BETA ADRENERGIC RECEPTOR REGULATION IN HUMAN AIRWAY MUSC

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DESCRIPTION (Adapted from applicant's abstract and specific aims): Beta-adrenergic receptors (b2ARs) on airway smooth muscle play an important role in regulating airway smooth muscle tone and airway patency, while beta-sympathomimetic drugs are the most widely used agents in asthma therapy and are universally recognized as the treatment of choice for acute asthma attacks. Despite the clinical importance of beta-agonists and a good understanding of how b2AR activation promotes airway smooth muscle relaxation, surprisingly little is known regarding the manner in which the b2AR signaling pathway is regulated in airway smooth muscle. The long-term objective of this project is to delineate the molecular and cellular mechanisms by which relevant physiological agents, such as inflammatory mediators, glucocorticoids, and beta-agonists themselves, alter b2AR responsiveness in human airway smooth muscle (HASM). The specific aims are: 1) characterization of the desensitization and recovery from desensitization of b2AR function in HASM cells; 2) characterization of the principal mechanisms by which b2AR signaling is regulated during the desensitization and resensitization processes; and 3) identification of the role of protein kinases in these processes.