Epithelial Regulation of Th2 Immune Responses in the Lung

肺中 Th2 免疫反应的上皮调节

基本信息

批准号：
8509573
负责人：
Marsha Wills-Karp
金额：
$ 37.31万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-20 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8509573
关键词：
Allergens Allergic Allergic inflammation Antigens Asthma Attenuated Automobile Driving Binding Bone Marrow Breathing Bronchoalveolar Lavage CCL20 gene CCR6 gene Cell Differentiation process Cell surface Chemotactic Factors Chloride Ion Chronic Disease Chronic lung disease Cities Complex Confidential Information Data Dendritic Cells Dendritic cell activation Dermatophagoides pteronyssinus antigen p 1 Development Disease Environment Eosinophilia Epithelial Epithelial Cells Etiology Event Extracellular Matrix Extrinsic asthma Feedback Funding Generations Glucans Goals Health House Dust Mite Allergens Human Resources IgE Immune response Immunity In Vitro Individual Inflammatory Response Instruction Interleukin-13 Investigation Language Last Name Lead Lung Maintenance Mediating Mediator of activation protein Medical center Mission Molecular Mus Myelogenous Names Particulate Matter Pathway interactions Pattern Recognition Pattern recognition receptor Pediatric Hospitals Peptide Hydrolases Play Principal Investigator Production Proteins Public Health Pyroglyphidae Recruitment Activity Regulation Research Research Design Research Methodology Research Personnel Role SYK gene Series Signal Pathway Signal Transduction Signaling Molecule Site Staging Surface T cell differentiation T-Lymphocyte TLR2 gene Techniques Testing Th2 Cells airborne allergen airway epithelium airway hyperresponsiveness airway inflammation airway obstruction airway remodeling allergic response antigen processing beta-Glucans conditioning cytokine dectin 1 effective therapy immunogenic in vivo lymph nodes mouse model novel receptor response syndecan

项目摘要

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

描述：请参阅说明。陈述该应用程序的广泛，长期目标和具体目标，提及该项目（即与代理机构的任务相关）。简单地描述实现这些目标的研究设计和方法。描述您将用来追求这些目标的基本原理和技术。此外，用两个或三个句子描述，以简单的语言描述这项研究与公共卫生的相关性。如果申请是资助的，则描述将成为公共信息。因此，请勿包含专有/机密信息。不要超过空间假如。过敏性哮喘是一种慢性疾病，近几十年来一直在增加。虽然病因哮喘尚不清楚，目前被认为是由于不适当的CD4+Th2介导的结果易感人群对机载过敏原的炎症反应。尽管进行了广泛的调查，但哮喘患者中造成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护取决于特定的激活气道表面的树突状细胞。最近的证据表明，树突状细胞的特定子集（DC）对于启动过敏性气道响应至关重对吸入抗原的免疫（髓样，MDC）或耐受性（浆细胞样，PDC）。但是，特定的DC子集募集到肺部并响应过敏原而激活的机制暴露是未知的。我们的初步数据共同提出了新的假设，即共同的假设过敏原，房屋尘螨，触发未成熟树突趋化剂CCL20的快速释放从其在细胞外基质分子syndecan-1上的存储位点，通过Dectin-1的激活识别β-葡聚糖的模式识别分子。 CCL20一旦发布就可以驱动优先免疫原性髓样树突状细胞子群的募集和激活，又指导Th2细胞分化和过敏性炎症的发展。此外，IL-13本身可以诱导来自气道上皮的CCL20为持续Th2细胞因子产生提供了扩增环。这从Syndecan驱动上皮CCL20释放的分子机制，优先的机制 CCL20/Syndecan-1募集和激活MDC，IL-13诱导CCL20的机制将树突细胞募集释放和永久延伸到肺中，并确切的贡献过敏原引起的气道高反应性和气道炎症的途径尚不清楚。因此我们提出以下特定旨在检验该假设并定义分子机制的特定旨在过敏原诱导的Th2细胞因子产生的诱导：1）确定Dectin-1信号的作用 HDM诱导的Syndecan-1/Ccl20复合物从气道上皮表面释放的途径细胞； 2）确定syndecan-1调节T细胞IL-的树突状细胞调节的机制 13体外和体内生产； 3）确定IL-13永久性的机制免疫原性DC亚群募集和进一步的Th2细胞因子产生。总体而言，结果这些研究应更好地了解驱动TH2（IL-13）细胞因子的机制生产并可能导致新型哮喘疗法的发展，这些疗法正在改变比改善。绩效网站（组织，城市，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。根据需要使用延续页面，以下面显示的格式提供所需的信息。从首席研究员开始。按字母顺序列出所有其他关键人员，首先姓氏。名称ERA CONSONS用户名组织在项目中的角色 Wills-Karp，Marsha Wildc7 CCHMC PI Finkelman，Fred Freefin CCHMC共同投资者