Mechanistic Insights From Bronchoscopy Airway Samples

The UCSF Airway Clinical Research Center has made longstanding and productive efforts to understand how type 2 immune responses in the airway act on epithelial cells to produce muco-obstructive pathology, a central feature of severe asthma and a major contributor to fatality from this disease. This center has made major contributions to identifying type 2 high asthma as the major asthma endotype, demonstrating that the type 2 cytokine IL-13 acts directly on airway epithelial cells to induce pathological changes in mucus, and showing that mucus plugging is a persistent feature of asthma that is associated with type 2 responses and with increased asthma severity. The overall objective of this proposal is to understand molecular mechanisms that account for alterations in secretory cell and mucus function that are important in severe asthma. The overarching hypothesis is that local type 2 immune responses induce IL-13-mediated changes in epithelial gene expression and that these changes, which involve several novel molecular mechanisms not previously explored, alter differentiation of secretory cells and production and secretion of mucins, leading to mucus plugging and airway obstruction. The proposal includes two highly related projects, each of which focuses on molecules and pathways that have previously unknown roles in secretory cell biology and mucus dysfunction. The proposed studies will provide new mechanistic insights that are highly relevant to the pathogenesis of severe asthma and may lead to novel therapeutic targets that address unmet needs.