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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：参见说明。说明申请的广泛、长期目标和具体目标，并提及该项目（即，与原子能机构的使命相关）。简要描述研究设计和实现这些目标的方法。描述你将用来追求这些目标的基本原理和技术。此外，用两三句话，用通俗的语言描述这项研究与公共卫生的相关性。如果申请得到资助，这样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过空间提供了过敏性哮喘是一种慢性疾病，近几十年来有上升趋势。虽然病因哮喘的发病机制尚不清楚，目前认为是由于不适当的CD 4 + Th 2介导的对空气传播的过敏原的炎症反应。尽管进行了广泛的调查，在哮喘个体中负责启动Th 2（IL-13）免疫应答的确切机制是未知Th 2免疫应答的启动和维持依赖于特异性激活树突状细胞在气道表面。最近的证据表明，树突状细胞的特定亚群 (DCs)是引发过敏性气道反应的关键，并在驱动对吸入抗原的免疫（髓样，mDC）或耐受（浆细胞样，pDC）。但特异性DC亚群被募集到肺并响应过敏原而被激活的机制暴露是未知的。我们的初步数据共同支持了一个新的假设，过敏原，屋尘螨，触发未成熟树突状细胞化学引诱物，CCL 20的快速释放，从其在细胞外基质分子syndecan-1上的储存位点，通过dectin-1的激活，识别β-葡聚糖的模式识别分子。CCL 20一旦发布，免疫原性骨髓树突状细胞亚群的募集和活化，其又指导Th 2细胞分化和过敏性炎症的发展。此外，IL-13本身可以诱导IL-13的释放。来自气道上皮的CCL 20为持续的Th 2细胞因子产生提供扩增环。的驱动上皮细胞CCL 20从多配体蛋白聚糖释放的分子机制， CCL 20/syndecan-1募集和激活mDC，IL-13诱导CCL 20的机制释放并使树突状细胞募集到肺中，这些树突状细胞的确切贡献过敏原诱导的气道高反应性和气道炎症的途径是未知的。因此我们我提出以下具体目标来检验这一假设，并确定其分子机制变应原诱导的Th 2细胞因子产生：1）确定dectin-1信号传导的作用 HDM诱导气道上皮细胞表面多配体蛋白聚糖-1/CCL20复合物释放的途径 2）确定多配体蛋白聚糖-1调节树突状细胞调节T细胞IL-1的机制。 3）为了确定IL-13使IL-13在体外和体内的产生持续的机制，免疫原性DC亚群的募集和进一步的Th 2细胞因子产生。总的来说，这些研究将有助于更好地理解Th 2（IL-13）细胞因子的驱动机制生产，并可能导致新的哮喘治疗的发展，而不是改善。履约地点（组织、城市、州）儿童医院医疗中心，俄亥俄州辛辛那提关键人员。参见说明。根据需要使用续页以如下所示的格式提供所需信息。从首席研究员开始。按字母顺序列出所有其他关键人员，姓在前。名称eRA Commons用户名组织在项目中的角色 Wills-Karp，Marsha Wildc Finkelman，Fred frefin CCHMC共同研究员