Although the epidemiologic linkage of chromosome 17q21 to asthma is very well established, the biologic mechanism(s) underpinning this association is not as well understood. Chromosome 17q21 contains a cluster of 9 genes of which ORMDL3 and GSDMB are the most studied in both genetic association studies, and in studies of their biology. Based on GSDMA being located next to ORMDL3 on chromosome 17q21 we hypothesize that GSDMA (like remodeling genes GSDMB and ORMDL3) may contribute to remodeling in asthma. The hypothesis regarding GSDMA is supported by Project 1’s novel preliminary data demonstrating that, a) GSDMA is highly expressed in bronchial epithelial cells in asthma compared to controls, b) GSDMA expression in bronchial epithelium is associated with reduced expression of anti-viral defense genes (OAS, IFIT, Mx2) and increased RV viral load, and c) RV infection of GSDMA expressing epithelium significantly increases expression of pro-airway remodeling gene TGFβ1. Thus, Project 1 will test the hypothesis that GSDMA expression in airway epithelium mediates airway remodeling (airway smooth muscle or ASM, fibroblast, mucus) through induction of TGFβ1 and other mediator pathways being investigated. In addition, Project 1 hypothesizes that there is a viral (RV) interaction with GSDMA expression in epithelium during acute viral triggered exacerbations of asthma that result in increased viral load, more severe RV infections with increased TGFβ1 expression and increased remodeling. Although we will not be performing mouse studies, our preliminary data demonstrates that mouse Gsdma (like human GSDMA) is selectively expressed in the lung in airway epithelium, and when Gsdma KO mice are challenged with HDM these mice develop significantly reduced remodeling (mucus, fibrosis, ASM) without reductions in airway inflammation. Thus, Project 1 will focus on understanding how GSDMA expression in human airway epithelium contributes to the pathogenesis of airway remodeling (ASM, peribronchial fibrosis, mucus) in severe asthma utilizing human severe asthma lung, BAL, and endobronchial biopsy specimens from “Severe Asthma Core B”. Our studies of GSDMA induced airway remodeling by lung structural cells (i.e. epithelium) integrates well with airway remodeling signals being investigated in Project 2 (LIGHT/TL1A) and Project 3 (TRM) to understand how the combination of signals control airway remodeling. Project 1 will fully utilize human severe asthma lung, BAL, endobronchial biopsy, and sputum specimens from Core B.