Compositions and methods for the treatment and diagnosis of cardiovascular disease

Abstract

The present invention relates to methods and compositions for the treatment and diagnosis of cardiovascular disease, including, but not limited to, atherosclerosis, ischemia/reperfusion, hypertension, restenosis, and arterial inflammation. Specifically, the present invention identifies and describes genes which are differentially expressed in cardiovascular disease states, relative to their expression in normal, or non-cardiovascular disease states, and/or in response to manipulations relevant to cardiovascular disease. Further, the present invention identifies and describes genes via the ability of their gene products to interact with gene products involved in cardiovascular disease. Still further, the present invention provides methods for the identification and therapeutic use of compounds as treatments of cardiovascular disease. Moreover, the present invention provides methods for the diagnostic monitoring of patients undergoing clinical evaluation for the treatment of cardiovascular disease, and for monitoring the efficacy of compounds in clinical trials. Additionally, the present invention describes methods for the diagnostic evaluation and prognosis of various cardiovascular diseases, and for the identification of subjects exhibiting a predisposition to such conditions.

What is claimed is:  
     
         1 . A method for identifying a substance to be tested for an ability to ameliorate symptoms of a fibroproliferative disease or oncogenic related disorder comprising, assaying the ability of the substance to modulate the expression of, or the activity of the encoded protein product of the rchd534 gene or the fchd540 gene.  
     
     
         2 . The method of  claim 1  in which the fibroproliferative disease is diabetic retinopathy.  
     
     
         3 . The method of  claim 1  in which the oncogenic related disorder is a tumor growth.  
     
     
         4 . The method of  claim 1  in which the oncogenic related disorder is angiogenesis.  
     
     
         5 . The method of  claim 1 , wherein the oncogenic related disorder is pancreatic cancer.  
     
     
         6 . The method of  claim 1 , wherein the expression of, or the activity of the encoded protein product of, the rchd534 gene or the fchd540 is reduced.  
     
     
         7 . The method of  claim 1  in which the expression of the gene is assayed by: 
 (a) exposing a sample of cells to a test substance;  
 (b) assaying the expression of said gene in the sample of cells; and  
 (c) comparing the expression level of the gene in the sample exposed to the substance to the expression level of the gene in a control sample of cells.  
 
     
     
         8 . The method of  claim 7  in which the substance is an oligonucleotide complementary to the 5′ region of the gene and blocks transcription via triple helix formation.  
     
     
         9 . The method of  claim 7  in which the substance is an antisense or ribozyme molecule that blocks translation of the gene.  
     
     
         10 . The method of  claim 1  in which the substance is a small organic or inorganic molecule that modulates the activity of the protein product by binding to the protein product.  
     
     
         11 . The method of  claim 10  in which the reduces the activity of the protein product by binding to the protein product.  
     
     
         12 . The method of  claim 1  in which the substance is an antibody that modulates the activity of the protein product by binding to the protein product.  
     
     
         13 . The method of  claim 12  in which the substance reduces the activity of the protein product by binding to the protein product.  
     
     
         14 . A method for enhancing TGF-β signalling in a cell, comprising contacting a cell expressing the fchd540 gene with a substance that reduces the expression of, or the activity of the encoded protein product of, the fchd540 gene, such that TGF-β signalling in the cell is enhanced.  
     
     
         15 . The method of  claim 14 , wherein the substance inhibits interaction between the fchd540 protein and a protein member of the TGF-β signalling pathway.  
     
     
         16 . The method of  claim 15 , wherein the member of the TGF-β signalling pathway is activated TβR1.  
     
     
         17 . The method of  claim 14 , wherein the substance inhibits the interaction between the rchd534 protein and the fchd540 protein.  
     
     
         18 . The method of  claim 14  in which the substance is an antisense or ribozyme molecule that blocks translation of the gene.  
     
     
         19 . The method of  claim 14  in which the substance is complementary to the 5′ region of the gene and blocks transcription via triple helix formation.  
     
     
         20 . The method of  claim 14  in which the substance is an antibody that inhibits the activity of the protein product.  
     
     
         21 . A method for ameliorating symptoms of fibroproliferative disease or an oncogenic related disorder comprising administering a substance that reduces the expression of, or the activity of the encoded protein product of, the fchd540 gene, to a patient exhibiting such symptoms.  
     
     
         22 . The method of  claim 21 , wherein the substance inhibits interaction between the fchd540 protein and a protein member of the TGF-β signalling pathway.  
     
     
         23 . The method of  claim 22 , wherein the member of the TGF-β signalling pathway is activated TβR1.  
     
     
         24 . The method of  claim 21 , wherein the substance inhibits the interaction between the rchd534 protein and the fchd540 protein.  
     
     
         25 . The method of  claim 22  in which the substance is an antisense or ribozyme molecule that blocks translation of the gene.  
     
     
         26 . The method of  claim 22  in which the substance is complementary to the 5′ region of the gene and blocks transcription via triple helix formation.  
     
     
         27 . The method of  claim 22  in which the substance is an antibody that inhibits the activity of the protein product.  
     
     
         28 . A method for enhancing TGF-β signalling in a cell, comprising contacting a cell expressing the rchd534 gene with a substance that reduces the expression of, or the activity of the encoded protein product of, the rchd534 gene, such that TGF-β signalling in the cell is enhanced.  
     
     
         29 . The method of  claim 28 , wherein the substance inhibits interaction between the rchd534 protein and a protein member of the TGF-β signalling pathway.  
     
     
         30 . The method of  claim 29 , wherein the member of the TGF-β signalling pathway is activated TβR1.  
     
     
         31 . The method of  claim 28 , wherein the substance inhibits the interaction between the rchd534 protein and the fchd540 protein.  
     
     
         32 . The method of  claim 28  in which the substance is an antisense or ribozyme molecule that blocks translation of the gene.  
     
     
         33 . The method of  claim 28  in which the substance is complementary to the 5′ region of the gene and blocks transcription via triple helix formation.  
     
     
         34 . The method of  claim 28  in which the substance is an antibody that inhibits the activity of the protein product.  
     
     
         35 . A method for ameliorating symptoms of fibroproliferative disease or an oncogenic related disorder comprising administering a substance that reduces the expression of, or the activity of the encoded protein product of, the rchd534 gene, to a patient exhibiting such symptoms.  
     
     
         36 . The method of  claim 35 , wherein the substance inhibits interaction between the rchd534 protein and a protein member of the TGF-β signalling pathway.  
     
     
         37 . The method of  claim 36 , wherein the member of the TGF-β signalling pathway is activated TβR1.  
     
     
         38 . The method of  claim 35 , wherein the substance inhibits the interaction between the rchd534 protein and the fchd540 protein.  
     
     
         39 . The method of  claim 35  in which the substance is an antisense or ribozyme molecule that blocks translation of the gene.  
     
     
         40 . The method of  claim 35  in which the substance is complementary to the 5′ region of the gene and blocks transcription via triple helix formation.  
     
     
         41 . The method of  claim 35  in which the substance is an antibody that inhibits the activity of the protein product.  
     
     
         42 . A method for diagnosing a fibroproliferative disease or an oncogenic related disorder comprising detecting the level of fchd540 transcript or rchd534 transcript present in a patient sample.  
     
     
         43 . The method of  claim 42 , wherein the fchd540 or the rchd534 transcript level detected is differential to that of a corresponding control sample.  
     
     
         44 . The method of  claim 43 , wherein the fchd540 or the rchd534 transcript level detected is higher than that of a corresponding control sample.  
     
     
         45 . The method of  claim 42  wherein the oncogenic related disorder is pancreatic cancer.  
     
     
         46 . A method for diagnosing a fibroproliferative disease or an oncogenic related disorder comprising detecting fchd540 or rchd534 protein level or protein activity present in a patient sample.  
     
     
         47 . The method of  claim 45 , wherein the fchd540 or the rchd534 protein level or activity detected is differential to that of a corresponding control sample.  
     
     
         48 . The method of  claim 46 , wherein the fchd540 or the rchd534 protein level or activity detected is higher than that of a corresponding control sample.  
     
     
         49 . The method of  claim 45  wherein the oncogenic related disorder is pancreatic cancer.  
     
     
         50 . A method for characterizing a fibroproliferative disease or oncogenic related disorder comprising, assaying, in a patient sample, overexpression of a gene encoding the fchd531 protein, the fchd540 protein or the rchd534 protein relative to expression in a control sample.  
     
     
         51 . The method of  claim 51 , wherein the oncogenic related disorder is pancreatic cancer.  
     
     
         52 . A method for monitoring the efficacy of a compound in clinical trials for the treatment of a fibroproliferative disease or oncogenic related disorder comprising, assaying, in a patient sample, overexpression of a gene encoding the fchd540 protein or the rchd534 protein relative to expression in a control sample.  
     
     
         53 . The method of  claim 52 , wherein the oncogenic related disorder is pancreatic cancer.