PDGF-RECEPTOR KINASE INHIBITORS FOR ATHEROSCLEROSIS

THE TWO MOST PREVALENT CAUSES OF DEATH IN WESTERN CIVILIZATION ARE MYOCARDIAL AND CEREBRAL INFARCTIONS, CONDITIONS THAT ARE PRIMARILY THE RESULT OF ATHEROSCLEROTIC LESIONS WITHIN THE BLOOD VESSELS SUPPLYING THE HEART AND BRAIN. EVIDENCE SUGGESTS THAT PLATELET-DERIVED GROWHT 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 PLAGUES RELATIVE TO NORMAL ARTERIAL TISSUE. LOCALIZED HIGH CONCENTRATIONS OF PDGF ARE ALSO THOUGHT TO BE PRODUCED BY ADHERING PLATELETS AT THE LESION SITE. PDGF EXERTS ITS MITOGENIC EFFECT ON CELLS THROUGH TWO SPECIFIC RECEPTOR PROTEIN-TYROSINE KINASES. THE OBJECTIVE OF THIS PROJECT IS TO FIND SPECIFIC INHIBITORSOF THESE PDGF-RECEPTOR KINASE ACTIVITIES FOR EVALUATION AS THERAPEUTIC DRUGS IN THE TREATMENT OF ATHEROCSLEROSIS. THISWILL BE DONE BY EXPRESSING AND PURIFYING RECOMBINANT ALPHA AND BETA PDGF-RECEPTOR KINASES AND DEVELOPMENT OF AN IN VITRO HIGH-THROUGHPUT KINASE INHIBITOR SCREEN AND SECONDARY CELLULAR SCREENS. AWARDEE'S STATEMENT OF THE POTENTIAL COMMERCIAL APPLICATIONSOF THE RESEARCH: PDGF-RECEPTOR KINASE INHIBITORS HAVE GREATPOTENTIAL FOR THE TREATMENT OF ATHEROSCLEROSIS AND A NUMBER OF OTHER PROLIFERATIVE DISORDERS, INCLUDING GLIOBLASTOMAS AND KAPOSI'S SARCOMA. AN EFFECTIVE DRUG OF THIS TYPE COULD HAVE THE POTENTIAL TO GENERATE REVENUES IN EXCESS OF $1 BILLION ANNUALLY.