AMP-KINASE CASCADE ACTIVATORS AND ATHEROGENESIS

MYOCARDIAL AND CEREBRAL INFARCTION, CONDITIONS WHICH ARE PRIMARILY THE RESULT OF ATHEROSCLEROTIC LESIONS WITHIN CORONARY AND CEREBRAL BLOOD VESSELS, ARE THE LEADING CAUSES OF DEATH IN WESTERN CIVILIZATION. A CASUAL LINK BETWEEN HYPERCHOLESTEROLEMIA AND THE PREMATURE DEVELOPMENT OF ATHEROSCLEROSIS IS WELL ESTABLISHED. HEPATIC BIOSYNTHESIS IS RESPONSIBLE FOR THE MAJORITY OF CHOLESTEROL TRANSPORTED IN PLEAMA LIPOPROTEIN. THE RATE LIMITING ENZYME OF CHOLESTEROL BIOSYNTHESIS, HMGCOA REDUCTASE, IS THEREFORE A PRIME TARGET FOR DRUG INTERVENTION. HMGCOA REDUCTASE IS REGULATED BY A BICYCLIC PROTEIN KINASE CASCADE, THE AMP-ACTIVATED PROTEIN KINASE CASCADE. IT IS THE AIM OF THIS PROJECT TO DEVELOP A PURIFICATION SCHEME FOR THE AMP-ACTIVATED KINASE WITH THEULTIMATE GOAL BEING TO DEVELOP A HIGH THROUGHPUT SCREEN TO DISCOVER COMPOUNDS TO ACTIVATE THE KINASE KINASE AND THEREBY AMPLIFY THE CASCADE. THE PHASE I OF THE PROJECT WILL IDENTIFY A SUIT BLE SOURCE FOR ENZYME PURIFCATION AND THEREBY AMPLIFY THE CASCADE. THE PHASE I OF THE PROJECT WILL IDENTIFY A SUITABLE SOURCE FOR ENZYME PURIFICATION AND DEVELOP AN ENZYME-BASED ASSAYS WILLBE DEVELOPED AND THE ENZYME CLONED IN PHASE II.