TRANSCRIPTIONAL INHIBITION OF THE SCAVENGER RECEPTOR

ADVANCED CARDIOVASCULAR DISEASE IS FREQUENTLY ASSOCIATED WITH LARGE COMPLEX ATHEROSCLEROTIC LESIONS OR ATHEROMAS. THESE LESIONS, WHICH ARE FIRST CHARACTERIZED AS FATTY STREAKS IN THE ARTERIAL WALL, CONTAIN CHOLESTEROL LADEN CELLS DERIVED FROM MACROPHAGES ("FOAM CELLS"). MACROPHAGES APPEAR TO CONVERT TO FOAM CELLS PRINCIPALLY THROUGH THE ACTIVITY OF A PROTEIN TERMED THE SCAVENGER RECEPTOR. THIS PROTEIN TRANSPORTS LARGE QUANTITIES OF OXIDATIVELY MODIFIED LOW DENSITY LIPOPROTEIN INTO THE MACROPHAGE, CAUSING UNCONTROLLED ACCUMULATION OF INTRACELLULAR CHOLESTEROL AND CHRONIC PROGRESSION OF THE FATTY STREAK. HERE, WE WILL USE A NOVEL APPROACH FOR THE TREATMENT OF ATHEROSCLEROSIS, NAMELY THE DEVELOPMENT OF DRUGS WHICH SPECIFICALLY INHIBIT PLAQUE PROGRESSION BY TRANSCRIPTIONAL INHIBITION OF THE SCAVENGER RECEPTOR IN THE FOAM CELL. WE HAVE DEVELOPED A UNIQUE ROBOTIC TECHNOLOGY TO IDENTIFY MOLECULES WHICH ACT AS SPECIFIC MODULATORS OF GENE TRANSCRIPTION. THE AUTOMATED SCREEN CAN ANALYZE 1,500 COMPOUNDS PER WEEK AGAINST MULTIPLE TARGET GENES. THE POTENTIAL IMPORTANCE OF DEVELOPING SUCH A DRUG FROM THE LEADS IDENTIFIED IN PHASE II IS UNDERLINED BY THE FACT THAT ANNUALLY IN THE U. S., APPROXIMATELY 760,000 PEOPLE DIE OF MYOCARDIAL INFARCTION AND A FURTHER 155,000 PEOPLE DIE OF CEREBROVASCULAR DISEASE.