Pathophysiology of Mucus Hypersecretion in Asthma

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DESCRIPTION: (provided by applicant):Mucus hypersecretion is a prominent feature of many pulmonary diseases. Under normal conditions the mucus secretedby the airway epithelium provides a viscoelastic barrier that acts as a primary defense mechanism against pathogens and noxious irritants. The lungs of humans with asthma and of animal models of asthma are rich in mucin-containing goblet cells and mucus plugs, indicating that mucus metaplasia is a feature of the asthma phenotype. Metaplasia results in the transformation of the airway epithelium from a largely non-secretory phenotype into a specialized mucus secreting phenotype. Thus, cells must assemble the molecular machinery required for secretory vesicle docking and fusion. In the airway epithelium, however, the composition and function of the secretory machinery is poorly understood. In various other cell types from humans and from lower organisms, the MUNC18 family of proteins are important regulators of exocytosis serving both positive and negative functions. The essential positive role for MUNC18 is demonstrated in mice, where the knockout of the murine MUNC18-1 (the neuron specific isoform) and the mutation of Drosophila MUNC18 ortholog ROP result in complete failures of neurosecretion and paralysis. Over-expression of ROP, however, causes a dose dependent inhibition of neurosecretion, thereby indicating a negative role for ROP in Drosophila, and by extension, MUNC18 in mammals. MUNC18 proteins are also expressed in non-neuronal tissues, including mast cells and pancreatic beta cells where they regulate secretion. Based on these observations, we propose to study the expression and function of MUNC18 by airway epithelial cells and the effects of MUNC18 over expression on mucus secretion both in vitro in NCI-H292 cells and in vivo in mouse models of pulmonary inflammation. Dr. Dickey?s laboratory has previously demonstrated that functional MUNC18-2 is expressed in rat mast cells. The project proposed here utilizes expertise and reagents available in his laboratory applies them to an important problem in asthma.