Role of Eosinophils in Airway Inflammation and Remodeling

嗜酸性粒细胞在气道炎症和重塑中的作用

• 批准号: 9054892
• 负责人: NIZAR N JARJOUR
• 金额: $ 215.34万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054892
• 关键词: Acute; Address; Affect; Aftercare; Allergens; Allergic; Allergic inflammation; Animal Model; Antibodies; Area; Asthma; Back; Basic Science; Biological Process; Biology; Biopsy; Blood Circulation; Bronchial Provocation Tests; Bronchoscopy; Bronchoscopy with Bronchoalveolar Lavage; Cell Line; Cells; Chronic; Churg-Strauss Syndrome; Clinical Research; Collaborations; Complement; Complex; Data; Disease; Disseminated eosinophilic collagen disease; Environment; Eosinophilia; Eosinophilic Esophagitis; Event; Extracellular Matrix; Extracellular Matrix Proteins; Faculty; Fibroblasts; Foundations; Functional disorder; Funding; Gastritis; Generations; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Hypersensitivity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-17; Interleukin-3; Interleukin-5; Isomerase; Journals; Knockout Mice; Laboratories; Macrophage-1 Antigen; Mediating; Mediator of activation protein; Mentors; Molecular; Molecular Biology; Paper; Participant; Patients; Phase IV Clinical Trials; Physicians; Play; Process; Program Research Project Grants; Publications; Recruitment Activity; Research; Research Personnel; Resources; Risk; Role; Scientist; Severities; Signal Pathway; Signal Transduction; Study models; T-Lymphocyte; TGFB1 gene; Testing; Therapeutic; Time; Translational Research; Travel; Universities; Up-Regulation; Wisconsin; Work; airway inflammation; airway remodeling; allergic airway inflammation; asthmatic airway; asthmatic patient; base; clinical practice; cytokine; design; eosinophil; eosinophilic inflammation; experience; human subject; in vivo; in vivo Model; insight; interest; macrophage; mepolizumab; mouse model; next generation; novel; periostin; programs; receptor; research study; response

DESCRIPTION (provided by applicant): Airway eosinophilia is an important marker of asthma severity, risk of exacerbation, and response to therapy. Based upon the current understanding of the function of eosinophils (EOS), the preliminary data and studies accomplished over the previous funding cycle, form the basis for the hypothesis that EOS play a pivotal role in asthma pathophysiology by enhancing airway inflammation and remodeling. The studies in this PPG renewal application are designed to answer clinically important questions formulated to take maximum advantage of our collective expertise and resources. They will allow us to address critically, comprehensively and interactively the role of EOS in allergic airway inflammation using ex vivo and in vivo experiments in human subjects complemented, as appropriate, by focused use of cell lines and animal models. Project 1 will investigate key EOS functions including promoting IL-17 responses and enhancing fibroblast (Fb) function via expression of SEMA7A, which leads to promoting myoFb differentiation and generation of extracellular matrix (ECM) components. The Th2 skewed environment in the asthmatic airway promotes the expression of periostin, an important marker of allergic inflammation. The proposed studies in Project 2 will determine how this ECM protein interacts with EOS to enhance their survival, mediator release, and response to EOS-active cytokines. Studies will define the requirements for periostin generation in the airway and recognition by the EOS integrin alphaMBeta2. Finally in Project 3, the molecular mechanisms regulating the pro-fibrotic cytokine, TGF-Beta1 signaling in EOS and Fb will be investigated focusing on the role of Pin1 interaction with proximal Smads as well as PI-3-K and Akt. Our group discovered that up-regulation of isomerase Pin1 is an essential step in the TGF-Beta1 signaling pathway and seek to determine how Pin1 influences Smad6 and Smad3 including the role of Akt and PI-3-Kgamma in this process. It can be argued that few other centers, if any, around the world are capable of doing the clinical studies needed to retrieve airway EOS and at the same time have the experience necessary to critically dissect EOS biological functions to the same level of sophistication that our group is capable of doing. The collaborative studies among the three laboratories and the rich clinical research experience will allow us to move back and forth from ex vivo to in vivo experiments to better understand the role of EOS in modulating allergic airway inflammation and remodeling. Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness.

描述（由申请人提供）：气道嗜酸性粒细胞增多是哮喘严重程度、恶化风险和治疗反应的重要标志。基于目前对嗜酸性粒细胞 (EOS) 功能的了解，在上一个资助周期中完成的初步数据和研究构成了以下假设的基础：EOS 通过增强气道炎症和重塑在哮喘病理生理学中发挥关键作用。此次 PPG 续展申请中的研究旨在回答临床重要问题，以最大限度地利用我们的集体专业知识和资源。它们将使我们能够批判性地、全面地、交互式地解决 EOS 在过敏性气道炎症中的作用，使用 适当时，通过重点使用细胞系和动物模型来补充人类受试者的离体和体内实验。项目 1 将研究 EOS 的关键功能，包括促进 IL-17 反应和通过 SEMA7A 的表达增强成纤维细胞 (Fb) 功能，从而促进 myoFb 分化和细胞外基质 (ECM) 成分的生成。哮喘气道中 Th2 倾斜的环境促进了骨膜素的表达，骨膜素是过敏性炎症的重要标志物。项目 2 中拟议的研究将确定这种 ECM 蛋白如何与 EOS 相互作用，以增强其存活、介质释放以及对 EOS 活性细胞因子的反应。研究将确定气道中骨膜素生成和 EOS 整合素 alphaMbeta2 识别的要求。最后，在项目 3 中，将研究调节 EOS 和 Fb 中促纤维化细胞因子、TGF-Beta1 信号传导的分子机制，重点是 Pin1 与近端 Smads 以及 PI-3-K 和 Akt 相互作用的作用。我们的小组发现异构酶 Pin1 的上调是 TGF-Beta1 信号通路中的重要步骤，并试图确定 Pin1 如何影响 Smad6 和 Smad3，包括 Akt 和 PI-3-Kgamma 在此过程中的作用。可以说，世界上很少有其他中心（如果有的话）能够进行检索气道 EOS 所需的临床研究，同时拥有批判性地剖析 EOS 生物学功能所需的经验，达到与我们小组能够做到的相同复杂程度。三个实验室之间的合作研究和丰富的临床研究经验将使我们能够从离体实验到体内实验更好地了解EOS在调节过敏性气道炎症和重塑中的作用。鉴于相当一部分严重哮喘患者存在嗜酸性粒细胞炎症，这些进展将对受这种非常常见疾病影响最严重的患者产生直接影响。