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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

说明：见说明书。说明应用程序的广泛、长期目标和具体目的，并参考健康关系