THERAPEUTIC TARGETING OF THE GABAA CHANNEL ON AIRWAY SMOOTH MUSCLE

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DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the airways whose global prevalence has taken on pandemic proportions. Although research has made great strides in elucidating the underlying mechanisms involved in asthma, in recent decades relatively few new additions have been made to the pharmacological armamentarium for this disease. Our laboratory has made several novel discoveries: (1) that 3-aminobutyric acid subtype A (GABAA) GABAA channels are expressed on airway smooth muscle cells, (2) that an endogenous GABAergic ligand-receptor system exists in the airway (3) that activation of endogenous airway smooth muscle GABAA channels potentiates relaxation, (4) that GABA (endogenously present in the airway) functions to modulate airway smooth muscle tone, (5) that systemic administration of a GABAA channel agonist administered in vivo attenuates agonist-induced airway constriction and that (6) part of propofol's broncho-relaxant effect is mediated by GABAA channels on airway smooth muscle. Since pharmacologic specificity of ligands/agonists directed at the GABAA channel is dictated by GABAA subunit composition, selective targeting of certain subunits restricted to a given tissue hold promise for improved therapy. Therefore, the goal of this research proposal is to elucidate the importance of airway smooth muscle GABAA channel subunit composition on the modulation of airway smooth muscle tone. The proposed experiments hold promise for determining how airway smooth muscle GABAA channel subunit heterogeneity can be harnessed to optimize relaxation of airway smooth muscle without promoting excessive sedation by globally activating all GABAA channels. The central significance of this proposal is the identification of a novel therapeutic mechanism to relax constricted airway smooth muscle following irritant induced bronchoconstriction. However, this work has the therapeutic potential to broadly impact the control of airway smooth muscle tone in the management of asthma and COPD. The specific therapeutic targeting of GABAA subunits expressed on airway smooth muscle coupled with traditional aerosol delivery methods to the airway, holds promise for a fundamental improvement in the pharmacologic therapy of asthma, a disease lacking in substantial improvements in drug therapy for several decades. This award will allow me to obtain the necessary investigational skills, experimental knowledge base, and fertile collaborative relationships to develop into a successful and independent clinician scientist. PUBLIC HEALTH RELEVANCE: The central significance of this proposal is the identification of a novel therapeutic mechanism to relax constricted airway smooth muscle. This work will harness the underutilized ability of anesthetics to allosterically enhance endogenous airway GABA effects at the airway smooth muscle GABAA channel. This proposal builds upon previous work from our laboratory identifying a limited repertoire of GABAA subunits comprising functional GABAA channels expressed on airway smooth muscle cells. The pharmacologic specific targeting of GABAA subunits expressed on airway smooth muscle coupled with traditional aerosol delivery methods to the airway, holds promise for a fundamental improvement in pharmacologic therapy of asthma, a disease lacking in substantial improvements in drug therapy for several decades.