The two most prevalent causes of death in Western civilization are myocardial and cerebral infarctions. These conditions are primarily the result of atherosclerotic lesions which occlude the blood vessels supplying the heart and brain. Considerable evidence has now accumulated which suggest that platelet-derived growth factor (PDGF) stimulates the growth of the cells which form these lesions. Localized high concentrations of PDGF are thought to arise at the lesions due to its release from damaged endothelium and adhering platelets at the lesion site. PDGF exerts its mitogenic effect on cells through a specific plasma membrane PDGF receptor protein-tyrosine kinase. The ultimate objective of the proposed project is to find specific inhibitors of PDGF receptor kinase activity for evaluation as therapeutic drugs in the treatment of atherosclerosis. In order to do this, Phase I of the project will purify the human PDGF-receptor and develop an assay for PDGF-dependent, PDGF receptor protein-tyrosine kinase activity, which is capable of being automated so that large numbers of potential inhibitor compounds can be screened. The potential importance of finding a drug which inhibits PDGF action is underlined by the fact that annually in the USA alone about 765,000 people die of heart disease, and 154,000 of cerebrovascular diseases.
