AN IN VITRO SCREEN FOR ATYPICAL BETA-ADRENERGIC AGONISTS

THE ULTIMATE GOAL OF THIS RESEARCH IS TO DEVELOP A THERAPY FOR OBESITY BASED UPON THE IDENTIFICATION OF NOVEL BETA-ADRENERGIC AGONISTS THAT ARE SELECTIVE STIMULATORS OF THERMOGENESIS IN HUMANS. ATYPICAL (NON-BETA1, BETA2) BETA-ADRENERGIC RECEPTORS (BETA-ARS) ARE THOUGHT TO MEDIATE SYMPATHETIC NERVOUS SYSTEM STIMULATION OF THERMOGENESIS. ATYPICAL BETA- AGONISTS HAVE BEEN SHOWN TO STIMULATE THERMOGENESIS AND PROMOTE WEIGHT LOSS IN ANIMAL MODELS AND IN HUMAN CLINICAL TRIALS, BUT DESPITE THEIR RELATIVE SELECTIVITY, INTERACTIONS WITH BETA1-AR AND BETA2-AR PRODUCE SIDE EFFECTS. IMPROVEMENTS IN AGONIST SELECTIVITY FOR STIMULATION OF THERMOGENESIS WOULD LEAD TO USEFUL THERAPEUTICS. THE SPECIFIC AIM OF THE PROPOSED RESEARCH IS TO ESTABLISH A SCREENING SYSTEM FOR SELECTIVE THERMOGENIC BETA-AGONISTS. DURING PHASE I, THE POLYMERASE CHAIN REACTION (PCR) AND MOLECULAR CLONING TECHNIQUES WILL BE EMPLOYED TO IDENTIFY AND ISOLATE GENES FOR ATYPICAL BETA-ARS EXPRESSED IN TISSUESTHAT ARE SITES FOR THERMOGENESIS IN HUMANS. DURING PHASE II, THE GENES FOR ATYPICAL BETA-ARS WILL BE INTRODUCED INTO CHINESE HAMSTER OVARY CELLS TO ESTABLISH A MATRIX OF CELL LINES EXPRESSING FUNCTIONAL ATYPICAL RECEPTORS, WHICH WILL THEN BE USED TO SCREEN POTENTIAL THERMOGENIC AGONISTS.