Clinical Core

这项建议的首要目标是确定气道暴露于过敏性疾病的机制。 刺激引发外周血嗜酸性粒细胞（EOS）附着并外渗到肺中成为效应细胞 有助于调节淋巴细胞和成纤维细胞的细胞，从而有助于气道炎症 以及哮喘的重塑。我们认为IL-3刺激EOS有助于Th 17淋巴细胞 通过EOS释放IL-1 β和产生与组织重塑相关的因子来发展（项目 1）。假设IL-3刺激的EOS来源的脑信号蛋白7A的产生激活成纤维细胞， 生产细胞外基质（EClVI）成分（项目1）。这些成分之一，骨膜蛋白，可以指导 EOS从血液到气道的进一步募集（项目2）。最后，气道ECM的产生也 通过涉及顺式-反式肽基-脯氨酰的信号传导机制由EOS分泌的TGF-β 1调节 异构酶，Pin 1（项目3）。外周血EOS的机制研究可以在体内验证， 节段性过敏原激发模型。建议研究的意义在于，每个项目将 有助于理解哮喘气道中EOS的生物学，可能识别出几种新的 可以改变肺重塑过程的药物靶点。为了实现这一目标，并提供服务， 项目核心A分为以下任务：具体任务1 -招募和表征过敏性 哮喘受试者参与涉及外周血和气道EOS的实验方案; 特异性Tasl< 2 -每周4天进行静脉切开术，用于从外周血中纯化EOS。 过敏或过敏性哮喘患者;特异性Tasl< 3 -进行节段性支气管镜检查 在哮喘受试者中使用变应原（Ag-SBP）进行支气管激发，并获得BAL液和支气管内 过敏原激发前后的活组织检查（Bx）;具体任务4 -进行基本处理， 不属于核心B的气道和血液样本的实验室分析，包括免疫组织化学， 从支气管内Bx建立成纤维细胞系;和具体任务5 -保持高质量 符合HIPAA的数据库，包括受试者人口统计学、临床和生理特征， 安全性数据和基本BAL分析，此外还在数据检索、分析和 并为所有项目提供统计支持。 相关性（参见说明）： 鉴于EOS在哮喘严重程度进展中的核心重要性，该提案将允许 更好地理解了气道重塑的分子基础，并开始发展出一种RISL信号， 可用于肺功能下降的早期检测。新招募和激活的学习能力 响应节段性变应原激发的气道EOS最大程度地促进发现翻译。

The overarching goal of this proposal is to define the mechanisms by which airway exposure to allergic stimuli primes peripheral blood eosinophils (EOS) to attach and extravasate into tlie lung to become effector cells contributing to the regulation of lymphocytes and fibroblasts thus contributing to ainway inflammation and remodeling in asthma. We propose that IL-3 stimulation of EOS contributes to Th17 lymphocyte development through EOS release of IL-1 p and production of factors relevant to tissue remodeling (Project 1). IL-3-stimulated EOS-derived production of semaphorin7A is hypothesized to activate fibroblasts to produce extracellular matrix (EClVI) components (Project 1). One of these components, periostin, may direct further recruitment of EOS from the blood to the airway (Project 2). Finally, airway ECM production is also regulated by EOS-secreted TGF-pi via signaling mechanisms involving the cis-trans peptidyl-prolyl isomerase, Pin1 (Project 3). Mechanistic studies with peripheral blood EOS can be validated in vivo using the segmental allergen challenge model. The significance of the proposed research is that each project will contribute to the understanding of EOS biology in the asthmatic airway, potentially identifying several new drug targets that could modify the process of lung remodeling. To accomplish this and provide service to the projects. Core A is divided into the following Tasks: Specific Task 1 - To recruit and characterize allergic asthma subjects for participation in experimental protocols involving peripheral blood and airway EOS; Specific Tasl< 2 - To perform phlebotomy 4 days a week for the purification of peripheral blood EOS from patients with allergies or allergic asthma; Specific Tasl< 3 - To perform bronchoscopies with segmental bronchoprovocation with allergen (Ag-SBP) in subjects with asthma and obtain BAL fluid and endobronchial biopsies (Bx) before and after allergen challenge; Specific Task 4 - To perform basic processing and laboratory analysis of airway and blood samples that are not part of Core B, including immunohistochemistry, establishing fibroblasts cell lines from endobronchial Bx; and Specific Task 5 - To maintain high-quality HIPAA-compliant databases that includes subject demographic, clinical and physiologic characteristics, safety data, and basic BAL analysis, in addition to providing assistance in data retrieval, analysis, and presentation and to provide statistical support for all projects. RELEVANCE (See instructions): Given the central importance of EOS in the progression of asthma severity, this proposal will allow for a better understanding ofthe molecular basis of ainway remodeling and begin to develop a risl< signature that could be used for early detection of lung function decline. The ability to study newly recruited and activated ainway EOS in response to segmental allergen challenge maximally facilitates discovery translation.