IL-13 and IL-17 dynamics in the asthmatic airway

该提案旨在更新哮喘和过敏性疾病合作研究中心，该中心一直专注于过敏性哮喘的启动和持续机制。在这些研究过程中，以及在我们实验室和其他多个实验室进行的早期工作中，已经清楚的是，两种细胞因子IL-13和IL-17通过对气道上皮细胞和气道平滑肌的空间和时间限制作用，对哮喘中最关键的功能终点（气道高反应性和粘液化生）做出重要贡献。在目前的提案中，个别项目将集中在每种细胞因子如何调节气道上皮细胞分化和粘液化生，这些细胞因子如何单独和联合调节气道平滑肌的收缩性，以及在气道壁中产生这些细胞因子的细胞的动态行为。这些项目中的每一个都将主要关注人类哮喘，并将严重依赖于临床受试者和生物样本核心，该核心将提供气道生理学的基本表征、IL-13和IL-17生物活性的证据以及用于3个项目中的每一个的支气管肺泡灌洗液、上皮刷和气道活检样本。这些样本和临床信息将从3个队列（ACE、RITA和SARP）中的受试者中获得，这些队列将分别入组接受节段性过敏原激发的受试者、接受吸入性糖皮质激素试验的轻度至中度哮喘受试者和重度哮喘患者。通过这些研究，我们希望获得IL-13和IL-17在哮喘中的动态作用的新见解，开发更好的工具来描述哮喘患者的亚群，并改善这种疾病的靶向治疗前景。

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.