This proposal seeks to renew an Asthma and Allergic Diseases Cooperative Research Center that has been focusing on the mechanisms of initiation and persistence of allergic asthma. During the course of these studies and earlier work done in our laboratories and multiple other labs, it has become clear that two cytokines, IL-13 and IL-17, make important contributions to the most critical functional endpoints in asthma (airway hyperresponsiveness and mucus metaplasia) through spatially and temporally restricted effects on airway epithelial cells and airway smooth muscle. In the current proposal, individual projects will focus on how each cytokine regulates airway epithelial cell differentiation and mucous metaplasia, how these cytokines work alone and in combination to regulate contractility of airway smooth muscle, and the dynamic behavior of the cells that generate these cytokines in the airway wall. Each of these projects will have a major focus on human asthma and will rely heavily on a Clinical Subject and Biospecimen Core that will provide basic characterization of airway physiology, evidence for IL-13 and IL-17 bioactivity, and samples of bronchoalveolar lavage fluid, epithelial brushings and airway biopsies for use in each of the 3 projects. These samples and clinical information will be obtained from subjects in 3 cohorts, ACE, RITA and SARP, that will enroll subjects for segmental allergen challenge, subjects with mild-to-moderate asthma undergoing a trial of inhaled corticosteroids and patients with severe asthma, respectively. Through the proposed studies we hope to gain new insights into the dynamic effects of IL-13 and IL-17 in asthma, to develop better tools to characterize subsets of patients with asthma and to improve the prospects for targeted therapy of this disease.
This proposal will examine how two cytokines, IL-13 and IL-17, specifically effect airway epithelial cells and airway smooth muscle to contribute to the most important causes of symptoms in patients with asthma. By examining the pathways responsible for these effects and focusing on human patients and tissues we hope to identify new strategies for treating this common and often devastating disease.
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