The two most prevalent causes of death in Western civilization are myocardial and cerebral infarctions, conditions which are primarily the result of atherosclerotic lesions within the blood vessels supplying the heart and brain. Considerable evidence has now accumulated which suggests that platelet derived growth factor (PDGF) stimulates the growth of the smooth muscle cells which are the predominant cell type of these lesions. PDGF expression has been measured directly in cells of atherosclerotic plaques, and PDGF beta-receptor levels have been found to be higher in the smooth muscle cells of plaques relative to normal arterial tissue. Localized high concentration of PDGF exerts its mitogenic effect on cells through two specific receptor protein-tyrosine kinases. The objective of this project is to find specific inhibitors of these PDGF-receptor kinase activities for evaluation as therapeutic drugs in the treatment of atherosclerosis. This will be done by expressing and purifying recombinant a and beta PDGF receptor kinases, development of an in vitro high- throughput kinase inhibitor screen, and secondary cellular screens. The potential importance of finding a drug which inhibits PDGF action is underlined by the fact that in the USE alone about 765,000 people die of heart disease, and 154,000 of cerebrovascular diseases annually.
