INHIBITION OF IL-1 DEPENDENT KINASE AND ATHEROGENESIS

THE TWO MOST PREVALENT CAUSES OF DEATH IN WESTERN CIVILIZATION, MYOCARDIAL AND CEREBRAL INFARCTIONS, ARE PRIMARILY THE RESULT OF ATHEROSCLEROTIC LESIONS. IT IS CLEAR THAT UNCONTROLLED PROLIFERATION OF VASCULAR SMOOTH MUSCLE CELLS (VSMCS) PLAYS A MAJOR ROLE IN ADVANCED LESION FORMATION. INTERLEUKIN-1 (IL-1), ACTING SYNERGISTICALLY WITH PDGF, IS A POTENT MITOGEN FOR VSMCS. BOTH OF THESE FACTORS ARE PRODUCED BY MACROPHAGES AT LESION SITES. THE INDUCTION BY IL-1 OF BOTH MACROPHASE CHEMOTACTIC PROTEIN-1 AND IL-1 ITSELF IN VASCULAR ENDOTHELIUM ENSURES THAT LESION IL-1 LEVELS REMAIN HIGH. THE OBJECTIVE OF THIS PROJECT IS TO FIND SPECIFIC INHIBITORS OF THE PROTEIN-TYROSINE KINASE THROUGH WHICH IL-1 EXERTS ITS EFFECTS ON CELLS. IN PHASE I, A PURIFICATION FOR THE KINASE WILL BE DEVELOPED. IN PHASE II, THIS WILL BE USED TO OBTAIN SEQUENCE INFORMATION FOR CLONING AND PRODUCTION OF LARGE AMOUNTS OF THE PROTEIN. IN VITRO HIGH-THROUGHPUT KINASE INHIBITOR SCREENS, AND SECONDARY CELLULAR SCREENS, WILL THEN BE DEVELOPED. THE INITIAL CLINICAL TARGET WOULD BE TO PREVENT VASCULAR RESTENOSIS FOLLOWING BALLOON ANGIOPLASTY. THE POTENTIAL IMPORTANCE OF FINDING DRUGS WHICH INHIBIT ATHEROGENESIS IS UNDERLINED BY THE FACT THAT EACH YEAR IN THE U.S.A. ALONE ABOUT 765,000 PEOPLE DIE OF HEART DISEASE AND 150,000 OF CEREBROVASCULAR DISEASE.