Regulation of Mucin Exocytosis by Munc18

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DESCRIPTION (provided by applicant): Gel-forming mucins secreted into the airways are thought to protect the lungs by clearance of inhaled pathogens and particulates. However, mucin hypersecretion can cause airflow obstruction and airway injury. Therefore, tight control of mucin secretion is critical for airway homeostasis. Munc18 proteins are essential components of the regulated secretory machinery of eukaryotic cells, such that their absence causes complete failure of secretion. We find that Munc18b is expressed at the apical membrane of airway secretory cells, and that heterozygous Munc18b null mice have a defect in airway mucin secretion. Since homozygous Munc18b null mice are not viable, we have generated conditional Munc18b deletant mice with a loss-of-function only in airway secretory cells. We have also generated transgenic mice overexpressing a gain-of-function Munc18b mutant in airway secretory cells. We hypothesize that the mice with Munc18b deleted in their airway secretory cells will completely fail to secrete airway mucins at baseline or with stimulation, and that the transgenic mice will hypersecrete airway mucins. These hypotheses will be tested in the following Specific Aims: 1) Assess changes in the structure of the airways of Munc18b null and transgenic mutant mice. 2) Determine baseline and stimulated secretory function in Munc18b null and transgenic mutant mice. The proposed studies will advance understanding of the structure and function of the airway secretory mechanism, and provide essential reagents for future studies to test the putative protective and pathologic roles of mucin secretion in lung diseases. PUBLIC HEALTH RELEVANCE: Mucus in the airways is needed to protect the lungs against inhaled particles and infections. On the other hand, too much mucus blocks the airways in cystic fibrosis and asthma. We will study how mucus is secreted into the airways to determine how this can be optimized for treatment of lung diseases.