EOL-1 dbcAMP

IL-1beta

EOL-1 dbcAMP
21.3
Dermal fibroblast IFN gamma
17.6

PMA/ionomycin

Dendritic cells none
59.9
Dermal fibroblast IL-4
38.7

Dendritic cells LPS
43.2
Dermal Fibroblasts rest
33.2

Dendritic cells anti-CD40
49.0
Neutrophils TNFa + LPS
3.2

Monocytes rest
51.8
Neutrophils rest
16.8

Monocytes LPS
59.5
Colon
9.7

Macrophages rest
53.6
Lung
13.6

Macrophages LPS
34.9
Thymus
29.5

HUVEC none
28.9
Kidney
20.9

HUVEC starved
55.9

[0881] CNS_neurodegeneration_v1.0 Summary: Ag4502 This panel confirms the expression of the CG119215-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

[0882] General_screening_panel_v1.4 Summary: Ag4502 Highest expression of the CG119215-01 gene is detected in breast cancer T47D cell line (CT=27.3). Moderate levels of expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

[0883] Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0884] In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0885] Panel 4.1D Summary: Ag4502 Highest expression of the CG119215-01 gene is detected in activated secondary Th2 cells (CT-30.8). This gene is expressed at moderate to low levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and Fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General screening_panel_v1.4 and also suggests a role for the genie product in cell Survival and proliferation. Therefore, modulation of the genie product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

[0886] AB. CG121501-01 and CG121501-02: Novel Bola Domain Containing Protein

[0887] Expression of gene CG1121501-01 and full length physical clone CG121501-02 was assessed using the primer-probe set Ag4509, described in Table ABA. Results of the RTQ-PCR runs are shown in Tables ABB, ABC and ABD.

[0888] Table ABA. Probe Name Ag4509

291TABLE ABAProbe Name Ag4509StartPrimersSequencesLengthPositionSEQ ID No.Forward5′-gctggacagttctcttctcctt-3′22304202ProbeTET-5′-tca attttaattt catacatcgc ccca-3′-27339203TAMRAReverse5′-gtcactgacatttcaggaggtt-3′22367204

[0889]

292

TABLE ABB

CNS_neurodegeneration_v1.0

Rel. Exp. (%) Ag4509, Run

Rel. Exp. (%) Ag4509, Run

Tissue Name
224702764
Tissue Name
224702764

AD 1 Hippo
7.3
Control (Path) 3
5.3

Temporal Ctx

AD 2 Hippo
31.0
Control (Path) 4
21.9

Temporal Ctx

AD 3 Hippo
6.9
AD 1 Occipital Ctx
8.1

AD 4 Hippo
11.3
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 Hippo
63.7
AD 3 Occipital Ctx
5.4

AD 6 Hippo
32.3
AD 4 Occipital Ctx
18.0

Control 2 Hippo
32.1
AD 5 Occipital Ctx
43.2

Control 4 Hippo
7.7
AD 6 Occipital Ctx
17.1

Control (Path) 3 Hippo
7.3
Control 1 Occipital Ctx
5.6

AD 1 Temporal Ctx
9.2
Control 2 Occipital Ctx
68.8

AD 2 Temporal Ctx
22.7
Control 3 Occipital Ctx
18.9

AD 3 Temporal Ctx
3.2
Control 4 Occipital Ctx
5.6

AD 4 Temporal Ctx
19.3
Control (Path) 1
100.0

Occipital Ctx

AD 5 Inf Temporal Ctx
66.0
Control (Path) 2
11.8

Occipital Ctx

AD 5 Sup Temporal
37.1
Control (Path) 3
3.1

Ctx

Occipital Ctx

AD 6 Inf Temporal Ctx
27.0
Control (Path) 4
24.0

Occipital Ctx

AD 6 Sup Temporal
29.1
Control 1 Parietal Ctx
6.2

Ctx

Control 1 Temporal
7.1
Control 2 Parietal Ctx
32.5

Ctx

Control 2 Temporal
39.8
Control 3 Parietal Ctx
21.6

Ctx

Control 3 Temporal
15.9
Control (Path) 1
96.6

Ctx

Parietal Ctx

Control 3 Temporal
10.2
Control (Path) 2
30.6

Ctx

Parietal Ctx

Control (Path) 1
55.1
Control (Path) 3
4.2

Temporal Ctx

Parietal Ctx

Control (Path) 2
46.0
Control (Path) 4
73.2

Temporal Ctx

Parietal Ctx

[0890]

293

TABLE ABC

General_screening_panel_v1.4

Rel. Exp. (%) Ag4509,

Rel. Exp. (%) Ag4509,

Tissue Name
Run 222695224
Tissue Name
Run 222695224

Adipose
3.1
Renal ca. TK-10
18.6

Melanoma*
7.7
Bladder
4.4

Hs688(A).T

Melanoma*
10.6
Gastric ca (liver met.)
20.9

Hs688(B).T

NCI-N87

Melanoma* M14
24.7
Gastric ca KATO III
65.1

Melanoma* LOXIMVI
36.6
Colon ca. SW-948
18.8

Melanoma* SK-MEL-5
100.0
Colon ca. SW480
94.6

Squamous cell
14.6
Colon ca.* (SW480 met)
25.0

carcinoma SCC-4

SW620

Testis Pool
3.2
Colon ca. HT29
23.5

Prostate ca* (bone met)
32.1
Colon ca HCT-116
48.3

PC-3

Prostate Pool
1.5
Colon ca CaCo-2
22.8

Placenta
0.6
Colon cancer tissue
9.8

Uterus Pool
0.8
Colon ca. SW1116
4.1

Ovarian ca. OVCAR-3
16.7
Colon ca. Colo-205
8.1

Ovarian ca. SK-OV-3
42.6
Colon ca. SW-48
6.0

Ovarian ca. OVCAR-4
18.0
Colon Pool
1.5

Ovarian ca. OVCAR-5
16.0
Small Intestine Pool
0.9

Ovarian ca. IGROV-1
13.3
Stomach Pool
1.4

Ovarian ca. OVCAR-8
7.1
Bone Marrow Pool
0.8

Ovary
1.6
Fetal Heart
3.7

Breast ca. MCF-7
23.8
Heart Pool
3.7

Breast ca. MDA-MB-231
44.1
Lymph Node Pool
2.2

Breast ca. BT 549
19.1
Fetal Skeletal Muscle
2.4

Breast ca. T47D
32.8
Skeletal Muscle Pool
9.0

Breast ca. MDA-N
23.7
Spleen Pool
2.1

Breast Pool
1.4
Thymus Pool
2.2

Trachea
4.6
CNS Cancer (glio/astro)
30.1

U87-MG

Lung
0.5
CNS cancer (glio/astro)
32.1

U-118-MG

Fetal Lung
3.5
CNS cancer (neuro, met)
23.2

SK-N-AS

Lung ca. NCI-N417
10.0
CNS Cancer (astro)
11.2

SF-539

Lung ca. LX-1
21.8
CNS cancer (astro) SNB-
18.8

75

Lung ca. NCI-H146
6.0
CNS cancer (glio)
13.4

SNB-19

Lung ca SHP-77
25.7
CNS cancer (glio)
16.8

SF-295

Lung ca. A549
31.6
Brain (Amygdala) Pool
3.3

Lung ca. NCI-H526
6.2
Brain (cerebellum)
4.7

Lung ca. NCI-H23
37.1
Brain (fetal)
1.6

Lung ca. NCI-H460
14.6
Brain (Hippocampus)
2.6

Pool

Lung ca. HOP-62
6.7
Cerebral Cortex Pool
5.4

Lung ca. NCI-H522
16.4
Brain (Substantia nigra)
4.5

Pool

Liver
0.4
Brain (Thalamus) Pool
6.2

Fetal Liver
9.9
Brain (whole)
4.0

Liver ca HepG2
11.7
Spinal Cord Pool
3.5

Kidney Pool
1.8
Adrenal Gland
4.8

Fetal Kidney
4.0
Pituitary gland Pool
1.2

Renal ca. 786-0
9.8
Salivary Gland
2.9

Renal ca. A498
4.7
Thyroid (female)
3.1

Renal ca. ACHN
5.3
Pancreatic ca. CAPAN2
13.5

Renal ca. UO-31
8.0
Pancreas Pool
3.1

[0891]

294

TABLE ABD

Panel 4.1D

Rel. Exp. (%) Ag4509,

Rel. Exp. (%) Ag4509,

Tissue Name
Run 197488025
Tissue Name
Run 197488025

Secondary Th1 act
82.4
HUVEC IL-1beta
53.6

Secondary Th2 act
100.0
HUVEC IFN gamma
42.9

Secondary Tr1 act
84.7
HUVEC TNF alpha + IFN
35.8

gamma

Secondary Th1 rest
7.3
HUVEC TNF alpha + IL4
38.2

Secondary Th2 rest
16.5
HUVEC IL-11
19.8

Secondary Tr1 rest
5.8
Lung Microvascular EC none
43.8

Primary Th1 act
78.5
Lung Microvascular EC
35.8

INFalpha + IL-1beta

Primary Th2 act
84.7
Microvascular Dermal EC
23.5

none

Primary Tr1 act
96.6
Microsvasular Dermal EC
24.3

TNFalpha + IL-1beta

Primary Th1 rest
7.3
Bronchial epithelium
41.5

TNFalpha + IL1beta

Primary Th2 rest
4.5
Small airway epithelium none
23.2

Primary Tr1 rest
12.9
Small airway epithelium
57.4

TNFalpha + IL-1beta

CD45RA CD4
64.2
Coronery artery SMC rest
27.7

lymphocyte act

CD45RO CD4
73.7
Coronery artery SMC
30.1

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
62.0
Astrocytes rest
16.0

Secondary CD8
62.0
Astrocytes TNFalpha + IL-
19.5

lymphocyte rest

1beta

Secondary CD8
22.8
KU-812 (Basophil) rest
49.7

lymphocyte act

CD4 lymphocyte none
1.6
KU-812 (Basophil)
58.6

PMA/ionomycin

2ry Th1/Th2/Tr1_anti-
11.4
CCD1106 (Keratinocytes)

CD95 CH11

none

LAK cells rest
20.4
CCD1106 (Keratinocytes)
68.3

TNFalpha + IL-1beta

LAK cells IL-2
30.6
Liver cirrhosis
8.4

LAK cells IL-2 + IL-12
33.7
NCI-H292 none
45.1

LAK cells IL-2 + IFN
26.1
NCI-H292 IL-4
71.2

gamma

LAK cells IL-2 + IL-18
32.3
NCI-H292 IL-9
88.9

LAK cells
21.6
NCI-H292 IL-13
70.7

PMA/ionomycin

NK Cells IL-2 rest
25.7
NCI-H292 IFN gamma
88.9

Two Way MLR 3 day
20.4
HPAEC none
19.9

Two Way MLR 5 day
40.6
HPAEC INF: alpha +
38.2

IL-1beta

Two Way MLR 7 day
24.1
Lung fibroblast none
26.6

PBMC rest
1.3
Lung fibroblast TNF alpha +
17.3

IL-1beta

PBMC PWM
38.7
Lung fibroblast IL-4
31.2

PBMC PHA-L
49.0
Lung fibroblast IL-9
39.2

Ramos (B cell) none
42.3
Lung fibroblast IL-13
27.5

Ramos (B cell)
62.4
Lung fibroblast IFN gamma
40.9

ionomycin

B lymphocytes PWM
46.7
Dermal fibroblast CCD 1070
51.8

rest

B lymphocytes CD40L
19.2
Dermal Fibroblast CCD1070
62.4

and IL-4

TNF alpha

EOL-1 dbcAMP
20.3
Dermal fibroblast CCD1070
34.2

IL-1beta

EOL-1 dbcAMP
10.9
Dermal fibroblast IFN gamma
32.8

PMA/ionomycin

Dendritic cells none
24.5
Dermal fibroblast IL-4
49.0

Dendritic cells LPS
18.6
Dermal Fibroblasts rest
21.8

Dendritic cells anti-CD40
24.8
Neutrophils TNFa + LPS
0.0

Monocytes rest
1.2
Neutrophils rest
0.4

Monocytes LPS
4.2
Colon
4.6

Macrophages rest
43.2
Lung
8.8

Macrophages LPS
18.7
Thymus
5.6

HUVEC none
36.3
Kidney
21.6

HUVEC starved
43.8

[0892] CNS_neurodegeneration_v1.0 Summary: Ag4509 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

[0893] General_screening_panel_v1.4 Summary: Ag4509 Highest expression of this gene is seen in a melanoma cancer cell line (CT=27.1). This gene is widely expressed in this panel, with high to moderate expression seen in brain, colon, gastric, lung, breast, ovarian, and melanoma cancer cell lines. This expression profile suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer.

[0894] Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

[0895] This gene is also expressed at moderate to low levels levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0896] Panel 4.1D Summary: Ag4509 Highest expression of this gene is seen in secondary activated Th2 cells (CT=29.1). This gene is also expressed at moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

[0897] AC. CG121894-01: Neurotrophin Receptor-Associated Cell Death Executor (NADE) Like

[0898] Expression of full length clone CG121894-01 was assessed using the primer-probe set Ag6792, described in Table ACA. Results of the RTQ-PCR runs are shown in Tables ACB and ACC.

295TABLE ACAProbe Name Ag6792StartPrimersSequencesLengthPositionSEQ ID NoForward5′-attgcattttgacctagtctgtaagtt-3′27468205ProbeTET-5′-tgtcagaagaggactttcatcaactttca-3′-TAMRA29499206Reverse5′-ctttacagtatgcaataaacatctttcc-3′28529207

[0899]

296

TABLE ACB

CNS_neurodegeneration_v1.0

Rel. Exp. (%) Ag6792, Run

Rel. Exp. (%) Ag6792, Run

Tissue
277731714
Tissue Name
277731714

AD 1 Hippo
4.4
Control (Path) 3
1.3

Temporal Ctx

AD 2 Hippo
17.1
Control (Path) 4
16.4

Temporal Ctx

AD 3 Hippo
3.6
AD 1 Occipital Ctx
4.0

AD 4 Hippo
4.0
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 Hippo
98.6
AD 3 Occipital Ctx
3.3

AD 6 Hippo
28.7
AD 4 Occipital Ctx
10.3

Control 2 Hippo
31.9
AD 5 Occipital Ctx
58.6

Control 4 Hippo
2.6
AD 6 Occipital Ctx
35.4

Control (Path) 3 Hippo
2.9
Control 1 Occipital Ctx
1.7

AD 1 Temporal Ctx
2.2
Control 2 Occipital Ctx
86.5

AD 2 Temporal Ctx
15.6
Control 3 Occipital Ctx
6.3

AD 3 Temporal Ctx
1.1
Control 4 Occipital Ctx
2.3

AD 4 Temporal Ctx
7.8
Control (Path) 1
100.0

Occipital Ctx

AD 5 Inf Temporal Ctx
78.5
Control (Path) 2
4.4

Occipital Ctx

AD 5 Sup Temporal
7.4
Control (Path) 3
1.0

Ctx

Occipital Ctx

AD 6 Inf Temporal Ctx
28.9
Control (Path) 4
9.2

Occipital Ctx

AD 6 Sup Temporal
24.1
Control 1 Parietal Ctx
1.9

Ctx

Control 1 Temporal
1.2
Control 2 Parietal Ctx
17.4

Ctx

Control 2 Temporal
57.0
Control 3 Parietal Ctx
20.0

Ctx

Control 3 Temporal
5.4
Control (Path) 1
95.9

Ctx

Parietal Ctx

Control 3 Temporal
2.8
Control (Path) 2
21.2

Ctx

Parietal Ctx

Control (Path) 1
71.2
Control (Path) 3
1.9

Temporal Ctx

Parietal Ctx

Control (Path) 2
27.7
Control (Path) 4
39.0

Temporal Ctx

Parietal Ctx

[0900]

297

TABLE ACC

General_screening_panel_v1.6

Rel. Exp. (%) Ag6792,

Rel. Exp. (%) Ag6792,

Tissue Name
Run 277640798
Tissue Name
Run 277640798

Adipose
2.4
Renal ca. TK-10
0.0

Melanoma*
0.0
Bladder
15.7

Hs688(A) I

Melanoma*
0.0
Gastric ca. (liver met.)
0.0

Hs688(B).T

NCI-N87

Melanoma* M14
0.0
Gastric ca. KATO III
0.6

Melanoma* LOXIMVI
1.1
Colon ca. SW-948
0.0

Melanoma* SK-MEL-5
0.0
Colon ca. SW480
21.8

Squamous cell
5.6
Colon ca* (SW480 met)
33.9

carcinoma SCC-4

SW620

Testis Pool
6.0
Colon ca. HT29
0.0

Prostate ca.* (bone met)
1.0
Colon ca. HCT-116
0.0

PC-3

Prostate Pool
1.6
Colon ca CaCo-2
0.0

Placenta
0.0
Colon cancer tissue
2.7

Uterus Pool
0.7
Colon ca SW1116
0.0

Ovarian ca. OVCAR-3
10.0
Colon ca. Colo-205
0.3

Ovarian ca. SK-OV-3
1.2
Colon ca. SW-48
0.4

Ovarian ca. OVCAR-4
1.6
Colon Pool
0.5

Ovarian ca OVCAR-5
1.7
Small Intestine Pool
12.1

Ovarian ca IGROV-1
0.2
Stomach Pool
3.7

Ovarian ca. OVCAR-8
5.1
Bone Marrow Pool
1.3

Ovary
2.0
Fetal Heart
0.0

Breast ca. MCF-7
7.0
Heart Pool
2.0

Breast ca. MDA-MB-
0.8
Lymph Node Pool
3.5

231

Breast ca. BT 549
0.0
Fetal Skeletal Muscle
0.0

Breast ca. T47D
0.0
Skeletal Muscle Pool
0.0

Breast ca. MDA-N
0.0
Spleen Pool
2.9

Breast Pool
3.7
Thymus Pool
5.8

Trachea
5.0
CNS cancer (glio/astro)
11.3

U87-MG

Lung
23.5
CNS cancer (glio/astro)
2.2

U-118-MG

Fetal Lung
0.8
CNS cancer (neuro met)
3.4

SK-N-AS

Lung ca NCI-N417
0.0
CNS cancer (astro)
0.0

SF-539

Lune ca LX-1
24.8
CNS cancer (astro) SNB-
0.9

75

Lung ca. NCI-H146
17.3
CNS cancer (glio)
0.7

SNB-19

Lung ca. SHP-77
42.0
CNS cancer (glio)
0.7

SF-295

Lung ca. A549
0.0
Brain (Amygdala) Pool
51.8

Lung ca. NCI-H526
6.0
Brain (cerebellum)
100.0

Lung ca. NCI-H23
10.8
Brain (fetal)
56.6

Lung ca. NCI-H460
3.2
Brain (Hippocampus)
55.5

Pool

Lung ca. HOP-62
0.4
Cerebral Cortex Pool
90.1

Lung ca. NCI-H522
0.9
Brain (Substantia nigra)
40.9

Pool

Liver
0.6
Brain (Thalamus) Pool
91.4

Fetal Liver
0.7
Brain (whole)
36.3

Liver ca. HepG2
0.0
Spinal Cord Pool
23.7

Kidney Pool
17.2
Adrenal Gland
1.8

Fetal Kidney
5.3
Pituitary gland Pool
6.2

Renal ca. 786-0
0.8
Salivary Gland
3.8

Renal ca. A498
0.0
Thyroid (female)
16.0

Renal ca ACHN
1.5
Pancreatic ca CAPAN2
3.5

Renal ca UO-31
0.0
Pancreas Pool
5.6

[0901] CNS_neurodegeneration_v1.0 Summary: Ag6792 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.6 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

[0902] General_screening_panel_v1.6 Summary: Ag6792 Expression of the CG121894-01 gene is highest in cerebellum (CT=31.2). In addition, this gene is expressed at significant levels in all other regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Interestingly, expression of this gene also appears to be downregulated in CNS cancer cell lines relative to normal brain tissues. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of brain cancer.

[0903] The CG121894-01 gene encodes a protein with homology to neurotrophin receptor-associated cell death executor (NADE) protein. The NADE protein was identified based on its interaction with p75NTR, a low affinity neurotrophin receptor that mediates cell survival as well as cell death of neural cells by NGF and other neurotrophins [J. Mukai et al., J. Biol. Chem. 275: 17566-17570, 2000, PubMed ID: 10764727]. NADE is the first signaling adaptor molecule identified in the involvement of p75NTR-mediated apoptosis induced by NGF, and it may play an important role in the pathogenesis of neurogenetic diseases.

[0904] Panel 4.1D Summary: Ag6792 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0905] AD. CG121954-01: RAL Guanine Nucleotide Dissociation Stimulator-Like Protein

[0906] Expression of gene CG121954-01 was assessed using the primer-probe set Ag6805, described in Table ADA.

298TABLE ADAProbe Name Ag6805PrimersSequencesLengthStart PositionSEQ ID NoForward5′-atctcatcctgcctcaggaa-3′20450208ProbeTET-5′-ctcctttcccaggatcaaggcca-3′-TAMRA23495209Reverse5′-gcccgtgcaatcttcct-3′17523210

[0907] CNS_neurodegeneration_v1.0 Summary: Ag6805 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0908] General_screening_panel_v1.6 Summary: Ag6805 Results from one experiment with this gene are not included. The amp plot indicates that there were experimental difficulties with this run.

[0909] Panel 4.1D Summary: Ag6805 Expression of this gene is low/undetectable (CTs>35) across all of the samples on this panel.

[0910] AE. CG122816-01: Novel Intracellular Protein

[0911] Expression of gene CG122816-01 was assessed using the primer-probe set Ag4539, described in Table AEA. Results of the RTQ-PCR runs are shown in Tables AEB, AEC and AED.

299TABLE AEAProbe Name Ag4539PrimersSequencesLengthStart PositionSEQ ID NoForward5′-gcacacgggaataacctt-3′191128211ProbeTET-5′-tctccagcttccagtgtgaactgaga-3′-TAMRA261147212Reverse5′-aagatcccagcttctccaaag-3′211193213

[0912]

300

TABLE AEB

CNS_neurodegeneration_v1.0

Rel. Exp. (%) Ag4539, Run

Rel. Exp. (%) Ag4539, Run

Tissue Name
224710156
Tissue Name
224710156

AD 1 Hippo
16.2
Control (Path) 3
3.5

Temporal Ctx

AD 2 Hippo
29.5
Control (Path) 4
42.6

Temporal Ctx

AD 3 Hippo
5.1
AD 1 Occipital Ctx
16.6

AD 4 Hippo
10.7
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 hippo
100.0
AD 3 Occipital Ctx
4.1

AD 6 Hippo
55.9
AD 4 Occipital Ctx
21.6

Control 2 Hippo
34.2
AD 5 Occipital Ctx
24.8

Control 4 Hippo
5.5
AD 6 Occipital Ctx
67.8

Control (Path) 3 Hippo
5.4
Control 1 Occipital
4.7

Ctx

AD 1 Temporal Ctx
10.4
Control 2 Occipital
90.1

Ctx

AD 2 Temporal Ctx
31.0
Control 3 Occipital
17.6

Ctx

AD 3 Temporal Ctx
5.8
Control 4 Occipital
3.9

Ctx

AD 4 Temporal Ctx
21.6
Control (Path) 1
79.0

Occipital Ctx

AD 5 Inf Temporal Ctx
95.3
Control (Path) 2
13.2

Occipital Ctx

AD 5 Sup Temporal Ctx
32.3
Control (Path) 3
5.6

Occipital Ctx

AD 6 Inf Temporal Ctx
33.2
Control (Path) 4
18.2

Occipital Ctx

AD 6 Sup Temporal Ctx
41.5
Control 1 Parietal Ctx
5.5

Control 1 Temporal Ctx
2.6
Control 2 Parietal Ctx
30.6

Control 2 Temporal Ctx
61.6
Control 3 Parietal Ctx
24.5

Control 3 Temporal Ctx
20.0
Control (Path) 1
82.9

Parietal Ctx

Control 4 Temporal Ctx
9.4
Control (Path) 2
21.5

Parietal Ctx

Control (Path) 1
62.4
Control (Path) 3
4.3

Temporal Ctx

Parietal Ctx

Control (Path) 2
48.6
Control (Path) 4
54.3

Temporal Ctx

Parietal Ctx

[0913]

301

TABLE AEC

General_screening_panel_v1.4

Rel. Exp. (%) Ag4539,

Rel. Exp. (%) Ag4539,

Tissue Name
Run 222735580
Tissue Name
Run 222735580

Adipose
2.2
Renal ca. TK-10
6.2

Melanoma*
6.1
Bladder
7.2

Hs688(B).T

Melanoma*
2.9
Gastric ca. (liver met.)
20.3

Hs688(B).T

NCI-N87

Melanoma* M14
1.2
Gastric ca KATO III
1.3

Melanoma* LOXIMVI
2.1
Colon ca SW-948
0.0

Melanoma* SK-MEL-5
9.0
Colon ca SW480
2.7

Sqnamous cell
0.3
Colon ca.* (SW480 met)
1.2

carcinoma SCC-4

SW620

Testis Pool
1.9
Colon ca. HT29
0.3

Prostate ca.* (bone met)
1.0
Colon ca. HCT-116
6.9

PC-3

Prostate Pool
0.3
Colon ca. CaCo-2
0.5

Placenta
1.0
Colon cancer tissue
0.5

Uterus Pool
0.2
Colon ca SW1116
0.6

Ovarian ca. OVCAR-3
6.5
Colon ca Colo-205
0.5

Ovarian ca. SK-OV-3
11.9
Colon ca SW-48
0.1

Ovarian ca. OVCAR-4
0.8
Colon Pool
4.4

Ovarian ca. OVCAR-5
8.1
Small Intestine Pool
4.6

Ovarian ca IGROV-1
0.8
Stomach Pool
2.2

Ovarian ca OVCAR-8
32.3
Bone Marrow Pool
5.4

Ovary
3.1
Fetal Heart
1.2

Breast ca. MCF-7
4.7
Heart Pool
2.1

Breast ca. MDA MB-
34.4
Lymph Node Pool
10.6

231

Breast ca. BT 549
3.8
Fetal Skeletal Muscle
2.6

Breast ca. T47D
9.9
Skeletal Muscle Pool
0.8

Breast ca. MDA-N
1.6
Spleen Pool
1.1

Breast Pool
4.6
Thymus Pool
1.8

Trachea
2.6
CNS cancer (glio/astro)
2.1

U87-MG

Lung
2.0
CNS cancer (glio/astro) U-
5.7

118-MG

Fetal Lung
9.8
CNS cancer (neuro, met)
2.4

SK-N-AS

Lung ca. NCI-N417
18.2
CNS cancer (astro) SF-539
10.7

Lung ca. LX-1
7.2
CNS cancer (astro) SNB-
94.0

75

Lung ca. NCI-H146
0.9
CNS cancer (glio) SNB-19
19.8

Lung ca. SHP-77
0.2
CNS cancer (glio) SF-295
15.7

Lung ca. A549
1.8
Brain (Amygdala) Pool
40.1

Lung ca. NCI-H526
24.3
Brain (cerebellum)
79.0

Lung ca. NCI-H23
44.4
Brain (fetal)
100.0

Lung ca NCI-H460
2.7
Brain (Hippocampus) Pool
46.0

Lung ca HOP-62
4.4
Cerebral Cortex Pool
85.9

Lung ca. NCI-H522
90.8
Brain (Substantia nigra)
89.5

Pool

Liver
0.0
Brain (Thalamus) Pool
62.9

Fetal Liver
1.5
Brain (whole)
55.1

Liver ca. HepG2
1.7
Spinal Cord Pool
12.3

Kidney Pool
10.4
Adrenal Gland
3.9

Fetal Kidney
5.6
Pituitary gland Pool
19.9

Renal ca. 786-0
2.1
Salivary Gland
1.6

Renal ca. A498
0.3
Thyroid (female)
1.1

Renal ca. ACHN
1.8
Pancreatic ca CAPAN2
2.3

Renal ca. UO 31
1.4
Pancreas Pool
6.6

[0914]

302

TABLE AED

Panel 4.1D

Rel. Exp. (%) Ag4539,

Rel. Exp. (%) Ag4539,

Tissue Name
Run 198385044
Tissue Name
Run 198385044

Secondary Th1 act
20.3
HUVEC IL-1beta
1.2

Secondary Th2 act
15.3
HUVEC IFN gamma
29.9

Seeondary Tr1 act
16.3
HUVEC TNF alpha + IFN
1.9

gamma

Secondary Th1 rest
10.4
HUVEC TNF alpha + IL4
5.9

Secondary Th2 rest
5.1
HUVEC IL-11
1.7

Secondary Tr1 rest
13.2
Lung Microvascular EC none
30.4

Primary Th1 act
14.0
Lung Microvascular EC
11.5

TNFalpha + IL-1beta

Primary Th2 act
47.3
Microvascular Dermal EC
5.6

none

Primary Tr1 act
30.1
Microsvascular Dermal EC
5.0

TNFalpha + IL-1beta

Primary Th1 rest
0.0
Bronchial epithelium
4.5

TNFalpha + IL1beta

Primary Th2 rest
0.0
Small airway epithelium none
2.4

Primary Tr1 rest
17.0
Small airway epithelium
7.3

TNFalpha + IL-1beta

CD45RA CD4
6.0
Coronery artery SMC rest
2.6

lymphocyte act

CD45RO CD4
32.8
Coronery artery SMC
5.1

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
10.9
Astrocytes rest
15.2

Secondary CD8
17.8
Astrocytes TNFalpha + IL-
10.9

lymphocyte rest

1beta

Secondary CD8
0.0
KU-812 (Basophil) rest
4.4

lymphocyte act

CD4 lymphocyte none
7.6
KU-812 (Basophil)
0.0

PMA/ionomycin

2ry Th1/Th2/Tr1_anti-
13.9
CCD1106 (Keratinocytes)
0.0

CD95 CH11

none

LAK cells rest
24.1
CCD1106 (Keratinocytes)
3.7

TNFalpha + IL-1beta

LAK cells IL-2
24.3
Liver cirrhosis
0.0

LAK cells IL-2 + IL-12
9.3
NCI-H292 none
6.9

LAK cells IL-2 + IFN
9.5
NCI-H292 IL-4
8.2

gamma

LAK cells IL-2 + IL-18
20.0
NCI-H292 IL-9
22.1

LAK cells
39.0
NCI-H292 IL-13
7.5

PMA/ionomycin

NK Cells IL-2 rest
12.6
NCI-H292 IFN gamma
6.8

Two Way MLR 3 day
6.9
HPAEC none
14.5

Two Way MLR 5 day
11.3
HPAEC TNF alpha +
5.0

IL-1beta

Two Way MLR 7 day
2.7
Lung fibroblast none
21.3

PBMC rest
0.0
Lung fibroblast INF alpha +
0.0

IL-1beta

PBMC PWN
9.6
Lung fibroblast IL-4
21.2

PBMC PHA-L
7.3
Lung fibroblast IL-9
22.5

Ramos (B cell) none
5.1
Lung fibroblast IL-13
25.9

Ramos (B cell)
2.9
Lung fibroblast IFN gamma
7.4

ionomycin

B lymphocytes PWM
5.1
Dermal fibroblast CCD1070
15.1

rest

B lymphocytes CD40L
12.2
Dermal fibroblast CCD1070
41.8

and IL-4

TNF alpha

EOL-1 dbcAMP
22.4
Dermal fibroblast CCD1070
14.2

IL-1beta

EOL-1 dbcAMP
9.7
Dermal fibroblast IFN gamma
6.9

PMA/ionomycin

Dendritic cells none
23.5
Dermal fibroblast IL-4
11.3

Dendritic cells LPS
21.0
Dermal Fibroblasts rest
0.0

Dendritic cells anti-CD40
25.2
Neutrophils TNFa + LPS
7.0

Monocytes rest
14.8
Neutrophils rest
19.8

Monocytes LPS
53.2
Colon
13.1

Macrophages rest
15.1
Lung
15.0

Macrophages LPS
4.2
Thymus
23.7

HUVEC none
14.9
Kidney
100.0

HUVEC starved
6.4

[0915] CNS_neurodegeneration_v1.0 Summary: Ag4539 This panel confirms the expression of this gene at low levels in the brain in an independent group of individuals. This gene is found to be down-regulated in the temporal cortex of Alzheimer's disease patients. Therefore, up-regulation of this gene or its protein product, or treatment with specific agonists for this receptor may be of use in reversing the dementia, memory loss, and neuronal death associated with this disease.

[0916] General_screening panel_v1.4 Summary: Ag4539 Highest expression of this gene is seen in fetal brain (CT=30). Moderate levels of expression are also seen throughout the CNS, including hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0917] Low but significant expression is seen in pancreas suggesting a role for this protein product in metabolic disease.

[0918] Moderate levels of expression are also seen in cell lines derived from brain, lung, breast, and ovary cancers.

[0919] Panel 4.1D Summary: Ag4539 Highest expression of this gene is detected in the kidney (CT=33.3). Thus, expression of this gene could be used to differentiate the kidney derived sample from other samples on this panel and as a marker of kidney tissue. In addition, therapeutic targeting of the expression or function of this gene may modulate kidney function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney, including lupus and glomerulonephritis.

[0920] AF. CG122825-01: Protein Phosphatase Inhibitor 2 Like

[0921] Expression of gene CG122825-01 was assessed using the primer-probe set Ag4540, described in Table AFA. Results of the RTQ-PCR runs are shown in Tables AFB, AFC and AFD.

303TABLE AFAProbe Name Ag4540PrimersSequencesLengthStart PositionSEQ ID NoForward5′-acatatcgtccagcagacaaa-3′21172214ProbeTET-5′-tgaaaatagatgaacaaagcactcct-3′-TAMRA26206215Reverse5′-tcatcacccatcgtactatgg-3′21234216

[0922]

304

TABLE AFB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4540,

(%) Ag4442,

Run

Run

Tissue Name
224710778
Tissue Name
224710778

AD 1 Hippo
13.4
Control (Path) 3
3.3

Temporal Ctx

AD 2 Hippo
43.8
Control (Path) 4
26.2

Temporal Ctx

AD 3 Hippo
20.2
AD 1 Occipital Ctx
15.3

AD 4 Hippo
11.7
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 Hippo
79.6
AD 3 Occipital Ctx
32.5

AD 6 Hippo
100.0
AD 4 Occipital Ctx
30.1

Control 2 Hippo
43.2
AD 5 Occipital Ctx
42.6

Control 4 Hippo
26.4
AD 6 Occipital Ctx
19.3

Control (Path) 3
8.1
Control 1 Occipital
16.8

Hippo

Ctx

AD 1 Temporal Ctx
23.8
Control 2 Occipital
55.9

Ctx

AD 2 Temporal Ctx
47.0
Control 3 Occipital
25.7

Ctx

AD 3 Temporal Ctx
15.4
Control 4 Occipital
24.0

Ctx

AD 4 Temporal Ctx
18.2
Control (Path) 1
90.8

Occipital Ctx

AD 5 Inf Temporal
85.3
Control (Path) 2
12.1

Ctx

Occipital Ctx

AD 5 Sup Temporal
67.4
Control (Path) 3
4.9

Ctx

Occipital Ctx

AD 6 Inf Temporal
76.3
Control (Path) 4
16.5

Ctx

Occipital Ctx

AD 6 Sup Temporal
78.5
Control 1 Parietal
18.3

Ctx

Ctx

Control 1 Temporal
5.0
Control 2 Parietal
48.0

Ctx

Ctx

Control 2 Temporal
60.3
Control 3 Parietal
11.1

Ctx

Ctx

Control 3 Temporal
21.3
Control (Path) 1
86.5

Ctx

Parietal Ctx

Control 3 Temporal
13.4
Control (Path) 2
31.9

Ctx

Parietal Ctx

Control (Path) 1
79.0
Control (Path) 3
5.8

Temporal Ctx

Parietal Ctx

Control (Path) 2
57.4
Control (Path) 4
45.1

Temporal Ctx

Parietal Ctx

[0923]

305

TABLE AFC

General_screening_panel_v1.4

Rel. Exp.

Rel. Exp.

(%) Ag4540,

(%) Ag4540,

Run

Run

Tissue Name
222735628
Tissue Name
222735628

Adipose
2.8
Renal ca. TK-10
8.7

Melanoma*
6.9
Bladder
6.4

Hs688(A).T

Melanoma*
7.7
Gastric ca. (liver met.)
16.2

Hs688(B).T

NCI-N87

Melanoma* M14
15.1
Gastric ca. KATO III
23.8

Melanoma*
6.9
Colon ca SW-948
3.2

LOXIMVI

Melanoma*
11.3
Colon ca. SW480
100.0

SK-MEL-5

Squamous cell
6.7
Colon ca.* (SW480
12.2

carcinoma SCC-4

met) SW620

Testis Pool
17.0
Colon ca. HT29
4.8

Prostate ca.* (bone
17.7
Colon ca. HCT-116
11.0

met) PC-3

Prostate Pool
2.2
Colon ca. CaCo-2
7.1

Placenta
1.4
Colon cancer tissue
6.7

Uterus Pool
1.0
Colon ca. SW1116
1.5

Ovarian ca.
4.6
Colon ca. Colo-205
6.3

OVCAR-3

Ovarian ca.
7.3
Colon ca. SW-48
4.9

SK-OV-3

Ovarian ca.
3.5
Colon Pool
7.8

OVCAR-4

Ovarian ca.
9.6
Small Intestine Pool
3.3

OVCAR-5

Ovarian ca.
5.5
Stomach Pool
2.4

IGROV-1

Ovarian ca
2.2
Bone Marrow Pool
1.4

OVCAR-8

Ovary
3.3
Fetal Heart
5.0

Breast ca MCF-7
20.2
Heart Pool
2.7

Breast ca. MDA-
8.5
Lymph Node Pool
5.9

MB-231

Breast ca. BT 549
11.0
Fetal Skeletal Muscle
2.8

Breast ca. T47D
41.2
Skeletal Muscle Pool
8.4

Breast ca. MBA-N
4.7
Spleen Pool
4.2

Breast Pool
4.8
Thymus Pool
5.8

Trachea
6.0
CNS cancer (glio/
7.8

astro) U87-MG

Lung
1.9
CNS cancer (glio/
9.3

astro) U-118-MG

Fetal Lung
16.3
CNS cancer (neuro;
6.9

met) SK-N-AS

Lung ca. NCI-N417
1.1
CNS cancer (astro)
11.1

SF-539

Lung ca. LX-1
12.3
CNS cancer (astro)
18.2

SNB-75

Lung ca NCI-H146
2.5
CNS cancer (glio)
4.8

SNB-19

Lung ca. SHP-77
2.2
CNS cancer (glio)
20.9

SF-295

Lung ca. A549
4.5
Brain (Amygdala)
3.8

Pool

Lung ca. NCI-H526
5.9
Brain (cerebellum)
3.3

Lung ca. NCI-H23
9.4
Brain (fetal)
3.0

Lung ca. NCI-H460
1.9
Brain (Hippocampus)
5.3

Pool

Lung ca. HOP-62
8.6
Cerebral Cortex Pool
7.9

Lung ca. NCI-H522
10.4
Brain (Substantia
6.9

nigra) Pool

Liver
0.7
Brain (Thalamus) Pool
11.7

Fetal Liver
1.4
Brain (whole)
5.3

Liver ca HepG2
3.6
Spinal Cord Pool
8.8

Kidney Pool
4.1
Adrenal Gland
4.4

Fetal Kidney
4.5
Pituitary gland Pool
2.4

Renal ca. 786-0
2.6
Salivary Gland
2.0

Renal ca. A498
4.8
Thyroid (female)
4.1

Renal ca. ACHN
3.8
Pancreatic ca.
3.8

CAPAN2

Renal ca. UO-31
0.5
Pancreas Pool
12.1

[0924]

306

TABLE AFD

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4540,

(%) Ag4540

Run

Run

Tissue Name
198385046
Tissue Name
198385046

Secondary Th1 act
35.8
HUVEC IL-1beta
9.3

Secondary Th2 act
49.3
HUVEC IFN gamma
9.2

Secondary Tr1 act
43.5
HUVEC TNF alpha +
11.4

IFN gamma

Secondary Th1 rest
50.3
HUVEC TNF alpha +
6.5

IL4

Secondary Th2 rest
59.0
HUVEC IL-11
5.8

Secondary Tr1 rest
68.8
Lung Microvascular
13.5

EC none

Primary Th1 act
24.5
Lung Microvascular
14.4

EC TNFalpha +

IL-1beta

Primary Th2 act
44.8
Microvascular Dermal
12.2

EC none

Primary Tr1 act
35.1
Microsvasular Dermal
12.5

EC TNFalpha +

IL-1beta

Primary Th1 rest
23.7
Bronchial epithelium
10.7

TNFalpha + IL1beta

Primary Th2 rest
16.6
Small airway
7.1

epithelium none

Primary Tr1 rest
9.5
Small airway
13.3

epithelium

TNFalpha + IL-1beta

CD45RA CD4
19.6
Coronery artery SMC
13.2

lymphocyte act

rest

CD45RO CD4
77.9
Coronery artery SMC
22.5

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
31.0
Astrocytes rest
9.7

Secondary CD8
47.0
Astrocytes
7.7

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
25.9
KU-812 (Basophil)
4.1

lymphocyte act

rest

CD4 lymphocyte
30.1
KU-812 (Basophil)
13.4

none

PMA/ionomycin

2ry Th1/Th2/
51.4
CCD1106
7.9

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
32.8
CCD1106
7.5

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
27.5
Liver cirrhosis
5.7

LAK cells IL-2 +
38.4
NCI-H292 none
10.2

IL-12

LAK cells IL-2 +
23.8
NCI-H292 IL-4
9.7

IFN gamma

LAK cells IL-2 +
12.9
NCI-H292 IL-9
14.9

IL-18

LAK cells
21.2
NCI-H292 IL-13
12.9

PMA/ionomycin

NK Cells IL-2 rest
40.6
NCI-H292 IFN gamma
10.7

Two Way MLR 3
34.2
HPAEC none
7.1

day

Two Way MLR 5
33.7
HPAEC TNF alpha +
15.6

day

IL-1 beta

Two Way MLR 7
25.0
Lung fibroblast none
13.7

day

PBMC rest
29.3
Lung fibroblast TNF
14.8

alpha + IL-1 beta

PBMC PWM
41.8
Lung fibroblast IL-4
7.6

PBMC PHA-L
40.3
Lung fibroblast IL-9
14.0

Ramos (B cell) none
52.5
Lung fibroblast IL-13
16.6

Ramos (B cell)
57.0
Lung fibroblast IFN
26.8

ionomycin

gamma

B lymphocytes
20.0
Dermal fibroblast
17.1

PWM

CCD1070 rest

B lymphocytes
20.0
Dermal fibroblast
29.5

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
8.1
Dermal fibroblast
7.3

CCD1070 IL-1beta

EOL-1 dbcAMP
7.7
Dermal fibroblast IFN
7.2

PMA/ionomycin

gamma

Dendritic cells none
19.2
Dermal fibroblast IL-4
20.9

Dendritic cells LPS
18.7
Dermal Fibroblasts
4.9

rest

Dendritic cells
8.4
Neutrophils TNFa +
12.3

anti CD40

LPS

Monocytes rest
19.8
Neutrophils rest
52.1

Monocytes LPS
17.1
Colon
4.2

Macrophages rest
20.3
Lung
12.2

Macrophages LPS
9.3
Thymus
51.1

HUVEC none
8.7
Kidney
100.0

HUVEC starved
9.4

[0925] CNS_neurodegeneration_v1.0 Summary: Ag4540 This panel confirms the expression the CG122825-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

[0926] General_screening_panel_v1.4 Summary: Ag4540 Highest expression of the CG122825-01 gene is detected in Colon cancer SW480 cell line (CT=30.6). Low levels of expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

[0927] Among tissues with metabolic or endocrine function, this gene is expressed at low levels in pancreas, skeletal muscle, and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0928] In addition, this gene is expressed at low levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0929] Panel 4.1 D Summary: Ag4540 Highest expression of the CG122825-01 gene is detected in kidney (CT=33.5). Therefore, expression of this gene may be used to differentiate kidney from other samples used in this panel. In addition therapeutic modulation of the protein encoded by this gene may be useful in the treatment of autoimmune and inflammatory diseases that affect kidney including lupus erythematosus and glomerulonephritis.

[0930] In addition, low levels of expression of this gene is also seen in thymus, resting neutrophils, Ramos (B) cells, PBMC cells, activated CD45RO CD4 lymphocyte, secondary Th1, Th2 and Tr1 cells, secondary CD8 lymphocytes, and 11.2 treated NK cells. Therefore, therapeutic modulation of the protein encoded by this gene may be useful in the treatment of autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel

[0931] AG. CG122843-01 and CG122843-02: Armadillo/Beta-Catenin-Like Repeat Containing Protein

[0932] Expression of gene CG122843-01 and full length physical clone CG122843-02 was assessed using the primer-probe set Ag4541, described in Table AGA. Results of the RTQ-PCR runs are shown in Tables AGB, AGC and AGD.

307TABLE AGAProbe Name Ag4541PrimersSequencesLengthStart PositionSEQ ID NoForward5′-aacagtgtcaaaacccaaqct-3′21369217ProbeTET-5′-cacttaaagctttctctggcatcaga-3′-TAMRA26397218Reverse5′-cctggattttgagcctgaat-3′20425219

[0933]

308

TABLE AGB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4541,

(%) Ag4541,

Run

Run

Tissue Name
224710779
Tissue Name
224710779

AD 1 Hippo
50.7
Control (Path) 3
18.3

Temporal Ctx

AD 2 Hippo
52.9
Control (Path) 4
21.8

Temporal Ctx

AD 3 Hippo
20.2
AD 1 Occipital
44.8

Ctx

AD 4 Hippo
19.6
AD 2 Occipital
0.0

Ctx (Missing)

AD 5 hippo
31.9
AD 3 Occipital
24.8

Ctx

AD 6 Hippo
100.0
AD 4 Occipital
38.7

Ctx

Control 2 Hippo
31.6
AD 5 Occipital
20.3

Ctx

Control 4 Hippo
84.7
AD 6 Occipital
23.3

Ctx

Control (Path) 3 Hippo
23.7
Control 1
6.0

Occipital Ctx

AD 1 Temporal Ctx
31.6
Control 2
42.0

Occipital Ctx

AD 2 Temporal Ctx
36.6
Control 3
31.0

Occipital Ctx

AD 3 Temporal Ctx
18.8
Control 4
22.1

Occipital Ctx

AD 4 Temporal Ctx
48.6
Control (Path) 1
81.2

Occipital Ctx

AD 5 Inf Temporal Ctx
73.2
Control (Path) 2
13.5

Occipital Ctx

AD 5 SupTemporal Ctx
63.3
Control (Path) 3
12.2

Occipital Ctx

AD 6 Inf Temporal Ctx
94.6
Control (Path) 4
10.7

Occipital Ctx

AD 6 Sup Temporal Ctx
36.9
Control 1 Parietal
16.4

Ctx

Control 1 Temporal Ctx
16.8
Control 2 Parietal
70.7

Ctx

Control 2 Temporal Ctx
43.8
Control 3 Parietal
14.8

Ctx

Control 3 Temporal Ctx
22.8
Control (Path) 1
34.4

Parietal Ctx

Control 4 Temporal Ctx
29.3
Control (Path) 2
34.2

Parietal Ctx

Control (Path) 1
47.3
Control (Path) 3
6.6

Temporal Ctx

Parietal Ctx

Control (Path) 2
22.2
Control (Path) 4
38.4

Temporal Ctx

Parietal Ctx

[0934]

309

TABLE AGC

General_screening_panel_v1.4

Rel. Exp. (%)

Rel. Exp. (%)

Ag4541, Run

Ag4541, Run

Tissue Name
222809242
Tissue Name
222809242

Adipose
0.4
Renal ca. TK-10
1.5

Melanoma*Hs688(A).T
0.5
Bladder
0.7

Melanoma* Hs688(B).T
0.0
Gastric ca. (liver met)
0.4

NCI-N87

Melanoma* M14
0.3
Gastric ca. KATO III
0.0

Melanoma* LOXIMVI
0.1
Colon ca. SW-948
0.0

Melanoma* SK-MEL-5
2.0
Colon ca. SW480
0.5

Squamous cell carcinoma
0.0
Colon ca.* (SW480 met)
0.4

SCC-4

SW620

Testis Pool
28.5
Colon ca. HT29
0.2

Prostate ca.* (bone met) PC-3
2.9
Colon ca. HCT-116
0.6

Prostate Pool
0.8
Colon ca. CaCo-2
0.3

Placenta
0.1
Colon cancer tissue
0.0

Uterus Pool
0.3
Colon ca. SW1116
0.1

Ovarian ca. OVCAR-3
0.8
Colon ca. Colo-205
0.1

Ovarian ca. SK-OV-3
0.2
Colon ca. SW-48
0.1

Ovarian ca. OVCAR-4
0.1
Colon Pool
0.7

Ovarian ca. OVCAR-5
3.3
Small Intestine Pool
1.4

Ovarian ca. IGROV-1
0.9
Stomach Pool
0.2

Ovarian ca. OVCAR-8
0.2
Bone Marrow Pool
0.3

Ovary
1.0
Fetal Heart
0.1

Breast ca. MCF-7
0.3
Heart Pool
0.3

Breast ca. MDA-MB-231
1.9
Lymph Node Pool
1.4

Breast ca. BT 549
0.0
Fetal Skeletal Muscle
0.4

Breast ca. T47D
6.7
Skeletal Muscle Pool
0.8

Breast ca. MDA-N
0.3
Spleen Pool
1.1

Breast Pool
0.5
Thymus Pool
1.8

Trachea
0.4
CNS cancer (glio/astro)
0.6

U87-MG

Lung
0.8
CNS cancer (glio/astro)
0.7

U-118-MG

Fetal Lung
0.4
CNS cancer (neuro; met)
3.0

SK-N-AS

Lung ca. NCI-N417
0.1
CNS cancer (astro) SF-
0.3

539

Lung ca. LX-1
0.4
CNS cancer (astro) SNB-
0.7

75

Lung ca. NCI-I1146
0.1
CNS cancer (glio) SNB-
1.1

19

Lung ca. SHP-77
0.3
CNS cancer (glio) SF-
2.3

295

Lung ca. A549
1.2
Brain (Amygdala) Pool
0.7

Lung ca. NCI-H526
0.0
Brain (cerebellum)
0.3

Lung ca. NCI-H23
7.9
Brain (fetal)
3.6

Lung ca. NCI-H460
0.9
Brain (Hippocampus)
1.5

Pool

Lung ca. HOP-62
1.6
Cerebral Cortex Pool
0.9

Lung ca. NCI-H522
100.0
Brain (Substantia nigra)
0.6

Pool

Liver
0.1
Brain (Thalamus) Pool
1.3

Fetal Liver
0.0
Brain (whole)
0.4

Liver ca. HepG2
1.1
Spinal Cord Pool
1.8

Kidney Pool
3.2
Adrenal Gland
0.6

Fetal Kidney
2.0
Pituitary gland Pool
1.5

Renal ca. 786-0
0.2
Salivary Gland
0.1

Renal ca. A498
0.5
Thyroid (female)
0.1

Renal ca. ACHN
1.7
Pancreatic ca. CAPAN2
0.0

Renal ca. UO-31
0.8
Pancreas Pool
1.2

[0935]

310

TABLE AGD

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4541,

(%) Ag4541,

Run

Run

Tissue Name
198395741
Tissue Name
1983395741

Secondary Th1 act
6.0
HUVEC IL-1beta
13.0

Secondary Th2 act
8.8
HUVEC IFN gamma
9.7

Secondary Tr1 act
0.0
HUVEC TNF alpha +
2.3

IFN gamma

Secondary Th1 rest
23.0
HUVEC TNF alpha +
2.2

IL4

Secondary Th2 rest
6.0
HUVEC IL-11
9.6

Secondary Tr1 rest
11.8
Lung Microvascular
13.5

EC none

Primary Th1 act
10.3
Lung Microvascular
19.3

EC TNFalpha +

IL-1beta

Primary Th2 act
7.6
Microvascular Dermal
19.2

EC none

Primary Tr1 act
16.6
Microsvasular Dermal
9.9

EC TNFalpha +

IL-1beta

Primary Th1 rest
2.8
Bronchial epithelium
13.3

TNFalpha + IL1beta

Primary Th2 rest
10.4
Small airway
3.5

epithelium none

Primary Tr1 rest
8.1
Small airway
16.2

epithelium

TNFalpha + IL-1beta

CD45RA CD4
8.7
Coronery artery SMC
5.5

lymphocyte act

rest

CD45RO CD4
30.1
Coronery artery SMC
8.7

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
17.6
Astrocytes rest
27.7

Secondary CD8
25.9
Astrocytes
7.2

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
18.0
KU-812 (Basophil)
2.1

lymphocyte act

rest

CD4 lymphocyte
21.2
KU-812 (Basophil)
6.6

none

PMA/ionomycin

2ry Th1/Th2/
13.5
CCD1106
14.7

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
1.9
CCD1106
13.2

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
18.3
Liver cirrhosis
8.1

LAK cells IL-2 +
2.6
NCI-H292 none
0.0

IL-12

LAK cells IL-2 +
10.8
NCI-H292 IL-4
0.0

IFN gamma

LAK cells IL-2 +
5.3
NCI-H292 IL-9
12.5

IL-18

LAK cells
2.5
NCI-H292 IL-13
2.4

PMA/ionomycin

NK Cells IL-2 rest
16.7
NCI-H292 IFN gamma
0.0

Two Way MLR 3
26.4
HPAEC none
9.9

day

Two Way MLR 5
8.9
HPAEC TNF alpha +
14.4

day

IL-1 beta

Two Way MLR 7
42.0
Lung fibroblast none
10.2

day

PBMC rest
5.5
Lung fibroblast TNF
2.6

alpha + IL-1 beta

PBMC PWM
7.7
Lung fibroblast IL-4
2.4

PBMC PHA-L
48.6
Lung fibroblast IL-9
10.6

Ramos (B cell) none
5.4
Lung fibroblast IL-13
15.6

Ramos (B cell)
24.7
Lung fibroblast IFN
16.2

ionomycin

gamma

B lymphocytes
12.1
Dermal fibroblast
3.1

PWM

CCD1070 rest

B lymphocytes
14.6
Dermal fibroblast
2.8

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
0.0
Dermal fibroblast
16.3

CCD1070 IL-1 beta

EOL-1 dbcAMP
4.7
Dermal fibroblast IFN
4.4

PMA/ionomycin

gamma

Dendritic cells none
8.0
Dermal fibroblast IL-4
0.0

Dendritic cells LPS
4.7
Dermal Fibroblasts
2.2

rest

Dendritic cells
2.8
Neutrophils TNFa +
8.0

anti CD40

LPS

Monocytes rest
18.6
Neutrophils rest
0.0

Monocytes LPS
2.2
Colon
7.6

Macrophages rest
5.3
Lung
2.5

Macrophages LPS
0.0
Thymus
76.8

HUVEC none
13.8
Kidney
100.0

HUVEC starved
8.3

[0936] CNS_neurodegeneration_v1.0 Summary: Ag4541 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

[0937] General_screening_panel_v1.4 Summary: Ag4541 Expression of this gene is highest in a sample derived from a lung cancer cell line (CT=27.2). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker to detect the presence of colon cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of colon cancer.

[0938] Among tissues with metabolic function, this gene is expressed at low but significant levels in pituitary, pancreas, and skeletal muscle. This expression suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

[0939] This gene is also expressed at low but significant levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0940] Panel 4.1D Summary: Ag4541 This gene is only expressed at detectable levels in the kidney and thymus (CTs=33.5-34). Thus, expression of this gene could be used to differentiate these samples from other samples on this panel and as a marker of these tissues. In addition, therapeutic targeting of the expression or function of this gene may modulate kidney and thymus function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney and thymus.

[0941] AH. CG124890-02: Metalloprotease Like

[0942] Expression of gene CG124890-02 was assessed using the primer-probe set Ag4477, described in Table AHA. Results of the RTQ-PCR runs are shown in Tables AHB, AHC, AHD, AHE and AHF.

311TABLE AHAProbe Name Ag4477PrimersSequencesLengthStart PositionSEQ ID NoForward5′-aattgctcggaagttacacaga-3′22257220ProbeTET-5′-acaatgcttcccaggctcgagctgat-3′-TAMRA26281221Reverse5′-ggatctttcaatgctcgtacaa-3′22320222

[0943]

312

TABLE AHB

CNS_neurodegeneration_v1.0

Rel. Exp.

Rel. Exp.

(%) Ag4477,

(%) Ag4477,

Run

Run

Tissue Name
224535491
Tissue Name
224535491

AD 1 Hippo
11.8
Control (Path) 3
5.4

Temporal Ctx

AD 2 Hippo
28.7
Control (Path) 4
28.5

Temporal Ctx

AD 3 Hippo
6.4
AD 1 Occipital Ctx
7.0

AD 4 Hippo
8.6
AD 2 Occipital Ctx
0.0

(Missing)

AD 5 Hippo
89.5
AD 3 Occipital Ctx
4.3

AD 6 Hippo
82.9
AD 4 Occipital Ctx
21.9

Control 2 Hippo
52.5
AD 5 Occipital Ctx
66.0

Control 4 Hippo
12.8
AD 6 Occipital Ctx
26.6

Control (Path) 3
7.0
Control 1 Occipital
3.1

Hippo

Ctx

AD 1 Temporal Ctx
13.2
Control 2 Occipital
66.4

Ctx

AD 2 Temporal Ctx
31.2
Control 3 Occipital
8.7

Ctx

AD 3 Temporal Ctx
4.3
Control 4 Occipital
8.2

Ctx

AD 4 Temporal Ctx
23.5
Control (Path) 1
100.0

Occipital Ctx

AD 5 Inf Temporal
94.0
Control (Path) 2
10.5

Ctx

Occipital Ctx

AD 5 Sup Temporal
44.1
Control (Path) 3
3.7

Ctx

Occipital Ctx

AD 6 Inf Temporal
73.2
Control (Path) 4
13.2

Ctx

Occipital Ctx

AD 6 Sup Temporal
69.3
Control 1 Parietal
6.4

Ctx

Ctx

Control 1 Temporal
6.3
Control 2 Parietal
34.6

Ctx

Ctx

Control 2 Temporal
51.1
Control 3 Parietal
18.6

Ctx

Ctx

Control 3 Temporal
20.0
Control (Path) 1
93.3

Ctx

Parietal Ctx

Control 3 Temporal
8.8
Control (Path) 2
21.3

Ctx

Parietal Ctx

Control (Path) 1
85.3
Control (Path) 3
3.7

Temporal Ctx

Parietal Ctx

Control (Path) 2
42.6
Control (Path) 4
43.2

Temporal Ctx

Parietal Ctx

[0944]

313

TABLE AHC

General_screening_panel_v1.

Rel. Exp.

Rel. Exp.

(%) Ag4477,

(%) Ag4477,

Run

Run

Tissue Name
222655885
Tissue Name
222655885

Adipose
7.2
Renal ca TK-10
18.6

Melanoma*
17.8
Bladder
17.7

Hs688(A).T

Melanoma*
24.1
Gastric ca (liver met.)
18.8

Hs688(B).T

NCI-N87

Melanoma* M14
35.6
Gastric ca. KATO III
51.1

Melanoma*
67.8
Colon ca. SW-948
17.0

LOXIMVI

Melanoma*
51.8
Colon ca. SW480
87.1

SK-MEL-5

Squamous cell
22.7
Colon ca* (SW480
54.0

carcinoma SCC-4

met) SW620

Testis Pool
8.0
Colon ca. HT29
36.1

Prostate ca.* (bone
52.9
Colon ca HCT-116
71.7

met) PC-3

Prostate Pool
4.6
Colon ca CaCo-2
47.6

Placenta
1.2
Colon cancer tissue
16.2

Uterus Pool
5.3
Colon ca. SW1116
6.5

Ovarian ca.
61.1
Colon ca Colo-205
12.0

OVCAR-3

Ovarian ca.
36.3
Colon ca. SW-48
11.7

SK-OV-3

Ovarian ca
18.0
Colon Pool
12.2

OVCAR-4

Ovarian ca
51.1
Small Intestine Pool
9.6

OVCAR-5

Ovarian ca.
19.3
Stomach Pool
7.8

IGROV-1

Ovarian ca.
19.8
Bone Marrow Pool
4.2

OVCAR-8

Ovary
10.1
Fetal Heart
11.3

Breast ca MCF-7
26.1
Heart Pool
6.4

Breast ca MDA-
49.7
Lymph Node Pool
12.2

MB-231

Breast ca BT 549
41.8
Fetal Skeletal Muscle
6.7

Breast ca. T47D
100.0
Skeletal Muscle Pool
8.2

Breast ca MDA-N
30.1
Spleen Pool
4.6

Breast Pool
12.9
Thymus Pool
8.3

Trachea
6.6
CNS cancer (glio/
32.8

astro) U87-MG

Lung
3.7
CNS cancer (glio/
37.9

astro) U-118-MG

Fetal Lung
17.3
CNS cancer (neuro;
36.3

met) SK-N-AS

Lung ca NCI-N417
9.8
CNS cancer (astro)
18.4

SF-539

Lung ca LX-1
57.0
CNS cancer (astro)
56.6

SNB-75

Lung ca. NCI-H146
6.7
CNS cancer (glio)
25.7

SNB-19

Lung ca. SHP-77
38.7
CNS cancer (glio)
28.7

SF-295

Lung ca. A549
41.8
Brain (Amygdala)
3.8

Pool

Lung ca. NCI-H526
16.0
Brain (cerebellum)
3.8

Lung ca. NCI-H23
32.3
Brain (fetal)
7.5

Lung ca. NCI-H460
24.8
Brain (Hippocampus)
4.9

Pool

Lung ca. HOP-62
14.2
Cerebral Cortex Pool
5.4

Lung ca NCI-H522
36.9
Brain (Substantia
4.5

nigra) Pool

Liver
0.7
Brain (Thalamus) Pool
8.2

Fetal Liver
15.8
Brain (whole)
4.5

Liver ca. HepG2
14.3
Spinal Cord Pool
4.6

Kidney Pool
18.3
Adrenal Gland
7.3

Fetal Kidney
27.7
Pituitary gland Pool
2.9

Renal ca. 786-0
19.1
Salivary Gland
2.4

Renal ca. A498
13.7
Thyroid (female)
4.8

Renal ca. ACHN
14.6
Pancreatic ca
12.2

CAPAN2

Renal ca. UO-31
33.2
Pancreas Pool
15.3

[0945]

314

TABLE AHD

Panel 3D

Rel. Exp.

Rel. Exp.

(%) Ag4477,

(%) Ag4477,

Run

Run

Tissue Name
193659674
Tissue Name
193659674

Daoy—
10.0
Ca Ski—Cervical
25.0

Medulloblastoma

epidermoid carcinoma

(metastasis)

TE671—
7.1
ES-2—Ovarian clear
13.1

Medulloblastoma

cell carcinoma

D283 Med—
48.0
Ramos—Stimulated
17.4

Medulloblastoma

with PMA/ionomycin

6 h

PFSK-1—
15.9
Ramos—Stimulated
20.2

Primitive

with PMA/ionomycin

Neuroectodermal

14 h

XF-498—CNS
8.4
MEG-01—Chronic
23.8

myelogenous leukemia

(megokaryoblast)

SNB-78—Glioma
10.7
Raji—Burkett's
2.3

lymphoma

SF-268—
19.9
Daudi—Burkitt's
19.8

Glioblastoma

lymphoma

T98G—Glioblastoma
19.9
U266—B-cell
13.4

plasmacytoma

SK-N-SH—
16.2
CA46—Burkitt's
8.8

Neuroblastoma

lymphoma

(metastasis)

SF-295—
6.5
RL—non-Hodgkin's
5.8

Glioblastoma

B-cell lymphoma

Cerebellum
6.8
JM1—pre-B-cell
7.8

lymphoma

Cerebellum
1.2
Jurkat—T cell
22.5

leukemia

NCI-H292—
51.4
TF-1—
47.0

Mucoepidermoid

Erythroleukemia

lung carcinoma

DMS-114—Small
100.0
HUT 78—T-cell
15.1

cell lung cancer

lymphoma

DMS-79—Small
100.0
U937—Histiocytic
16.3

cell lung cancer

lymphoma

NCI-H146—Small
9.4
KU-812—
39.2

cell lung cancer

Myelogenous leukemia

NCI-H526—Small
34.6
769-P—Clear cell
11.3

cell lung cancer

renal carcinoma

NCI-N417—Small
13.1
Caki-2—Clear cell
5.1

cell lung cancer

renal carcinoma

NCI-H82—Small
11.0
SW 839—Clear cell
4.9

lung cancer

renal carcinoma

NCI-H157—
18.3
G401—Wilms' tumor
8.5

Squamous cell lung

cancer (metastasis)

NCI-H1155—Large
24.3
Hs766T-Pancreatic
31.6

cell lung cancer

carcinoma (LN

metastasis)

NCI-H1299—Large
24.5
CAPAN-1—Pancreatic
7.7

cell lung cancer

adenocarcinoma

(liver matastasis)

NCI-H727—Lung
20.6
SU86 86—Pancreatic
22.5

carcinoid

carcinoma (liver

metastasis)

NCI-UMC-11—
20.4
BxPC-3—Pancreatic
7.0

Lung carcinoid

adenocarcinoma

LX-1—Small cell
21.2
HPAC—Pancreatic
8.4

lung cancer

adenocarcinoma

Colo-205—Colon
5.0
MIA PaCa-2—
2.2

cancer

Pancreatic carcinoma

KM12—Colon
22.5
CFPAC-1—Pancreatic
15.2

cancer

ductal adenocarcinoma

KM20L2—Colon
6.3
PANC-1—Pancreatic
25.3

cancer

epitheliod ductal

carcinoma

NCI-H716—Colon
17.3
T24—Bladder
15.1

cancer

carcinoma (transitional

cell)

SW-48—Colon
12.2
5637—Bladder
13.2

adenocrcinoma

carcinoma

SW116—Colon
4.7
HT-1197—Bladder
9.9

adenocarcinoma

carcinoma

LS 174T—Colon
25.2
UM-UC-3—Bladder
6.5

adenocarcinoma

carcinma (transitional

cell)

SW-948—Colon
1.8
A204—
5.4

adenocarcinoma

Rhabdomyosarcoma

SW-480—Colon
6.5
HT-1080—
23.0

adenocarcinoma

Fibrosarcoma

NCI-SNU-5—
8.9
MG-63—
7.4

Gastric carcinoma

Osteosarcoma

KATO III—Gastric
42.9
SK-LMS-1—
17.4

carcinoma

Leiomyosarcoma

(vulva)

NCI-SNU-16—
6.0
SJRH30—
9.2

Gastric carcinoma

Rhabdomyosarcoma

(met to bone marrow)

NCI-SNU-1—
26.1
A431—Epidermoid
9.3

Gastric carcinoma

carcinoma

RT-1—Gastric
11.0
WM266-4—
7.0

adenocarcinoma

Melanoma

Rf-48—Gastric
0.1
DU 145—Prostate
0.4

adenocarcinoma

carcinoma (brain

metastasis)

MKN-45—Gastric
23.5
MDA-MB-468—
27.4

carcinoma

Breast adenocarcinoma

NCI-N87—Gastric
6.0
SCC-4—Squamous
0.5

carcinoma

cell carcinoma of

tongue

OVCAR-5—
2.5
SCC-9—Squamous
0.5

Ovarian carcinoma

cell carcinoma of

tongue

RL95-2—Uterine
6.1
SCC-15—Squamous
0.5

carcinoma

cell carcinoma of

tongue

HelaS3—Cervical
9.3
CAL 27—Squamous
32.5

adenocarcinoma

cell carcinoma of

tongue

[0946]

315

TABLE AHE

Panel 4.1D

Rel. Exp.

Rel. Exp.

(%) Ag4477,

(%) Ag4477,

Run

Run

Tissue Name
193605074
Tissue Name
193605074

Secondary Th1 act
57.4
HUVEC IL-1beta
32.5

Secondary Th2 act
62.0
HUVEC IFN gamma
32.5

Secondary Tr1 act
40.1
HUVEC TNF alpha +
24.1

IFN gamma

Secondary Th1 rest
8.4
HUVEC TNF alpha +
23.8

IL4

Secondary Th2 rest
18.8
HUVEC IL-11
18.2

Secondary Tr1 rest
12.4
Lung Microvascular
47.6

EC none

Primary Th1 act
49.0
Lung Microvascular
29.7

EC TNFalpha +

IL-1beta

Primary Th2 act
71.2
Microvascular Dermal
27.7

EC none

Primary Tr1 act
61.6
Microsvasular Dermal
20.4

EC TNFalpha +

IL-1beta

Primary Th1 rest
10.9
Bronchial epithelium
36.1

TNFalpha + IL1beta

Primary Th2 rest
6.7
Small airway
14.4

epithelium none

Primary Tr1 rest
23.2
Small airway
36.1

epithelium

TNFalpha + IL-1beta

CD45RA CD4
54.7
Coronery artery SMC
25.0

lymphocyte act

rest

CD45RO CD4
72.2
Coronery artery SMC
25.9

lymphocyte act

TNFalpha + IL-1beta

CD8 lymphocyte act
45.4
Astrocytes rest
11.2

Secondary CD8
51.4
Astrocytes
10.0

lymphocyte rest

TNFalpha + IL-1beta

Secondary CD8
24.8
KU-812 (Basophil)
58.2

lymphocyte act

rest

CD4 lymphocyte
10.1
KU-812 (Basophil)
100.0

none

PMA/ionomycin

2ry Th1/Th2/
23.2
CCD1106
44.1

Tr1_anti-CD95

(Keratinocytes) none

CH11

LAK cells rest
18.4
CCD1106
34.2

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
29.7
Liver cirrhosis
4.2

LAK cells IL-2 +
20.7
NCI-H292 none
35.8

IL-12

LAK cells IL-2 +
19.2
NCI-H292 IL-4
51.8

IFN gamma

LAK cells IL-2 +
21.8
NCI-H292 IL-9
66.0

IL-18

LAK cells
34.2
NCI-H292 IL-13
63.7

PMA/ionomycin

NK Cells IL-2 rest
35.8
NCI-H292 IFN gamma
63.7

Two Way MLR 3
20.0
HPAEC none
14.0

day

Two Way MLR 5
33.7
HPAEC TNF alpha +
42.9

day

IL-1 beta

Two Way MLR 7
22.7
Lung fibroblast none
17.6

day

PBMC rest
7.9
Lung fibroblast TNF
12.6

alpha + IL-1 beta

PBMC PWM
33.4
Lung fibroblast IL-4
26.8

PBMC PHA-L
31.6
Lung fibroblast IL-9
33.4

Ramos (B cell) none
45.1
Lung fibroblast IL-13
22.2

Ramos (B cell)
67.8
Lung fibroblast IFN
39.8

ionomycin

gamma

B lymphocytes
43.8
Dermal fibroblast
33.7

PWM

CCD1070 rest

B lymphocytes
24.5
Dermal fibroblast
53.6

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
52.9
Dermal fibroblast
26.2

CCD1070 IL-1beta

EOL-1 dbcAMP
25.2
Dermal fibroblast IFN
12.3

PMA/ionomycin

gamma

Dendritic cells none
21.5
Dermal fibroblast IL-4
28.1

Dendritic cells LPS
12.7
Dermal Fibroblasts
15.2

rest

Dendritic cells
20.4
Neutrophils TNFa +
0.8

anti CD40

LPS

Monocytes rest
22.7
Neutrophils rest
2.4

Monocytes LPS
15.7
Colon
4.6

Macrophages rest
20.6
Lung
9.3

Macrophages LPS
9.2
Thymus
22.4

HUVEC none
23.7
Kidney
13.8

HUVEC starved
25.5

[0947]

316

TABLE AHF

general oncology screening panel_v_2.4

Rel. Exp.

Rel. Exp.

(%) Ag4477,

(%) Ag4477,

Run

Run

Tissue Name
268695121
Tissue Name
268695121

Colon cancer 1
26.1
Bladder NAT 2
0.8

Colon NAT 1
10.1
Bladder NAT 3
0.5

Colon cancer 2
26.2
Bladder NAT 4
5.1

Colon NAT 2
15.1
Prostate
18.3

adenocarcinoma 1

Colon cancer 3
77.4
Prostate
2.6

adenocarcinoma 2

Colon NAT 3
17.7
Prostate
8.4

adenocarcinoma 3

Colon malignant
100.0
Prostate
14.7

cancer 4

adenocarcinoma 4

Colon NAT 4
7.4
Prostate NAT 5
4.0

Lung cancer 1
10.1
Prostate
2.9

adenocarcinoma 6

Lung NAT 1
1.6
Prostate
3.0

adenocarcinoma 7

Lung cancer 2
80.1
Prostate
1.4

adenocarcinoma 8

Lung NAT 2
1.1
Prostate
17.7

adenocarcinoma 9

Squamous cell
32.5
Prostate NAT 10
2.0

carcinoma 3

Lung NAT 3
1.5
Kidney cancer 1
8.6

Metastatic melanoma 1
26.6
Kidney NAT 1
4.5

Melanoma 2
2.5
Kidney cancer 2
28.1

Melanoma 3
2.6
Kidney NAT 2
12.9

Metastatic melanoma 4
43.8
Kidney cancer 3
8.4

Metastatic melanoma 5
51.8
Kidney NAT 3
5.3

Bladder cancer 1
1.8
Kidney cancer 4
17.8

Bladder NAT 1
0.0
Kidney NAT 4
6.8

Bladder cancer 2
4.1

[0948] CNS_neurodegeneration_v1.0 Summary: Ag4477 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

[0949] General_screening_panel_v1.4 Summary: Ag4477 Highest expression of this gene is seen in a breast cancer cell line (CT=23.7). This gene is widely expressed in this panel, with high levels of expression seen in brain, colon, gastric, lung, breast, ovarian, and melanoma cancer cell lines. This expression profile suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer.

[0950] Among tissues with metabolic function, this gene is expressed at high to moderate levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

[0951] This gene is also expressed at high to moderate levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0952] In addition, this gene is expressed at much higher levels in fetal liver tissue (CT=26.4) when compared to expression in the adult counterpart (CT=31) Thus, expression of this gene may be used to differentiate between the fetal and adult source of this tissue.

[0953] Panel 3D Summary: Ag4477 Expression of this gene is ubiquitous on this panel, with highest expression in a a small cell lung cancer cell line (CT=25.2). This expression is in agreement with the prominent expression seen in panel 1.4 and suggests a role for this gene product in cellular growth and proliferation.

[0954] Panel 4.1D Summary: Ag4477 Expression of this gene is ubiquitous on this panel, with highest expression in PMA/ionomycin treated basophils (CT=26.1). This gene is also expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types fi-or lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

[0955] general oncology screening panel_v—2.4 Summary: Ag4477 This gene is widely expressed in this panel, with highest expression in colon cancer (CT=26). This gene is also more highly expressed in colon and lung cancer as compared to the corresponding normal adjacent tissue. In addition, high to moderate levels of expression are seen in melanoma and prostate cancers. Thus, expression of this gene could be used as a marker of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of melanoma, colon, lung and kidney cancer.

[0956] AI. CG59266-01 and CG59266-02 and CG59266-03: T10 Ser/Thr-Rich Protein

[0957] Expression of gene CG59266-01, variant CG59266-02, and full length physical clone CG59266-03 was assessed using the primer-probe sets Ag3521 and Ag3563, described in Tables AIA and AIB. Results of the RTQ-PCR runs are shown in Tables AIC, AID, AIE and AIF. Please note that CG59266-03 represents a full-length physical clone of the CG59266-02 gene, validating the prediction of the gene sequence.

317TABLE AIAProbe Name Ag3521PrimersSequencesLengthStart PositionSEQ ID NoForward5′-ccaacagggatgaattctacag-3′22180223ProbeTET-5′-ccctccaagttagctgacttctgggg-3′-TAMRA26206224Reverse5′-cactgaggatctcgttgttgtt-3′22233225

[0958]

318

TABLE AIB

Probe Name Ag3563

Primers
Sequences
Length
Start Position
SEQ ID No

Forward
5′-ccaacagggatgaattctacag-3′
22
180
226

Probe
TET-5′-ccctccaagttagctgacttctgggg-3′-TAMRA
26
206
227

Reverse
5′-cactgaggatctcgttgttgtt-3′
22
233
228

[0959]

319

TABLE AIC

CNS_neurodegeneration_v1.0

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag3521, Run
Ag3563, Run

Ag3521, Run
Ag3563, Run

Tissue Name
210630169
210629742
Tissue Name
210630169
210629742

AD 1 Hippo
13.6
15.0
Control (Path)
4.8
7.3

3 Temporal

Ctx

AD 2 Hippo
29.1
23.5
Control (Path)
30.6
29.9

4 Temporal

Ctx

AD 3 Hippo
8.4
8.6
AD 1 Occipital
19.5
17.3

Ctx

AD 4 Hippo
9.8
8.2
AD 2 Occipital
0.0
0.0

Ctx (Missing)

AD 5 Hippo
100.0
100.0
AD 3 Occipital
9.4
8.4

Ctx

AD 6 Hippo
40.3
58.2
AD 4 Occipital
19.9
22.7

Ctx

Control 2
28.9
33.2
AD 5 Occipital
44.8
24.0

Hippo

Ctx

Control 4
11.7
15.7
AD 6 Occipital
16.3
56.6

Hippo

Ctx

Control (Path)
6.3
5.4
Control 1
4.5
8.2

3 Hippo

Occipital Ctx

AD 1
19.2
26.2
Control 2
68.8
80.1

Temporal Ctx

Occipital Ctx

AD 2
28.9
29.3
Control 3
20.3
16.4

Temporal Ctx

Occipital Ctx

AD 3
8.8
7.8
Control 4
11.0
7.1

Temporal Ctx

Occipital Ctx

AD 4
18.8
20.2
Control (Path)
73.2
71.2

Temporal Ctx

1 Occipital Ctx

AD 5 Inf
81.2
84.7
Control (Path)
15.3
16.2

Temporal Ctx

2 Occipital Ctx

AD 5 Sup
39.5
52.9
Control (Path)
4.9
4.2

Temporal Ctx

3 Occipital Ctx

AD 6 Inf
45.1
44.4
Control (Path)
17.6
20.0

Temporal Ctx

4 Occipital Ctx

AD 6 Sup
39.8
49.3
Control 1
8.6
11.1

Temporal Ctx

Parietal Ctx

Control 1
5.5
8.4
Control 2
38.7
45.1

Temporal Ctx

Parietal Ctx

Control 2
47.0
46.0
Control 3
20.6
22.2

Temporal Ctx

Parietal Ctx

Control 3
17.0
17.1
Control (Path)
74.7
74.7

Temporal Ctx

1 Parietal Ctx

Control 3
9.7
8.9
Control (Path)
26.2
25.2

Temporal Ctx

2 Parietal Ctx

Control (Path)
54.0
58.2
Control (Path)
4.7
5.1

1 Temporal

3 Parietal Ctx

Ctx

Control (Path)
38.4
35.6
Control (Path)
45.1
55.5

2 Temporal

4 Parietal Ctx

Ctx

[0960]

320

TABLE AID

General_screening_panel_v1.4

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag3521, Run
Ag3563, Run

Ag3521, Run
Ag3563, Run

Tissue Name
216874344
217311280
Tissue Name
216874344
217311280

Adipose
7.5
9.1
Renal ca TK-10
15.8
15.0

Melanoma*
31.4
26.8
Bladder
16.6
17.0

Hs688(A).T

Melanoma*
26.1
26.2
Gastric ca (liver
32.1
39.0

Hs688(B).T

met.) NCl-N87

Melanoma*
97.3
97.9
Gastric ca. KATO
45.7
57.4

M14

111

Melanoma*
9.2
7.6
Colon ca SW-948
8.9
9.7

LOXIMVI

Melanoma* SK-
51.1
37.4
Colon ca SW480
29.7
28.5

MEL-5

Squamous cell
13.7
13.0
Colon ca * (SW480
15.2
18.8

carcinoma SCC-

met) SW620

4

Testis Pool
4.1
4.8
Colon ca. HT29
31.9
27.5

Prostate ca.*
13.9
16.6
Colon ca. HCT-116
25.3
27.5

(bone met) PC-

3

Prostate Pool
6.5
5.0
Colon ca. CaCo-2
18.2
18.7

Placenta
10.8
9.6
Colon cancer tissue
15.0
16.6

Uterus Pool
2.3
3.4
Colon ca. SW1116
8.4
8.1

Ovarian ca.
10.2
11.3
Colon ca. Colo-205
3.8
5.2

OVCAR-3

Ovarian ca. SK-
12.2
16.2
Colon ca SW-48
6.0
7.2

OV-3

Ovarian ca.
17.9
16.2
Colon Pool
12.4
8.0

OVCAR-4

Ovarian ca.
46.7
55.4
Small Intestine
4.2
6.3

OVCAR-5

Pool

Ovarian ca.
6.3
7.7
Stomach Pool
4.0
4.5

IGROV-1

Ovarian ca.
6.7
7.0
Bone Marrow Pool
3.7
4.3

OVCAR-8

Ovary
4.4
5.6
Fetal Heart
9.6
11.8

Breast ca. MCF-
17.2
20.6
Heart Pool
11.0
11.6

7

Breast ca.
15.4
15.8
Lymph Node Pool
9.2
8.1

MDA-MB-231

Breast ca. BT
29.3
32.3
Fetal Skeletal
4.3
4.2

549

Muscle

Breast ca. T47D
69.3
81.2
Skeletal Muscle
13.7
12.9

Pool

Breast ca.
40.6
51.4
Spleen Pool
11.7
11.0

MDA-N

Breast Pool
7.3
7.9
Thymus Pool
10.2
11.5

CNS cancer

Trachea
8.4
7.9
(glio/astro) U87-
35.4
35.1

MG

Lung
1.5
1.1
CNS cancer
62.0
64.2

(glio/astro) U-118-

MG

Fetal Lung
16.3
18.3
CNS cancer
6.9
6.6

(neuro;met) SK-N-

AS

Lung ca. NCl-
3.7
2.6
CNS cancer (astro)
17.1
16.8

N417

SF-539

Lung ca. LX-1
18.6
17.1
CNS cancer (astro)
29.7
29.3

SNB-75

Lung ca. NCl-
2.9
4.2
CNS cancer (glio)
8.6
8.0

H146

SNB-19

Lung ca. SHP-
21.9
15.2
CNS cancer (glio)
48.3
44.4

77

SF-295

Lung ca. A549
18.0
19.3
Brain (Amygdala)
9.6
14.3

Pool

Lung ca. NCl-
2.3
2.5
Brain (cerebellum)
14.2
18.2

H526

Lung ca. NCl-
8.2
9.2
Brain (fetal)
8.2
8.2

H23

Lung ca. NCl-
9.0
9.8
Brain
11.7
12.0

H460

(Hippocampus)

Pool

Lung ca. HOP-
11.7
10.0
Cerebral Cortex
17.8
18.4

62

Pool

Lung ca NCl-
13.4
11.5
Brain (Substantia
15.7
21.3

H522

nigra) Pool

Liver
1.9
2.7
Brain (Thalamus)
17.4
20.6

Pool

Fetal Liver
100.0
100.0
Brain (whole)
14.4
17.2

Liver ca
7.7
8.3
Spinal Cord Pool
13.9
14.1

HepG2

Kidney Pool
11.8
11.5
Adrenal Gland
17.4
19.9

Fetal Kidney
5.1
4.8
Pituitary gland
4.4
3.8

Pool

Renal ca. 786-0
19.9
17.9
Salivary Gland
4.6
4.9

Renal ca. A498
8.8
9.4
Thyroid (female)
9.1
8.6

Renal ca.
7.4
8.0
Pancreatic ca.
11.2
11.0

ACHN

CAPAN2

Renal ca. UO-
14.1
19.2
Pancreas Pool
9.0
11.0

31

[0961]

321

TABLE AIE

Panel 4.1D

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag3521, Run
Ag3563, Run

Ag3521, Run
Ag3563, Run

Tissue Name
169840438
169850764
Tissue Name
169840438
169850764

Secondary Th1 act
29.9
33.7
HUVEC IL-1beta
38.7
41.8

Secondary Th2 act
47.6
38.4
HUVEC IFN gamma
59.9
31.0

Secondary Tr1 act
65.5
46.0
HUVEC TNF alpha +
48.3
41.2

IFN gamma

Secondary Th1 rest
31.9
24.5
HUVEC TNF alpha +
43.5
27.4

IL4

Secondary Th2 rest
48.3
49.7
HUVEC IL-11
26.1
19.6

Secondary Tr1 rest
62.9
37.9
Lung Microvascular
87.7
58.6

EC none

Primary Th1 act
46.3
31.6
Lung Microvascular
67.4
70.2

EC TNFalpha + IL-

1beta

Primary Th2 act
42.9
44.1
Microvascular
40.1
31.2

Dermal EC none

Primary Tr1 act
55.1
26.6
Microvascular
39.5
26.8

Dermal EC

TNFalpha + IL-1beta

Primary Th1 rest
55.9
42.3
Bronchial epithelium
33.4
27.4

TNFalpha + IL1beta

Primary Th2 rest
39.2
29.3
Small airway
18.6
20.2

epithelium none

Primary Tr1 rest
49.7
46.3
Small airway
25.3
28.7

epithelium TNF alpha +

IL-1beta

CD45RA CD4
39.2
36.9
Coronery artery
38.4
27.5

lymphocyte act

SMC rest

CD45RO CD4
40.6
44.8
Coronery artery
31.2
29.7

lymphocyte act

SMC TNFalpha +

IL-1beta

CD8 lymphocyte act
44.1
42.3
Astrocytes rest
21.8
22.1

Secondary CD8
29.9
36.6
Astrocytes TNFalpha +
22.2
23.2

lymphocyte rest

IL-1beta

Secondary CD8
39.2
26.1
KU-812 (Basophil)
56.3
47.3

lymphocyte act

rest

CD4 lymphocyte
24.0
21.9
KU-812 (Basophil)
40.3
43.5

none

PMA/ionomycin

2ry
51.4
44.1
CCD1106
26.8
27.0

Th1/Th2/Tr1_anti-

(Keratinocytes) none

CD95 CH11

LAK cells rest
54.7
51.4
CCD1106
26.1
25.5

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
55.5
65.1
Liver cirrhosis
15.0
12.1

LAK cells IL-2 + IL-
49.3
38.4
NCl-H292 none
19.8
18.8

12

LAK cells IL-2 + IFN
48.6
42.3
NCl-H292 IL-4
26.4
25.7

gamma

LAK cells IL-2 + IL-
75.3
49.3
NCl-H292 IL-9
49.3
45.4

18

LAK cells
19.8
31.9
NCl-H292 IL-13
23.3
25.9

PMA/ionomycin

NK Cells IL-2 rest
59.0
55.9
NCl-H292 IFN
25.2
18.4

gamma

Two Way MLR 3
64.6
53.6
HPAEC none
33.7
27.7

day

Two Way MLR 5
40.1
26.2
HPAEC TNF alpha +
39.2
45.1

day

IL-1 beta

Two Way MLR 7
34.4
24.7
Lung fibroblast none
47.6
66.4

day

PBMC rest
26.2
28.7
Lung fibroblast TNF
25.2
21.5

alpha + IL-1 beta

PMBC PWM
43.2
40.1
Lung fibroblast IL-4
50.3
52.5

PBMC PHA-L
29.3
31.2
Lung fibroblast IL-9
74.7
44.4

Ramos (B cell) none
69.3
59.5
Lung fibroblast IL-
61.6
28.7

13

Ramos (B cell)
77.4
63.3
Lung fibroblast IFN
76.8
43.2

ionomycin

gamma

B lymphocytes
41.8
23.3
Dermal fibroblast
54.3
45.4

PWM

CCD1070 rest

B lymphocytes
77.4
55.5
Dermal fibroblast
88.3
84.7

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
45.1
50.0
Dermal fibroblast
22.2
43.2

CCD1070 IL-1 beta

EOL-1 dbcAMP
57.4
48.3
Dermal fibroblast
25.9
25.3

PMA/ionomycin

IFN gamma

Dendritic cells none
100.0
68.3
Dermal fibroblast IL-
59.9
56.3

4

Dendritic cells LPS
59.9
38.4
Dermal Fibroblasts
37.9
44.4

rest

Dendritic cells anti-
89.5
92.0
Neutrophils
5.8
19.1

CD40

TNFa + LPS

Monocytes rest
92.0
100.0
Neutrophils rest
90.8
80.7

Monocytes LPS
75.3
74.7
Colon
19.9
17.8

Macrophages rest
94.0
92.7
Lung
50.0
29.7

Macrophages LPS
45.1
33.2
Thymus
67.4
47.0

HUVEC none
27.4
21.5
Kidney
24.1
19.2

HUVEC starved
40.1
33.2

[0962]

322

TABLE AIF

general oncology screening panel_v_2.4

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag3521, Run
Ag3563, Run

Ag3521, Run
Ag3563, Run

Tissue Name
267173530
267300296
Tissue Name
267173530
267300296

Colon cancer
22.2
38.4
Bladder NAT 2
0.4
1.3

1

COLON NAT
24.5
24.8
Bladder NAT 3
0.3
1.7

1

Colon cancer
47.6
35.8
Bladder NAT 4
8.3
7.9

2

Colon NAT 2
17.6
24.0
Prostate
34.6
29.1

adenocarcinoma 1

Colon cancer
29.1
86.5
Prostate
4.5
5.4

1

adenocarcinoma 2

Colon NAT 3
17.7
24.1
Prostate
18.0
20.2

adenocarcinoma 3

Colon
42.0
46.0
Prostate
12.7
21.6

malignant

adenocarcinoma 4

cancer 4

Colon NAT 4
9.3
10.0
Prostate NAT 5
6.7
9.8

Lung cancer 1
26.8
33.7
Prostate
5.8
8.3

adenocarcinoma 6

Lung NAT 1
5.9
6.3
Prostate
8.1
7.3

adenocarcinoma 7

Lung cancer 2
34.4
50.3
Prostate
1.5
3.2

adenocarcinoma 8

Lung NAT 2
9.8
9.9
Prostate
19.1
36.6

adenocarcinoma 9

Squamous cell
47.6
66.0
Prostate NAT 10
3.0
3.4

carcinoma 3

Lung NAT 3
1.3
4.1
Kidney cancer 1
45.1
55.9

Metastatic
11.3
12.7
Kidney NAT 1
21.3
24.0

melanoma 1

Melanoma 2
7.3
11.9
Kidney cancer 2
100.0
100.0

Melanoma 3
5.8
2.3
Kidney NAT 2
33.7
39.8

Metastatic
32.3
43.8
Kidney cancer 3
40.6
35.1

melanoma 4

Metastatic
41.8
62.9
Kidney NAT 3
13.9
24.8

melanoma 5

Bladder
3.8
2.0
Kidney cancer 4
24.3
25.5

cancer 1

Bladder NAT
0.0
0.0
Kidney NAT 4
18.6
24.5

1

Bladder
5.2
5.6

cancer 2

[0963] CNS_neurodegeneration_v1.0 Summary: Ag3521/Ag3563 Two experiments with the same probe and primer set produce results that are in excellent agreement. This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

[0964] General_screening_panel_v1.4 Summary: Ag3521/Ag3563 Two experiments with the same probe and primer set produce results that are in excellent agreement. Highest expression is seen in fetal liver (CTs=25). Interestingly, this gene is expressed at much higher levels in fetal liver when compared to adult liver (CTs=30). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance growth or development of this organ in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases. This gene is also expressed at moderate levels in other tissues with metabolic function, including, pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

[0965] Prominent expression of this gene is also widely seen in samples derived from cancer cell lines, with high levels of expression seen in brain, colon, gastric, lung, breast, ovarian, and melanoma cancer cell lines. This expression profile suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer.

[0966] This gene is also expressed at high to moderate levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

[0967] Panel 4.1D Summary: Ag3521/Ag3563 Two experiments with the same probe and primer set produce results that are in excellent agreement. Highest expression is seen in resting monocytes and dendritic cells (CTs=27). This gene is also expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_v1.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

[0968] general oncology screening panel_V—2.4 Summary: Ag3521/Ag3563 Two experiments with the same probe and primer set produce results that are in excellent agreement. Highest expression is seen in kidney cancer (CTs=27). In addition, this gene is more highly expressed in lung, colon and kidney cancer than in the corresponding normal adjacent tissue. Prominent expression is also seen in melanoma and prostate cancer. Thus, expression of this gene could be used as a marker of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of lung and kidney cancer.

[0969] AK. CG97563-01 and CG97563-02 and CG97563-03 and CG97563-04 and CG97563-05: Ring Finger (C3HC4 Type Zinc Finger) Protein

[0970] Expression of gene CG97563-01, variants CG97563-02, CG97563-03, CG97563-04 and full length physical clone CG97563-05 was assessed using the primer-probe sets Ag4841 and Ag5039, described in Tables AKA and AKB. Results of the RTQ-PCR runs are shown in Tables AKC, AKD, AKE and AKF.

323TABLE AKAProbe Name Ag4841PrimersSequencesLengthStart PositionSEQ ID NoForward5′-gctgtcacagtaagtgcttgaa-3′22532229ProbeTET-5′-tccaaagtcagccaccaagctgaata-3′-TAMRA26579230Reverse5′-gtctcagggcagatgttcagt-3′21608231

[0971]

324

TABLE AKB

Probe Name Ag5039

Primers
Sequences
Length
Start Position
SEQ ID No

Forward
5′-gctgtcacagtaagtgcttgaa-3′
22
532
232

Probe
TET-5′-tccaaagtcagccaccaagctgaata-3′-TAMRA
26
579
233

Reverse
5′-gtctcagggcagatgttcagt-3′
21
608
234

[0972]

325

TABLE AKC

CNS_neurodegeneration_v1.0

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag4841, Run
Ag5039, Run

Ag4841, Run
Ag5039, Run

Tissue Name
249271255
249286378
Tissue Name
249271255
249286378

AD 1 Hippo
1.9
17.3
Control (Path)
1.0
9.7

3 Temporal

Ctx

AD 2 Hippo
4.3
33.4
Control (Path)
5.0
42.6

4 Temporal

Ctx

AD 3 Hippo
1.4
12.9
AD 1
3.7
32.8

Occipital Ctx

AD 4 Hippo
1.7
15.3
AD 2
0.0
0.0

Occipital Ctx

(Missing)

AD 5 Hippo
10.0
100.0
AD 3
1.5
5.4

Occipital Ctx

AD 6 Hippo
4.8
47.3
AD 4
4.2
17.2

Occipital Ctx

Control 2
5.0
40.9
AD 5
6.3
56.6

Hippo

Occipital Ctx

Control 4
1.5
9.9
AD 6
2.0
19.3

Hippo

Occipital Ctx

Control (Path)
1.0
5.6
Control 1
0.8
7.4

3 Hippo

Occipital Ctx

AD 1
3.5
28.3
Control 2
9.4
89.5

Temporal Ctx

Occipital Ctx

AD 2
5.4
41.8
Control 3
2.8
24.3

Temporal Ctx

Occipital Ctx

AD 3
1.4
13.7
Control 4
1.3
12.2

Temporal Ctx

Occipital Ctx

AD 4
3.7
35.6
Control (Path)
9.0
91.4

Temporal Ctx

1 Occipital

Ctx

AD 5 Inf
8.2
69.7
Control (Path)
1.7
15.5

Temporal Ctx

2 Occipital

Ctx

AD 5 Sup
4.8
44.1
Control (Path)
0.6
2.3

Temporal Ctx

3 Occipital

Ctx

AD 5 Inf
4.8
34.9
Control (Path)
2.8
23.5

Temporal Ctx

4 Occipital

Ctx

AD 6 Sup
5.4
50.7
Control 1
1.5
13.9

Temporal Ctx

Parietal Ctx

Control 1
100.0
6.8
Control 2
5.3
31.9

Temporal Ctx

Parietal Ctx

Control 2
6.2
47.0
Control 3
2.4
19.6

Temporal Ctx

Parietal Ctx

Control 3
2.7
24.1
Control (Path)
9.9
54.7

Temporal Ctx

1 Parietal Ctx

Control 3
1.2
14.9
Control (Path)
3.8
38.4

Temporal Ctx

2 Parietal Ctx

Control (Path)
8.2
72.2
Control (Path)
0.8
7.1

1 Temporal

3 Parietal Ctx

Ctx

Control (Path)
5.8
52.9
Control (Path)
5.7
37.9

2 Temporal

4 Parietal Ctx

Ctx

[0973]

326

TABLE AKD

General_screening_panel_v1.5

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag4841, Run
Ag5039, Run

Ag4841, Run
Ag5039, Run

Tissue Name
228796250
228967308
Tissue Name
228796250
228967308

Adipose
8.7
6.6
Renal ca. TK-10
33.0
26.6

Melanoma*
15.0
13.7
Bladder
22.8
15.0

Hs688(A).F

Melanoma*
15.9
13.8
Gastric ca. (liver
42.9
38.4

Hs688(B).T

met.) NCl-N87

Melanoma*
17.6
20.4
Gastric ca. KATO
26.2
23.0

M14

111

Melanoma*
10.6
9.7
Colon ca. SW-948
7.5
8.5

LOXIMVI

Melanoma* SK-
27.0
23.7
Colon ca SW480
34.2
26.2

MEL-5

Squamous cell
3.8
3.4
Colon ca * (SW480
12.9
10.2

carcinoma SCC-

met) SW620

4

Testis Pool
4.3
4.4
Colon ca. HT29
13.3
11.2

Prostate ca.*
4.0
11.6
Colon ca HCT-116
56.3
50.3

(bone met) PC-

3

Prostate Pool
9.6
5.3
Colon ca CaCo-2
55.5
20.4

Placenta
8.5
2.9
Colon cancer tissue
17.7
14.3

Uterus Pool
11.1
8.6
Colon ca. SW1116
5.5
5.0

Ovarian ca.
4.7
5.8
Colon ca Colo-205
4.4
3.3

OVCAR-3

Ovarian ca SK-
32.3
29.1
Colon ca. SW-48
1.6
1.4

OV-3

Ovarian ca
10.4
6.2
Colon Pool
20.0
14.0

OVCAR-4

Ovarian ca
38.4
33.9
Small Intestine
13.3
13.4

OVCAR-5

Pool

Ovarian ca.
15.3
14.2
Stomach Pool
8.3
6.8

IGROV-1

Ovarian ca.
16.3
14.9
Bone Marrow Pool
7.4
5.6

OVCAR-8

Ovary
22.2
15.4
Fetal Heart
6.9
6.7

Breast ca. MCF-
24.0
18.8
Heart Pool
10.3
7.4

7

Breast ca.
20.6
19.9
Lymph Node Pool
15.6
17.2

MDA-MB-231

Breast ca. BT
19.6
15.8
Fetal Skeletal
5.2
3.9

549

Muscle

Breast ca. T47D
10.4
8.3
Skeletal Muscle
21.5
20.4

Pool

Breast ca.
5.9
7.0
Spleen Pool
12.0
10.3

MDA-N

Breast Pool
18.2
14.8
Thymus Pool
13.1
9.3

Trachea
10.8
8.7
CNS cancer
18.8
21.0

(glio/astro) U87-

MG

Lung
1.1
1.4
CNS cancer
32.8
27.4

(glio/astro) U-118-

MG

Fetal Lung
18.2
13.5
CNS cancer
11.3
10.7

(neuro;met) SK-N-

AS

Lung ca NCl-
4.4
4.4
CNS cancer (astro)
5.6
5.7

N417

SF-539

Lung ca. LX-1
22.5
20.7
CNS cancer (astro)
45.7
37.9

SNB-75

Lung ca. NCl-
4.5
3.2
CNS cancer (glio)
24.0
13.8

11146

SNB-19

Lung ca SHP-
16.6
9.9
CNS cancer (glio)
92.0
84.7

77

SF-295

Lung ca. A549
25.2
12.9
Brain (Amygdala)
19.6
17.3

Pool

Lung ca. NCl-
4.4
4.0
Brain (cerebellum)
100.0
100.0

H526

Lung ca. NCl-
26.4
18.9
Brain (fetal)
37.4
34.6

H23

Lung ca NCl-
18.3
18.9
Brain
21.3
18.6

H460

(Hippocampus)

Pool

Lung ca. HOP-
21.9
16.0
Cerebral Cortex
36.3
25.9

62

Pool

Lung ca. NCl-
12.9
12.0
Brain (Substantia
32.8
25.7

H522

nigra) Pool

Liver
2.9
2.7
Brain (Thalamus)
33.4
26.6

Pool

Fetal Liver
12.2
7.7
Brain (whole)
31.0
28.7

Liver ca.
22.4
24.1
Spinal Cord Pool
20.4
23.7

HepG2

Kidney Pool
26.4
23.0
Adrenal Gland
16.0
13.0

Fetal Kidney
11.9
9.0
Pituitary gland
6.7
5.5

Pool

Renal ca 786-0
11.2
10.7
Salivary Gland
6.9
6.7

Renal ca. A498
9.9
9.3
Thyroid (female)
10.3
7.3

Renal ca.
19.3
18.2
Pancreatic ca.
12.6
13.8

ACHN

CAPAN2

Renal ca. UO-
35.8
27.9
Pancreas Pool
27.0
21.5

31

[0974]

327

TABLE AKE

Panel 4.1D

Rel. Exp. (%)
Rel. Exp. (%)

Rel. Exp. (%)
Rel. Exp. (%)

Ag4841, Run
Ag5039, Run

Ag4841, Run
Ag5039, Run

Tissue Name
223335756
223743255
Tissue Name
223335756
223743255

Secondary Th1 act
8.5
5.1
HUVEC IL-1beta
17.8
11.4

Secondary Th2 act
7.5
11.3
HUVEC IFN gamma
17.1
17.0

Secondary Tr1 act
7.0
6.2
HUVEC TNF alpha +
13.3
13.4

IFN gamma

Secondary Th1 rest
7.1
4.9
HUVEC TNF alpha +
20.0
17.7

IL4

Secondary Th2 rest
8.6
9.2
HUVEC IL-11
8.9
9.9

Secondary Tr1 rest
6.9
5.0
Lung Microvascular
37.6
33.4

EC none

Primary Th1 act
6.5
3.6
Lung Microvascular
28.5
16.4

EC TNFalpha + IL-

1beta

Primary Th2 act
7.7
10.2
Microvascular
14.8
15.6

Dermal EC none

Primary Tr1 act
6.7
8.4
Microvascular
17.4
18.7

Dermal EC

TNFalpha + IL-1beta

Primary Th1 rest
3.6
2.9
Bronchial epithelium
20.2
19.9

TNFalpha + IL1beta

Primary Th2 rest
6.0
3.5
Small airway
11.0
13.0

epithelium none

Primary Tr1 rest
6.0
8.7
Small airway
17.3
12.9

epithelium TNFalpha +

IL-1beta

CD45RA CD4
8.5
7.4
Coronery artery
6.5
8.0

lymphocyte act

SMC rest

CD45RO CD4
7.2
6.3
Coronery artery
10.2
9.6

lymphocyte act

SMC TNFalpha +

IL-1beta

CD8 lymphocyte act
6.2
4.5
Astrocytes rest
7.3
6.0

Secondary CD8
6.2
6.6
Astrocytes TNFalpha +
7.7
8.0

lymphocyte rest

IL-1beta

Secondary CD8
2.4
2.2
KU-812 (Basophil)
11.3
10.9

lymphocyte act

rest

CD4 lymphocyte
6.2
3.3
KU-812 (Basophil)
7.4
9.0

none

PMA/ionomycin

2ry
5.8
8.4
CCD1106
18.2
14.7

Th1/Th2/Tr1_anti-

(Keratinocytes) none

CD95 CH11

LAK cells rest
13.9
15.1
CCD1106
10.0
12.6

(Keratinocytes)

TNFalpha + IL-1beta

LAK cells IL-2
5.2
4.8
Liver cirrhosis
2.5
4.3

LAK cells IL-2 + IL-
6.5
6.3
NCl-H292 none
20.3
17.6

12

LAK cells IL-2 + IFN
7.7
5.2
NCl-H292 IL-4
25.7
23.8

gamma

LAK cells IL-2 + IL-
8.0
8.5
NCl-H292 IL-9
26.2
28.3

18

LAK cells
6.7
5.5
NCl-H292 IL-13
35.4
26.6

PMA/ionomycin

NK Cells IL-2 rest
10.2
8.1
NCl-H292 IFN
24.5
21.8

gamma

Two Way MLR 3
13.3
9.6
HPAEC none
12.2
12.4

day

Two Way MLR 5
6.3
5.3
HPAEC TNF alpha +
21.8
17.7

day

IL-1 beta

Two Way MLR 7
3.2
2.5
Lung fibroblast none
12.7
14.2

day

PBMC rest
8.1
6.4
Lung fibroblast TNF
9.9
6.1

alpha + IL-1 beta

PBMC PWM
7.1
6.2
Lung fibroblast IL-4
14.6
9.4

PBMC PHA-L
6.5
5.0
Lung fibroblast IL-9
13.6
12.5

Ramos (B cell) none
41.5
39.0
Lung fibroblast IL-
10.7
8.2

13

Ramos (B cell)
40.9
36.9
Lung fibroblast IFN
12.4
9.8

ionomycin

gamma

B lymphocytes
9.5
8.7
Dermal fibroblast
13.7
12.3

PWM

CCD1070 rest

B lymphocytes
39.8
35.6
Dermal fibroblast
10.8
11.0

CD40L and IL-4

CCD1070 TNF alpha

EOL-1 dbcAMP
7.1
8.5
Dermal fibroblast
9.5
6.6

CCD1070 IL-1 beta

EOL-1 dbcAMP
11.8
6.5
Dermal fibroblast
17.9
8.1

PMA/ionomycin

IFN gamma

Dendritic cells none
25.0
27.2
Dermal fibroblast IL-
25.7
17.3

4

Dendritic cells LPS
13.7
10.8
Dermal Fibroblasts
17.6
19.3

rest

Dendritic cells anti-
47.0
42.3
Neutrophils
28.1
20.4

CD40

TNFa + LPS

Monocytcs rest
42.0
39.5
Neutrophils rest
100.0
100.0

Monocytes LPS
19.8
16.4
Colon
5.1
3.9

Macrophages rest
49.7
48.6
Lung
10.4
10.4

Macrophages LPS
7.3
4.7
Thymus
12.2
5.4

HUVEC none
11.7
12.8
Kidney
91.4
17.9

HUVEC starved
16.3
13.2

[0975]

328

TABLE AKF

Panel 5D

Rel. Exp. (%)

Ag5039, Run

Tissue Name
223784821

97457_Patient-02go_adipose
80.1

97476_Patient-07sk_skeletal muscle
44.8

97477_Patient-07ut_uterus
47.6

97478_Patient-07pl_placenta
26.2

97481_Patient-08sk_skeletal muscle
67.8

97482_Patient-08ut_uterus
41.2

97483_Patient-08pl_placenta
21.6

97486_Patient-09sk_skeletal muscle
13.4

97487_Patient-09ut_uterus
53.2

97488_Patient-09pl_placenta
29.7

97492_Patient-10ut_uterus
49.3

97493_Patient-10pl_placenta
40.9

97495_Patient-11go_adipose
62.9

97496_Patient-11sk_skeletal muscle
35.6

97497_Patient-11ut_uterus
56.6

97498_Patient-11pl_placenta
27.2

97500_Patient-12go_adipose
84.7

97501_Patient-12sk_skeletal muscle
59.9

97502_Patient-12ut_uterus
71.7

97503_Patient-12pl_placenta
23.7

94721_Donor 2 U - B_Mesenchymal Stem Cells
34.6

94723_Donor 2 U - C_Mesenchymal Stem Cells
33.9

94709_Donor 2 AM - A_adipose
54.3

94710_Donor 2 AM - B_adipose
25.7

94711_Donor 2 AM - C_adipose
19.9

94712_Donor 2 AD - A_adipose
66.4

94713_Donor 2 AD - B_adipose
61.6

94714_Donor 2 AD - C_adipose
65.1

94742_Donor 3 U - A_Mesenchymal Stem Cells
19.2

94743_Donor 3 U - B_Mesenchymal Stem Cells
35.4

94730_Donor 3 AM - A_adipose
36.6

94731_Donor 3 AM - B_adipose
21.2

94732_Donor 3 AM - C_adipose
22.2

94733_Donor 3 AD - A_adipose
38.4

94734_Donor 3 AD - B_adipose
21.9

94735_Donor 3 AD - C_adipose
39.2

77138_Liver_HepG2untreated
100.0

73556_Heart_Cardiac stromal cells (primary)
40.6

81735_Small Intestine
65.1

72409_Kidney_Proximal Convoluted Tubule
32.1

82685_Small intestine_Duodenum
21.2

90650_Adrenal_Adrenocortical adenoma
15.6

72410_Kidney_HRCE
82.4

72411_Kidney_HRE
84.1

73139_Uterus_Uterine smooth muscle cells
22.8

[0976] CNS_neurodegeneration_v1.0 Summary: Ag4841/Ag5039 Two experiments with two different probe and primer sets produce results that are in reasonable agreement. This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene at high to moderate levels in all regions of the brain examined. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

[0977] General_screening panel_v1.5 Summary: Ag4841/Ag5039 Two experiments with the same probe and primer set produce results that are in excellent agreement. Highest expression of this gene is seen in the cerebellum (CTs=26). This gene is also expressed hig to moderate levels in all regions of the CNS examined, including the hippocampus, thalamus, substantia nigra, amygdala, and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy. In addition, the high expression in the cerebellum suggests that this gene product may be a useful and specific target of drugs for the treatment of CNS disorders that have this brain region as the site of pathology, such as autism and the ataxias.

[0978] Prominent expression of this gene is also seen in a cluster of samples derived from brain cancer cell lines. This gene is widely expressed in this panel, with moderate expression seen in brain, colon, gastric, lung, breast, ovarian, and melanoma cancer cell lines. This expression profile suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer.

[0979] Among tissues with metabolic function, this gene is expressed at moderate levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

[0980] Panel 4.1D Summary: Ag4841/Ag5039 Two experiments with the same probe and primer set produce results that are in very (good agreement. Highest expression of this gene is seen in resting neutrophils (CTs=28), with moderate to low expression seen in all samples on this panel. This expression is reduced in neutrophils activated by TNF-alpha+LPS. This expression profile suggests that the protein encoded by this gene is produced by resting neutrophils but not by activated neutrophils. Therefore, the gene product may reduce activation of these inflammatory cells and be useful as a protein therapeutic to reduce or eliminate the symptoms in patients with Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, lupus erythematosus, or psoriasis. In addition, small molecule or antibody antagonists of this gene product may be effective in increasing, the immune response in patients with AIDS or other immunodeficiencies.

[0981] Panel 5D Summary: Ag5039 Highest expression is seen in a sample derived from liver (CT=31.8). In addition, moderate to low levels of expression are seen in other samples with metabolic function, including skeletal muscle and placent. Please see Panel 1.4 for discussion of utility of this gene in metabolic disease.

Example D

Identification of Single Nucleotide Polymorphisms in NOVX Nucleic Acid Sequences

[0982] Variant sequences are also included in this application. A variant sequence can include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be referred to as a “cSNP” to denote that the nucleotide sequence containing the SNP originates as a cDNA. A SNP can arise in several ways. For example, a SNP may be due to a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a transversion. A SNP can also arise from a deletion of a nucleotide or an insertion of a nucleotide, relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration of the amino acid encoded by the gene at the position of the SNP. Intragenic SNPs may also be silent, when a codon including a SNP encodes the same amino acid as a result of the redundancy of the genetic code. SNPs occurring, outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation of the expression pattern. Examples include alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message.

[0983] SeqCalling assemblies produced by the exon linking process were selected and extended using the following criteria. Genomic clones having, regions with 98% identity to all or part of the initial or extended sequence were identified by BLASTN searches using the relevant sequence to query human genomic databases. The genomic clones that resulted were selected for further analysis because this identity indicates that these clones contain the genomic locus for these SeqCalling assemblies. These sequences were analyzed for putative coding regions as well as for similarity to the known DNA and protein sequences. Programs used for these analyses include Grail, Genscan, BLAST, HMMER, FASTA, Hybrid and other relevant programs.

[0984] Some additional genomic regions may have also been identified because selected SeqCalling assemblies map to those regions. Such SeqCalling sequences may have overlapped with regions defined by homology or exon prediction. They may also be included because the location of the fragment was in the vicinity of genomic regions identified by similarity or exon prediction that had been included in the original predicted sequence. The sequence so identified was manually assembled and then may have been extended using one or more additional sequences taken from CuraGen Corporation's human SeqCalling database. SeqCalling fragments suitable for inclusion were identified by the CuraTools™ program SeqExtend or by identifying SeqCalling fragments mapping to the appropriate regions of the genomic clones analyzed.

[0985] The regions defined by the procedures described above were then manually integrated and corrected for apparent inconsistencies that may have arisen, for example, from miscalled bases in the original fragments or from discrepancies between predicted exon junctions, EST locations and regions of sequence similarity, to derive the final sequence disclosed herein. When necessary, the process to identify and analyze SeqCalling assemblies and genomic clones was reiterated to derive the full length sequence (Alderborn et al., Determination of Single Nucleotide Polymorphisms by Real-time Pyrophosphate DNA Sequencing. Genome Research. 10 (8) 1249-1265, 2000).

[0986] Variants are reported individually but any combination of all or a select subset of variants are also included as contemplated NOVX embodiments of the invention.

[0987] NOV1a SNP Data

[0988] Two polymorphic variants of NOV1a have been identified and are shown in Table 38A.

329NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified133793301530AG468GluGly133793251851AG565GluGly

[0989] NOV2a SNP Data

[0990] One polymorphic variant of NOV2a has been identified and is shown in Table 38B.

330NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified13379331527GA143AspAsn

[0991] NOV6a SNP Data

[0992] One polymorphic variant of NOV6a has been identified and is shown in Table 38C.

331NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified133793921225TC364LeuLeu

[0993] NOV7a SNP Data

[0994] One polymorphic variant of NOV7a has been identified and is shown in Table 38D.

332NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified133793323040CT1011ProSer

[0995] NOV9a SNP Data

[0996] One polymorphic variant of NOV9a has been identified and is shown in Table 38F.

333NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModifiedC110.2858808GA270ValIle

[0997] NOV10a SNP Data

[0998] Two polymorphic variants of NOV10a have been identified and are shown in Table 38F

334NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified13379346177CT 2ProSer13379347644GA157LeuLeu

[0999] NOV14a SNP Data

[1000] Three polymorphic variants of NOV14a have been identified and are shown in Table 38G

335NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified133793531320GC377SerSer133793521969CT594LeuLeu133793512345CC 0

[1001] NOV15a SNP Data

[1002] Two polymorphic variants of NOV15a have been identified and are shown in Table 38H

336NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified133794881140CT369CysCys133794891239CT402GlyGly

[1003] NOV18a SNP Data

[1004] Three polymorphic variants of NOV18a have been identified and are shown in Table 38I

337NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified133794961518GA456GluGlu133794971605CT485SerSer133795012433GA761ThrThr

[1005] NOV19a SNP Data

[1006] Four polymorphic variants of NOV19a have been identified and are shown in Table 38J.

338NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified13379323232AG74ProPro13379339399GA130SerAsn133793351185AG392GlnArg133793341230TG407ValGly

[1007] NOV24a SNP Data

[1008] Three polymorphic variants of NOV24a have been identified and are shown in

339NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified13379371969TC320LeuPro133793701237AG409SerSer133793691469GT0

[1009] NOV28a SNP Data

[1010] Three polymorphic variants of NOV28a have been identified and arc shown in

340NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified133794981410CT450AlaAla133794991502AG481AsnSer133795001562AG501GlnArg

[1011] NOV31a SNP Data

[1012] One polymorphic variant of NOV31a has been identified and is shown in Table 38M

341NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified13379464616GA0

[1013] NOV34a SNP Data

[1014] Two polymorphic variants of NOV34a have been identified and are shown in Table 38N.

342NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified13379495677TC225IleIle13379491783CT261ArgTrp

[1015] NOV35a SNP Data

[1016] Three polymorphic variants of NOV35a have been identified and are shown in Table 38O

343NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified13379453317GA75CysTyr13379456540TC149ThrThr13379455821GA0

[1017] NOV36a SNP Data

[1018] One polymorphic variants of NOV36a has been identified and is shown in Table 38P.

344NucleotidesAmino AcidsVariantPositionInitialModifiedPositionInitialModified133794771197AG0

Number	Date	Country
60303046	Jul 2001	US
60303828	Jul 2001	US
60358932	Feb 2002	US
60304502	Jul 2001	US
60305011	Jul 2001	US
60305262	Jul 2001	US
60307536	Jul 2001	US
60306085	Jul 2001	US
60308228	Jul 2001	US
60323449	Sep 2001	US
60308877	Jul 2001	US
60311753	Aug 2001	US
60309255	Aug 2001	US
60361765	Mar 2002	US

Novel human proteins, polynucleotides encoding them and methods of using the same

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