Claims
- 1. A method for diagnosing glaucoma comprising detecting an aberrant level or bioactivity of a Wnt pathway component or a frizzled related protein gene product in a patient sample.
- 2. The method of claim 1, wherein the patient sample comprises cells of the trabecular meshwork cells tissue or patient tears.
- 3. The method of claim 1, wherein an aberrantly high level of a frizzled related protein gene product is diagnostic of a glaucomatous state.
- 4. The method of claim 3 wherein the frizzled related protein gene product is an FRP-1 nucleic acid or an FRP-1 polypeptide.
- 5. The method of claim 1, wherein the Wnt pathway component is selected from the group consisting of: a Wnt gene, a Frizzled gene, a glycogen synthase-kinase gene, a protein kinase C gene, a beta-catenin gene, a TCF gene, a TCF regulated gene and a hedgehog gene.
- 6. The method of claim 1, wherein the Wnt pathway component bioactivity is a beta-catenin bioactivity.
- 7. The method of claim 6, wherein the beta-catenin bioactivity is measured by determining the level of phosphorylated beta-catenin.
- 8. The method of claim 6, wherein an aberrantly level of phosphorylated beta-catenin is diagnostic of glaucoma.
- 9. The method of claim 1, wherein the Wnt pathway component bioactivity is a kinase.
- 10. The method of claim 8, wherein the kinase is a glycogen synthase kinase-3 or a protein kinase C.
- 11. The method of claim 10, wherein an aberrantly level of a glycogen synthase kinase-3 activity or a protein kinase C activity is diagnostic of a glaucomatous state.
- 12. A method for diagnosing glaucoma comprising detecting at least one human polymorphic allele in a Wnt pathway component encoding gene or in a frizzled related protein encoding gene obtained from a patient sample.
- 13. The method of claim 12, wherein the patient sample is a blood sample or a cheek swab sample.
- 14. The method of claim 12, wherein the human polymorphic allele is in the FRP-1 gene.
- 15. The method of claim 14, wherein the human polymorphic allele is in the FRP-1 gene promoter.
- 16. The method of claim 15, FRP-1 gene promoter polymorphic allele is associated with increased expression of an FRP-1 gene product.
- 17. A method of identifying an anti-glaucomatous compound comprising:
contacting a cell expressing a Wnt pathway component or a frizzled related protein gene product with a test compound; and detecting a level or bioactivity of said Wnt pathway component or said frizzled related protein gene product in the presence of the test compound; wherein an increase or decrease in the level or bioactivity of the Wnt pathway component or the frizzled related protein gene product in the presence of the test compound as compared to the level or bioactivity detected in the absence of the test compound identifies said test compound as an anti-glaucomatous compound.
- 18. The method of claim 17, wherein a decrease in the level or bioactivity of a frizzled related protein gene product detected in the presence of the test as compared to the level or bioactivity detected in the absence of the test compound identifies said test compound as an anti-glaucomatous compound.
- 19. The method of claim 18, wherein the frizzled related protein gene is FRP-1.
- 20. The method of claim 17, wherein and increase in the level or bioactivity of a Wnt pathway component detected in the presence of the test as compared to the level or bioactivity detected in the absence of the test compound identifies said test compound as an anti-glaucomatous compound.
- 21. The method of claim 20, wherein the Wnt pathway component is selected from the group consisting of: a Wnt gene product, a Frizzled gene product, a glycogen synthase-kinase gene product, a protein kinase C gene product, a beta-catenin gene product, a TCF gene product, a TCF regulated gene product, and a hedgehog gene product.
- 22. The method of claim 20, wherein the Wnt pathway component bioactivity is a beta-catenin bioactivity.
- 23. The method of claim 22, wherein the beta-catenin bioactivity is measured by determining the level of phosphorylated beta-catenin.
- 24. The method of claim 23, wherein a decrease in the level of phosphorylated beta-catenin in the presence of the test compound as compared to the level of phosphorylated beta-catenin in the absence of the test compound identifies said test compound as an anti-glaucomatous compound.
- 25. The method of claim 17, wherein the Wnt pathway component bioactivity is a kinase activity.
- 26. The method of claim 25, wherein the kinase activity is a glycogen synthase kinase-3 activity and wherein a change in the level of the kinase activity in the presence of the test compound as compared to the level of the kinase activity in the absence of the test compound identifies said test compound as an anti-glaucomatous compound.
- 27. The method of claim 25, wherein the kinase activity is a protein kinase C activity and wherein a change in the level of the kinase activity in the presence of the test compound as compared to the level of the kinase activity in the absence of the test compound identifies said test compound as an anti-glaucomatous compound.
- 28. A method of identifying an anti-glaucomatous compound comprising:
contacting a cell sample with a test compound; and measuring a level or bioactivity of a Wnt responsive gene; wherein an increase in the level of the Wnt responsive gene in the presence of the test compound as compared to the level or bioactivity of the Wnt responsive gene in the absence of the test compound identifies said test compound as an anti-glaucomatous compound.
- 29. The method of claim 28, wherein the Wnt responsive gene is selected from the group consisting of: a hedgehog gene, an engrailed gene, a Lef/tcf-regulated gene, a synthetic reporter gene.
- 30. A method for treating glaucoma in a human subject, comprising
administering to the subject, a therapeutically effective amount of a compound that modulates the level or bioactivity of a Wnt pathway component or frizzled related protein gene product.
- 31. The method of claim 24, wherein the compound is selected from the group consisting of: a protein, peptide, peptidomimetic, small molecule or nucleic acid.
- 32. The method of claim 31, wherein the nucleic acid is selected from the group consisting of: a gene, antisense, ribozyme and triplex nucleic acid.
- 33. The method of claim 31, wherein the nucleic acid is a frizzled related protein gene nucleic acid.
- 34. The method of claim 30, wherein the compound is an antagonist of a frizzled related protein gene product.
- 35. The method of claim 34, wherein the compound is a gene therapeutic.
- 36. The method of claim 34, wherein the compound is a protein therapeutic.
- 37. The method of claim 30, wherein the compound is an agent that increases the level of a Wnt pathway component gene or bioactivity.
- 38. A method of claim 30,;wherein the compound is comprised of an antagonist
of a mutant frizzled related protein gene or gene product.
- 39. A method of claim 38, wherein the compound is an antisense, ribozyme or triple helix molecule.
- 40. A method of claim 38, wherein the compound is a small molecule, peptide, or eptidomimetic.
- 41. A method of claim 38, wherein the compound is an antibody.
- 42. A method for screening for a frizzled related protein agonist or antagonist comprising the steps of:
a) combining a frizzled related protein polypeptide or bioactive fragments thereof, a frizzled related protein binding partner and a test compound under conditions wherein, but for the test compound, the frizzled related protein protein and frizzled related protein binding partner binding partner are able to interact; and b) detecting the extent to which a frizzled related protein/frizzled related protein binding partner complex is formed in the presence of the test compound, wherein an increased amount of complex formation in the presence of the test compound relative to in the absence of a test compound indicates that the test compound is a frizzled related protein agonist and a decreased amount of complex formation in the presence of the test compound relative to in the absence of the test compound indicates that the test compound is a frizzled related protein antagonist.
- 43. A method of claim 43, which additionally comprises the step of preparing a pharmaceutical composition from the test compound.
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 60/186,073, filed Feb. 29, 2000, the entire contents of which are incorporated herein by reference.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60186073 |
Feb 2000 |
US |