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 刺激素质血液嗜酸性粒细胞（EOS）附着并拓展肺部以成为效应子 有助于调节淋巴细胞和成纤维细胞的细胞，从而导致Ainway炎症 并重塑哮喘。我们建议IL-3刺激EOS有助于Th17淋巴细胞 通过EOS释放IL-1 P的开发以及与组织重塑相关的因素的产生（项目 1）。假设IL-3刺激的EOS衍生的Semaphorin7a产生可以激活成纤维细胞 产生细胞外基质（ECLVI）组件（项目1）。这些成分之一，骨膜蛋白，可能指导 从血液到气道进一步招募EO（项目2）。最后，气道ECM生产也是 由EOS分泌的TGF-PI通过涉及CIS-型肽蛋白酶的信号传导机制调节 异构酶，PIN1（项目3）。使用外周血EOS的机械研究可以在体内验证 分段过敏原挑战模型。拟议研究的意义是每个项目将 有助于理解哮喘气道中的EOS生物学，有可能识别几个新的 可以改变肺部重塑过程的药物靶标。实现这一目标并为 项目。核心A分为以下任务：特定任务1-招募和表征过敏 参与涉及外周血和气道EOS的实验方案的哮喘受试者； 特定的TASL <2-每周4天进行静脉切开术，以纯化外周血EOS 过敏或过敏性哮喘的患者；特定的tasl <3-进行分段的支气管镜检查 用过敏原（AG-SBP）在患有哮喘的受试者中用过敏原（AG-SBP）支气管前体，并获得BAL液体和支气管负体 过敏原挑战之前和之后的活检（BX）；特定任务4-执行基本处理和 气道和不属于核心B的一部分的实验室分析，包括免疫组织化学， 建立来自支气管内BX的细胞系的成纤维细胞；和特定的任务5-保持高质量 HIPAA兼容数据库，包括受试者人群，临床和生理特征， 安全数据和基本BAL分析，除了提供数据检索，分析和 演示并为所有项目提供统计支持。 相关性（请参阅说明）： 鉴于EOS在哮喘严重程度的进展中的核心重要性，该提议将允许 更好地理解Ainway重塑的分子基础，并开始发展一个risl <签名 可用于早期检测肺功能下降。研究新招募和激活的能力 Ainway EOS应对节段过敏原挑战最大程度地促进了发现翻译。