NEW TARGETS IN ASTHMA THERAPY: BETA-ADRENERGIC RECEPTOR KINASE

BETA-ADRENERGIC AGONISTS ARE USED IN THE TREATMENT OF CHRONIC AND EXERCISE-INDUCED ASTHMA. THESE AGENTS WORK THROUGH THE BETA-ADRENERGIC RECEPTOR/ADENYLATE CYCLASE-COUPLED EFFECTOR SYSTEM, PRODUCING RELAXATION OF THESMOOTH MUSCLE OF THE TRACHEA AND BRONCHIAL TREE, AND THEREBY RELIEVING ASTHMATIC SYMPTOMS. AGONIST BINDING BY THE RECEPTOR LEADS TO DESENSITIZATION AND REDUCED AGONIST RESPONSE. A NOVEL PROTEIN KINASE, BETA-ADRENERGIC RECEPTOR KINASE, IS INTIMATELY INVOLVED IN THIS PROCESS. THE AIM OF THIS RESEARCH IS TO ESTABLISH THE MEANS OF IDENTIFYING SPECIFIC INHIBITORS OF THIS KINASE THAT COULD BE USED TO EXTEND THE EFFECTIVENESS OF BETA-AGONISTS. SPECIFICALLY, A RANGE OF AVAILABLE HUMAN CELLS AND TISSUES WILL BE SCREENED AS POTENTIAL SOURCES OF THE KINASE AND THEN IT WILL BE PURIFIED FROM THE BEST SOURCE. CANDIDATE PEPTIDES WILL BE PREPARED AND EXAMINED AS MODEL SUBSTRATES FOR THE KINASE. THE COMPONENTS WILL THEN BE CONFIGURED TO AHIGH-THROUGHPUT ASSAY DESIGNED TO IDENTIFY POTENTIAL DRUGS. IN PHASE II, ONCOGENE SCIENCE, INC., WILL CLONE AND EXPRESS THE KINASE, IF THIS IS REQUIRED, AND INITIATE SCREENING. SECONDARY SCREENS DESIGNED TO EVALUATE THE SPECIFICITY AND IN VIVO EFFECTIVENESS OF LEAD COMPOUNDS FROM THE PRIMARY HIGH-THROUGHPUT SCREEN WILL ALSO BE ESTABLISHED.