Epithelial Regulation of Th2 Immune Responses in the Lung

说明：请参阅说明。说明应用程序的广泛、长期目标和具体目标，并提及与健康相关的 项目(即与该机构使命的相关性)。简明扼要地描述实现这些目标的研究设计和方法。描述 你将用来追求这些目标的基本原理和技术。 此外，用两三句简单明了的话描述这项研究与公共卫生的相关性。如果应用程序得到资助，则此 原样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过空格 但前提是。 过敏性哮喘是一种慢性疾病，近几十年来一直在上升。虽然该病的病因 目前对哮喘的认识还不是很清楚，目前认为它的发生是由于不适当的CD4+Th2介导的结果 易感人群对空气传播过敏原的炎症反应。尽管进行了广泛的调查， 哮喘患者启动Th2(IL-13)免疫反应的确切机制是 未知。Th2免疫反应的启动和维持依赖于特定的激活 在呼吸道表面的树突状细胞。最近的证据表明，树突状细胞的特定亚群 (DC)在启动过敏性呼吸道反应中起关键作用，并在驱动 对吸入抗原的免疫力(髓系，MDCS)或耐受性(浆细胞，PDCs)。然而， 特定DC亚群被招募到肺并被激活以应对变应原的机制 暴露在危险中的人是未知的。我们的初步数据共同支持了新的假设，即共同的 过敏原，屋尘螨，触发未成熟的树突状细胞趋化物质CCL20的快速释放， 从细胞外基质分子Syndecan-1上的存储位置，通过Dectin-1的激活，a 识别β-葡聚糖的模式识别分子。CCL20一旦发布，将推动优先 免疫原性髓系树突状细胞亚群的募集和激活，进而引导Th2细胞 变态反应性炎症的分化和发展。此外，IL-13本身可以诱导释放 来自呼吸道上皮细胞的CCL20为持续产生Th2细胞因子提供了一个扩增环。这个 驱动上皮细胞CCL20从Syndecan释放的分子机制，优先机制 CCL20/syndecan-1对MDCs的募集和激活及IL-13诱导CCL20的机制 释放并保持树突状细胞在肺内的募集，以及这些细胞的确切贡献 过敏原诱导的呼吸道高反应性和呼吸道炎症的途径尚不清楚。因此，我们 提出以下具体目标来检验这一假说并定义其背后的分子机制 变应原诱导Th2细胞因子的产生：1)确定Dectin-1信号转导的作用 HDM诱导Syndecan-1/CCL20复合体从呼吸道上皮细胞表面释放的途径 2)确定Syndecan-1调节树突状细胞对T细胞IL-1的调节机制。 在体外和体内产生；3)确定IL-13使 免疫原性DC亚群的募集和Th2细胞因子的进一步产生。总的来说，以下各项的结果 这些研究应该能更好地理解驱动Th2(IL-13)细胞因子的机制 生产，并可能导致新的哮喘疗法的发展，而不是疾病的修改 而不是改善。 演出现场(S)(组织、市、州) 俄亥俄州辛辛那提儿童医院医疗中心 关键人员。请参阅说明。根据需要使用续页，以如下所示的格式提供所需信息。 从首席调查员开始。按字母顺序列出所有其他关键人员，姓氏在前。 名称时代共享用户名项目上的组织角色 威尔斯-卡普，玛莎·怀尔德7 CCHMC Pi 弗雷德·弗雷芬·芬克尔曼CCHMC联合调查员

DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. Allergic asthma is a chronic disease which has been on the rise in recent decades. Although the etiology of asthma is not well understood, it is currently thought to arise as a result of inappropriate CD4+Th2-mediated inflammatory responses to airborne allergens in susceptible individuals. Despite extensive investigation, the exact mechanisms responsible for the initiation of Th2 (IL-13) immune responses in asthmatic individuals are unknown. The initiation and maintenance of Th2 immune responses are dependent upon specific activation of dendritic cells at the airway surface. Recent evidence suggests that specific subsets of dendritic cells (DCs) are critical for the initiation of allergic airway responses and play an important role in driving either immunity (myeloid, mDCs) or tolerance (plasmacytoid, pDCs) to inhaled antigens. However, the mechanisms by which specific DC subsets are recruited to the lung and activated in response to allergen exposure are unknown. Our preliminary data collectively upport the novel hypothesis that the common allergen, house dust mite, triggers the rapid release of the immature dendritic cell chemoattractant, CCL20, from its storage sites on the extracellular matrix molecule syndecan-1, through the activation of dectin-1, a pattern recognition molecule which recognizes beta-glucans. CCL20 once released drives the preferential recruitment and activation of the immunogenic myeloid dendritic cell subset which in turn directs Th2 cell differentiation and the development of allergic inflammation. Moreover, IL-13 itself can induce the release of CCL20 from the airway epithelium providing an amplication loop for continued Th2 cytokine production. The molecular mechanisms driving epithelial CCL20 release from syndecan, the mechanisms of preferential recruitment and activation of mDCs by CCL20/syndecan-1, the mechanisms by which IL-13 induces CCL20 release and perpetuates dendritic cell recruitment into the lung, and the exact contributions of these pathways to allergen-induced airway hyperresponsiveness and airway inflammation are unknown. Thus we propose the following specific aims to test this hypothesis and define the molecular mechanisms underlying allergen-induced induction of Th2 cytokine production: 1)To determine the role of dectin-1 signaling pathways in the HDM-induced release of syndecan-1/CCL20 complexes from the surface of airway epithelial cells; 2) To determine the mechanism by which syndecan-1 regulates dendritic cell conditioning of T cell IL- 13 production in vitro and in vivo; 3)To determine the mechanisms by which IL-13 perpetuates the recruitment of immunogenic DC subsets and further Th2 cytokine production. Collectively, the results of these studies should provide a better understanding of the mechanisms driving Th2 (IL-13) cytokine production and may lead to the development of novel asthma therapies which are disease modifying rather than ameliorative. PERFORMANCE SITE(S) (organization, city, state) Children's Hospital Medical Center Cincinnati, OH KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Wills-Karp, Marsha Wildc7 CCHMC PI Finkelman, Fred frefin CCHMC Co-Investigator