Claims
- 1. A method of inhibiting the generation of active thrombin on the surface of a cell of a mammal, the method comprising producing an ER resident chaperone protein in said cell.
- 2. The method of claim 1, wherein said cell is an endothelial cell.
- 3. The method of claim 1, wherein said cell is a smooth muscle cell.
- 4. The method of claim 1, wherein said cell is a macrophage.
- 5. The method of claim 1, wherein said cell is a monocyte.
- 6. The method of claim 1, wherein said ER resident chaperone protein is GRP78/BiP.
- 7. The method of claim 1, wherein said ER resident chaperone protein is selected from the group consisting of GRP94, GRP72, Calreticulin, Calnexin, Protein disulfide isomerase, cis/trans-Prolyl isomerase, and HSP47.
- 8. The method of claim 1, wherein the production of said ER resident chaperone protein within said cell results in a decrease in the level of tissue factor procoagulant activity on the surface of said cell.
- 9. The method of claim 1, wherein said cell is present within said mammal.
- 10. The method of claim 9, wherein said cell is present within an atherosclerotic plaque in said mammal.
- 11. The method of claim 1, wherein a polynucleotide encoding said ER resident chaperone protein, operably linked to a promoter, is introduced into said cell, whereby said ER resident chaperone protein is produced.
- 12. The method of claim 11, wherein said polynucleotide is introduced into said cell using a viral vector.
- 13. The method of claim 12, wherein said viral vector is an adenoviral vector.
- 14. The method of claim 11, wherein said polynucleotide is introduced into said cell using a nonviral vector.
- 15. The method of claim 14, wherein said nonviral vector is introduced into said cell as naked DNA or using liposome-mediated transfection.
- 16. The method of claim 1, wherein said ER resident chaperone protein is produced by administering to said cell a compound that induces the expression or activation of an endogenous ER resident chaperone protein.
- 17. The method of claim 16, wherein said compound is a cytokine.
- 18. A method of preventing or treating a thrombotic disease or condition in a mammal, the method comprising producing an ER resident chaperone protein within a population of cells of said mammal, whereby the generation of active thrombin on the surface of said population of cells is inhibited.
- 19. The method of claim 18, wherein said population of cells comprises endothelial cells.
- 20. The method of claim 18, wherein said population of cells comprises smooth muscle cells.
- 21. The method of claim 18, wherein said population of cells comprises macrophages.
- 22. The method of claim 18, wherein said population of cells comprises monocytes.
- 23. The method of claim 18, wherein said ER resident chaperone protein is GRP78/BiP.
- 24. The method of claim 18, wherein said ER resident chaperone protein is selected from the group consisting of GRP94, GRP72, Calreticulin, Calnexin, Protein disulfide isomerase, cis/trans-Prolyl isomerase, and HSP47.
- 25. The method of claim 18, wherein the production of said ER resident chaperone protein within said population of cells results in a decrease in the level of tissue factor procoagulant activity on the surface of said population of cells.
- 26. The method of claim 18, wherein said population of cells is present within an atherosclerotic plaque in said mammal.
- 27. The method of claim 18, wherein said mammal has had a myocardial infarction and is undergoing angioplasty or stenting.
- 28. The method of claim 27, wherein said mammal is undergoing stenting, and said population of cells is present on the surface of a stent within said mammal.
- 29. The method of claim 18, wherein said mammal is undergoing cranial radiation.
- 30. The method of claim 18, wherein said mammal is undergoing vascular surgery.
- 31. The method of claim 18, wherein a polynucleotide encoding said ER resident chaperone protein, operably linked to a promoter, is introduced into said population of cells, whereby said ER resident chaperone protein is produced.
- 32. The method of claim 31, wherein said polynucleotide is introduced into said cell using a viral vector.
- 33. The method of claim 32, wherein said viral vector is an adenoviral vector.
- 34. The method of claim 31, wherein said polynucleotide is introduced into said cell using a nonviral vector.
- 35. The method of claim 34, wherein said nonviral vector is introduced into said cell as naked DNA or using liposome-mediated transfection.
- 36. The method of claim 18, wherein said ER resident chaperone protein is produced by administering to said population of cells a compound that induces the expression or activation of an endogenous ER resident chaperone protein.
- 37. The method of claim 36, wherein said compound is a cytokine.
- 38. A method of identifying a compound that is useful in the treatment or prevention of a thrombotic disease or condition, the method comprising:
(1) contacting a cell that expresses an ER resident chaperone protein, or that is capable of expressing an ER resident chaperone protein, with said compound; and (2) detecting the functional effect of said compound on said ER resident chaperone protein; wherein an increase in the expression or activity of said ER resident chaperone protein in said cell indicates that said compound would be useful in the treatment or prevention of said thrombotic disease or condition.
- 39. The method of claim 38, wherein said ER resident chaperone protein is GRP78/BiP.
- 40. The method of claim 38, wherein said ER resident chaperone protein is selected from the group consisting of GRP94, GRP72, Calreticulin, Calnexin, Protein disulfide isomerase, cis/trans-Prolyl isomerase, and HSP47.
- 41. The method of claim 38, wherein said cell is an endothelial cell.
- 42. The method of claim 38, wherein said cell is a smooth muscle cell.
- 43. The method of claim 38, wherein said cell is a macrophage.
- 44. The method of claim 38, wherein said cell is a monocyte.
- 45. The method of claim 38, wherein said compound induces said expression or activation of said ER resident chaperone protein in said cell without inducing ER stress in said cell.
- 46. A method of treating or preventing a thrombotic disease in a mammal, the method comprising administering to said mammal a therapeutically or prophylactically effective amount of a compound identified using the method of claim 38.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional Application No. 60/197,146, filed Apr. 14, 2000, which application is incorporated herein by reference for all purposes.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60197146 |
Apr 2000 |
US |