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

本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我们实验室和其他多个实验室的早期工作中，我们已经清楚地发现，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，对哮喘最关键的功能终点（气道高反应性和粘液化生）做出了重要贡献。在目前的提案中，个别项目将重点关注每种细胞因子如何调节气道上皮细胞分化和粘膜化生，这些细胞因子如何单独或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，并将严重依赖临床受试者和生物标本核心，这将提供气道生理学的基本特征，IL-13和IL-17生物活性的证据，以及支气管肺泡灌洗液样本，上皮刷洗和气道活检，用于三个项目中的每一个。这些样本和临床信息将从ACE、RITA和SARP三个队列的受试者中获得，这些队列将分别招募接受部分过敏原挑战的受试者、接受吸入皮质类固醇试验的轻度至中度哮喘患者和严重哮喘患者。我们希望通过提出的研究获得IL-13和IL-17在哮喘中的动态作用的新见解，开发更好的工具来表征哮喘患者亚群，并改善该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.