Airway mucus forms a protective layer against inhaled particles and pathogens. However, excessive mucus secretion in response to inflammatory stimuli can lead to airflow obstruction. Mucus hypersecretion can be divided into two distinct stages: metaplasia of an epithelial layer that consists predominantly of ciliated and Clara cells into a layer that consists predominantly of mucus-secreting goblet cells; this is followed by regulated secretion of mucus from the metaplastic epithelium. At a molecular level, secretory metaplasia involves expression of genes encoding three sets of proteins: secretory products; components of an exocytic machinery; and signal transduction pathways connecting extracellular secretory signals to exocytic membrane fusion. Secreted macromolecules and signal transduction pathways are subjects of intensive study, but little is known about the exocytic machinery. Munc18 proteins are ubiquitous components of the exocytic machinery of secretory cells. Their absence leads to a complete failure of secretion, and their overexpression also impairs secretion. Together, these data indicate the critical role played by Munc18 proteins and suggest that their expression is tightly regulated. We have found that Munc18B is highly upregulated in metaplastic airway epithelium of mice, and that its promoter region contains elements known to respond to inflammatory stimuli. We propose to suppress expression of Munc18B to test the protective and pathophysiologic roles of mucus secretion in models of allergic and infectious lung inflammation in mice, and to analyze the control of Munc18B expression in mice and humans to gain insight into the molecular pathogenesis of mucus metaplasia.
Aim 1 : Further characterize the cellular biology of Munc18 proteins in the regulation of airway mucus secretion in murine and human cells.
Aim 2 : Analyze the protective and pathophysiologic roles of mucus hypersecretion in murine models of allergic asthma and bacterial pneumonia by reducing the capability of airway goblet cells to secrete mucus through reduction of Munc18B expression.
Aim 3 : Identify critical cis-acting DNA elements and transcription factors that control expression of the Munc18B gene in metaplastic airway epithelium of mice.
Aim 4 : Confirm the importance of cis-acting DNA elements and transcription factors that control expression of the Munc18B gene in airway secretory metaplasia of humans.
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