Derangements of the Notch Pathway in Airway Epithelial Differentiation in COPD

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In the airway of normal individuals and in response to injury, there is epithelial cell regeneration with basal cell proliferation and subsequent differentiation to maintain the normal pseudostratified epithelium. But as the clinical phenotype of chronic obstructive pulmonary disease (COPD) progresses, the differentiation status of the airway epithelium begins to change as indicated by an increased thickness of the epithelial layer, with proportionally more basal cells and less ciliated cells, goblet cell hyperplasia, and eventually squamous metaplasia. In addition to the injury mediated by cigarette smoke and inflammation, there is increasing evidence that the development of COPD is associated with latent infection of the epithelium with adenoviruses. The focus of this project is on the changes of gene expression in the airway epithelium that contribute to its altered differentiated state in COPD. Our preliminary studies with gene expression microarrays combined with the developmental biology literature have implicated the Notch signaling pathway as being critical to airway epithelial differentiation. Notch is considered a primary "gatekeeper" against differentiation, with activation of the Notch pathway blocking differentiation, whereas suppression of the pathway is associated with allowing the cells to proceed toward a specific fate. Based on this background, the studies proposed in this project are designed to test the hypothesis that COPD is associated with derangements of the Notch signaling pathway in the airway epithelium, contributing to the abnormal pattern of airway epithelial differentiation that characterizes this disorder. To test this hypothesis the following specific aims are proposed. Specific aim 1. To evaluate the hypothesis that the Notch signaling pathway is activated in the airway epithelium of individuals with COPD. Specific aim 2. To examine the hypothesis that the airway epithelium cannot regenerate following injury in a normal fashion in COPD, in part, because the normal pathways of the Notch signaling are disordered. Specific aim 3. To test the hypothesis that group C adenovirus infection plays a role in the disordered Notch signaling in the airway epithelium in COPD.