INHIBITION OF MCP-1 GENE EXPRESSION AND ALTHEROGENESIS

THE TWO MOST PREVALENT CAUSES OF DEATH IN WESTERN CIVILIZATION, MYOCARDIAL AND CEREBRAL INFARCTIONS, ARE PRIMARILY THE RESULT OF ATHEROSCLEROTIC LESIONS. TWO MAJOR CONTRIBUTING FACTORS TO LESION FORMATION ARE THE ACCUMULATION OF CHOLESTEROL-ESTER-RICH MACROPHAGE-DERIVED 'FOAM CELLS,' AND HYPER-PROLIFERATION OF SMOOTH MUSCLE CELLS AND MACROPHAGES, DUE AT LEAST IN PART TO MITOGENS RELEASED BY THE LATTER. BOTH OF THESE PROCESSES COULD BE INHIBITED BY PREVENTING MONOCYTE RECRUITMENT TO LESION SITES. PRESENT EVIDENCE SUGGESTS THAT THE MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1) PLAYS AN IMPORTANT ROLE IN THIS PROCESS. THE MAJOR OBJECTIVE OF THIS PROJECT IS THEREFORE TO FIND INHIBITORS OF MCP-1 GENE EXPRESSION IN ORDER TO INVESTIGATE THEIR THERAPEUTIC POTENTIAL FOR INHIBITION OR PREVENTION OF ATHEROGENESIS. THIS WILL BE DONE BY DEVELOPING A HIGH-THROUGHPUT CELLULAR SCREEN TO FIND COMPOUNDS WHICH INHIBIT THE EXPRESSION OF A LUCIFERASE REPORTER GENE LINKED TO THE 5'- AND 3'-REGULATORY ELEMENTS OF THE MCP-1 GENE. IN PHASE I CONSTRUCTS WILL BE PREPARED AND TESTED IN TRANSIENT TRANSFECTANTS. THE POTENTIAL IMPORTANCE OF FINDING DRUGS WHICH INHIBIT ATHEROGENESIS IS UNDEDERLINED 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.