Clinical Core

临床核心

• 批准号: 9249665
• 负责人: NIZAR N JARJOUR
• 金额: $ 37.7万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249665
• 关键词: Allergens; Allergic; Asthma; Biology; Biopsy; Blood specimen; Bronchial Provocation Tests; Bronchoscopy; Cell Line; Characteristics; Clinical; Data; Data Storage and Retrieval; Databases; Development; Early Diagnosis; Effector Cell; Exposure to; Extracellular Matrix; Extrinsic asthma; Fibroblasts; Goals; Health Insurance Portability and Accountability Act; Hypersensitivity; Immunohistochemistry; Inflammation; Interleukin-1; Interleukin-3; Laboratories; Liquid substance; Lung; Lymphocyte; Modeling; Molecular; Patients; Peptidylprolyl Isomerase; Peripheral Blood Involvement; Physiological; Process; Production; Protocols documentation; Recruitment Activity; Regulation; Research; Respiratory physiology; Role; Safety; Services; Severities; Signal Transduction; Stimulus; Tissues; Translations; Venous blood sampling; airway inflammation; airway remodeling; asthmatic airway; eosinophil; in vivo; new therapeutic target; periostin; peripheral blood; response

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.

该提案的总体目标是定义气道暴露于过敏的机制 刺激促使外周血嗜酸性粒细胞 (EOS) 附着并渗入肺部，成为效应细胞 有助于调节淋巴细胞和成纤维细胞的细胞，从而导致炎症 和哮喘重塑。我们认为 IL-3 刺激 EOS 有助于 Th17 淋巴细胞 通过 EOS 释放 IL-1 p 并生产与组织重塑相关的因子进行开发（项目 1).据推测，IL-3 刺激 EOS 产生 semaphorin7A 可以激活成纤维细胞 产生细胞外基质 (EClVI) 成分（项目 1）。这些成分之一，骨膜素，可能直接 进一步将 EOS 从血液招募到气道（项目 2）。最后，气道 ECM 的生产也 EOS 分泌的 TGF-pi 通过涉及顺式-反式肽基-脯氨酰的信号传导机制进行调节 异构酶，Pin1（项目 3）。使用外周血 EOS 进行的机制研究可以在体内进行验证 分段过敏原挑战模型。拟议研究的意义在于每个项目将 有助于了解哮喘气道中的 EOS 生物学，有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向 项目。核心 A 分为以下任务： 具体任务 1 - 招募和表征过敏 哮喘受试者参与涉及外周血和气道 EOS 的实验方案； 具体 Tasl< 2 - 每周 4 天进行静脉切开术，以纯化外周血 EOS 过敏体质或过敏性哮喘患者；具体 Tasl< 3 - 进行分段支气管镜检查 对哮喘受试者进行过敏原支气管激发 (Ag-SBP)，并获取支气管肺泡灌洗液 (BAL) 和支气管内液 过敏原激发前后的活检（Bx）；具体任务 4 - 执行基本处理和 对不属于核心 B 部分的气道和血液样本进行实验室分析，包括免疫组织化学， 从支气管内 Bx 建立成纤维细胞系；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、临床和生理特征， 安全数据和基本 BAL 分析，此外还提供数据检索、分析和分析方面的帮助 介绍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 ainway 重塑的分子基础并开始开发 risl< 特征 可用于早期发现肺功能下降。研究新招募和激活的能力 ainway EOS 应对分段过敏原挑战，最大限度地促进发现转化。