ETHANOL MEDIATED CILIA MOTILITY DYSFUNCTION

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DESCRIPTION (Adapted from the applicant's abstract): Alcoholics have a high incidence of pulmonary diseases due to altered lung host defenses. A major airway defense function that is impaired during alcohol ingestion is mucociliary clearance, which is dependent on the coordinated beating of cilia that line the airways. Studies from this laboratory indicate that short term ethanol exposure stimulates ciliary motility through a nitric oxide-dependent mechanism that requires the activation of both cAMP- and cGMP-dependent protein kinases (PKA and PKG). In contrast, chronic exposure to ethanol causes desensitization of ciliary motility such that the cell no longer responds to stimulation by beta-agonists. In this context we hypothesize that: Chronic ethanol exposure impairs airway ciliary responsiveness by downregulating NO-dependent protein kinase activity resulting in altered phosphorylation of cilia target proteins and impaired mucociliary clearance. The test this hypothesis experiments will befocused around four specific aims: 1) Characterize the differences in airway cell signal transduction between acute ethanol cilia stimulation and chronic ethanol cilia desensitization; 2) Determine the intracellular factor(s) that ethanol targets resulting in chronic ciliary desensitization; 3) Determine the phosphorylation targets in the cilia axoneme that ethanol mediates through protein kinase activation; and 4) Characterize the effects in vivo of acute and chronic ethanol exposure on airway kinase activation and ciliary responsiveness. The impact of alcohol-related respiratory illnesses on society is great. The studies outlined in this proposal will explore a novel nitric oxide/PKA/PKG-dependent mechanism by which ethanol impairs ciliary function. Establishing how ethanol both acutely stimulates and chronically desensitized ciliary motility in the airway epithelium will provide meaningful insight into the role alcohol ingestion plays in the pathogenesis of bronchitis, pneumonia and lung cancer.