Claims
- 1. A method for identifying a compound capable of treating a metabolic disorder, comprising assaying the ability of the compound to modulate an MMP-12 nucleic acid expression or MMP-12 polypeptide activity, thereby identifying a compound capable of treating a metabolic disorder.
- 2. The method of claim 1, wherein the metabolic disorder is selected from the group consisting of obesity, overweight, diabetes, insulin resistance, cachexia, and anorexia.
- 3. The method of claim 1, wherein the ability of the compound to modulate a MMP-12 nucleic acid expression or a MMP-12 polypeptide activity is determined by detecting a MMP-12 activity of a cell.
- 4. The method of claim 1, wherein the MMP-12 is selected from the group consisting of:
a) a polypeptide comprising an amino acid sequence which is at least 90 percent identical to the amino acid sequence of SEQ ID NO:2 or 5; and b) a naturally occurring allelic variant of a polypeptide consisting of the amino acid sequence of SEQ ID NO:2, wherein the polypeptide is encoded by a nucleic acid molecule which hybridizes to a complement of a nucleic acid molecule consisting of SEQ ID NO:1 in 6×SSC at 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 65° C.
- 5. A method for identifying a compound capable of modulating a MMP-12 mediated metabolic activity, comprising:
(a) contacting a cell which expresses MMP-12 with a test compound; and (b) assaying the ability of the test compound to modulate the expression of a MMP-12 nucleic acid or the activity of a MMP-12 polypeptide, thereby identifying a compound capable of modulating a MMP-12 mediated metabolic activity.
- 6. A method for identifying a compound capable of modulating a MMP-12 mediated metabolic activity, comprising:
(a) contacting a composition comprising a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5 with a test compound; and (b) assaying the ability of the test compound to modulate the activity of the polypeptide, thereby identifying a compound capable of modulating a MMP-12 mediated metabolic activity.
- 7. The method of claim 5, wherein the MMP-12 is a polypeptide selected from the group consisting of:
a) a polypeptide comprising an amino acid sequence which is at least 90 percent identical to the amino acid sequence of SEQ ID NO:2 or 5, wherein said percent identity is calculated using the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4; and b) a naturally occurring allelic variant of a polypeptide consisting of the amino acid sequence of SEQ ID NO:2, wherein the polypeptide is encoded by a nucleic acid molecule which hybridizes to a complement of a nucleic acid molecule consisting of SEQ ID) NO:1 in 6×SSC at 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 65° C.
- 8. The method of claim 6, wherein the MMP-12 is a polypeptide selected from the group consisting of:
a) a polypeptide comprising an amino acid sequence which is at least 90 percent identical to the amino acid sequence of SEQ ID NO:2 or 5, wherein said percent identity is calculated using the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4; and b) a naturally occurring allelic variant of a polypeptide consisting of the amino acid sequence of SEQ ID NO:2, wherein the polypeptide is encoded by a nucleic acid molecule which hybridizes to a complement of a nucleic acid molecule consisting of SEQ ID NO:1 in 6×SSC at 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 65° C.
- 9. A method for modulating a MMP-12 mediated metabolic activity comprising contacting a cell or a tissue expressing the MMP-12 with a MMP-12 modulator, thereby modulating the MMP-12 mediated metabolic activity.
- 10. The method of claim 9, wherein the compound or modulator is selected from the group consisting of a small molecule MMP-12 agonist, a small molecule MMP-12 antagonist, a small molecule MMP-12 inverse agonist, an anti-MMP-12 antibody, an antisense MMP-12 molecule, and a MMP-12 ribozyme.
- 11. The method of claim 9, wherein the MMP-12 mediated metabolic activity comprises an activity selected from the group consisting of:
a) the ability to modulate lipid homeostasis; b) the ability to modulate glucose homeostasis; c) the ability to modulate insulin homeostasis; d) the ability to modulate adipocyte growth; and e) the ability to modulate the differentiation of adipose cell progenitors into adipocytes.
- 12. The method of claim 1, wherein the ability of the compound to modulate an NMP-12 nucleic acid expression or MMP-12 polypeptide activity is determined by detecting any one of:
a) cleavage of a MMP-12 target molecule; b) modulation of insulin sensitivity; c) modulation of glucose tolerance; d) modulation of hyperplastic growth; e) modulation of cell differentiation; f) modulation of hypertrophic growth; g) binding to a MMP-12 target molecule; h) binding to a MMP-12 cofactor; and i) metalloprotease enzyme activity.
- 13. The method of claim 5, wherein the ability of the compound to modulate an MMP-12 nucleic acid expression or MMP-12 polypeptide activity is determined by detecting any one of:
a) cleavage of a MMP-12 target molecule; b) modulation of insulin sensitivity; c) modulation of glucose tolerance; d) modulation of hyperplastic growth; e) modulation of cell differentiation; f) modulation of hypertrophic growth; g) binding to a MMP-12 target molecule; h) binding to a MMP-12 cofactor; and i) metalloprotease enzyme activity.
- 14. The method of claim 6, wherein the ability of the compound to modulate an MMP-12 nucleic acid expression or MMP-12 polypeptide activity is determined by detecting any one of:
a) cleavage of a MMP-12 target molecule; b) modulation of insulin sensitivity; c) modulation of glucose tolerance; d) modulation of hyperplastic growth; e) modulation of cell differentiation; f) modulation of hypertrophic growth; g) binding to a MMP-12 target molecule; h) binding to a MMP-12 cofactor; and i) metalloprotease enzyme activity.
- 15. A method for treating a subject having a metabolic disorder characterized by aberrant MMP-12 polypeptide activity or aberrant MMP-12 nucleic acid expression, comprising administering to the subject a MMP-12 modulator, thereby treating the subject having a metabolic disorder.
- 16. The method of claim 15, wherein said metabolic disorder is selected from the group consisting of obesity, overweight, diabetes, insulin resistance, cachexia, and anorexia.
- 17. The method of claim 15, wherein the modulator is selected from the group consisting of a small molecule MMP-12 agonist, a small molecule MMP-12 antagonist, a small molecule MMP-12 inverse agonist, an anti-MMP-12 antibody, an antisense MMP-12 molecule, and a MMP-12 ribozyme.
- 18. A pharmaceutical formulation for the treatment of metabolic disorders, comprising a compound selected from:
a) a compound that activates MMP-12 polypeptide activity or MMP-12 nucleic acid expression, and b) a compound that inhibits MMP-12 polypeptide activity or MMP-12 nucleic acid expression; wherein the formulation further comprises a pharmaceutically acceptable carrier.
- 19. The pharmaceutical formulation of claim 18, wherein the compound is selected from the group consisting of a small molecule MMP-12 agonist, a small molecule MMP-12 antagonist, a small molecule MMP-12 inverse agonist, an anti-MMP-12 antibody, an antisense MMP-12 molecule, and a MMP-12 ribozyme.
- 20. The pharmaceutical formulation of claim 19 in which the compound is an oligonucleotide encoding an antisense or ribozyme molecule that targets MMP-12 transcripts and inhibits translation or an oligonucleotide that forms a triple helix with the promoter of the MMP-12 gene and inhibits transcription.
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 60/346,354, filed Jan. 7, 2002, the contents of which are incorporated herein by this reference.
Provisional Applications (1)
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Number |
Date |
Country |
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60346354 |
Jan 2002 |
US |