A major goal of the overall AADCRC proposal is to define the role of the epithelial cell barrier in the pathogenesis of asthma and allergic disease and develop new preventative strategies. This project is derived from new insights we developed in the intestinal epithelium that show virus plus autophagy genetic susceptibility can lead to intestinal disease. We propose to translate these findings into the airway epithelium and determine the function of autophagy genes during homeostasis and in the response to airway damage that occurs subsequent to viral infection and allergen exposure. We will test the hypothesis that autophagy gene function is diminished in the airway epithelium of asthma patients (or a subset of patients) and that pharmacologic modulation of this pathway will improve function of these cells. In particular, we will test if one of the known stimulants of autophagy, interferon-gamma, that plays a role in stimulating autophagy. In support of this hypothesis, our preliminary studies show: (1) pharmacologic inhibition of autophagic flux in mice alters mucus cell morphology in both intestine and lung;(2) inhibition of autophagic flux in mouse tracheal epithelial cells show diminished secretion of Muc5ac;(3) genetic loss of Atg5 function in the mouse airway epithelium leads pathology that has features of chronic asthma;(4) mouse colonic and airway goblet cells contain an enrichment of active LCS (5) cultured human tracheal epithelial cells show diminished function in response to inhibition of autophagic flux. Together these findings suggest that autophagy genes are functional in airway and the gut epithelium and that understanding the role of this pathway in the asthmatic airway epithelium, in combination with the two other projects in this proposal will provide new insights and potential new therapeutic avenues for this disease. To further develop these insights and translate them, we have the following specific aims: (1) Determine the role of autophagy proteins in respiratory epithelial differentiation, homeostasis, and remodeling in mouse models;and (2) Define the autophagy abnormality in human asthma and alter it to improve function. The studies synergize with the approach to epithelial remodeling in Project 2 and epithelial injury in Project 3 to form a novel and comprehensive approach to epithelial function in asthma and allergy.
The cause of altered epithelial function in asthma is not yet clearly defined and thus limits potential therapies. This proposal aims in this project directly address this issue by defining a new pathway for controlling airway epithelial function in experimental mouse models and in humans with asthma. The proposed studies will define the role of a new pathway in the function of the airway epithelium and determine if it can be pharmacologically manipulated.
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