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: 8646953
• 负责人: NIZAR N JARJOUR
• 金额: $ 211.03万
• 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/8646953
• 关键词: Acute; Address; Affect; Aftercare; Allergens; Allergic; Allergic inflammation; Animal Model; Antibodies; Area; Asthma; Back; Basic Science; Biological Process; Biology; Biopsy; Blood; Blood Circulation; Bronchoscopy; Bronchoscopy with Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cell Line; Cells; Chronic; Churg-Strauss Syndrome; Clinical Research; Collaborations; Complement; Complex; Data; Development; Disease; Disseminated eosinophilic collagen disease; Drug Targeting; Environment; Eosinophilia; Eosinophilic Esophagitis; Event; Extracellular Matrix; Extracellular Matrix Proteins; Extrinsic asthma; Faculty; Fibroblasts; Fibrosis; Foundations; Functional disorder; Funding; Gastritis; Generations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Hypersensitivity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-17; Interleukin-3; Interleukin-5; Isomerase; Journals; Knowledge; Laboratories; Lymphocyte; Macrophage-1 Antigen; Measures; Mediating; Mediator of activation protein; Membrane Proteins; Mentors; Molecular; Molecular Biology; Paper; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phase IV Clinical Trials; Phenotype; Physicians; Play; Process; Production; Program Research Project Grants; Publications; Published Comment; Recruitment Activity; Refractory; Regulation; Relative (related person); Research; Research Personnel; Resources; Risk; Role; Scientist; Semaphorins; Severities; Signal Pathway; Signal Transduction; Stream; Study models; T-Lymphocyte; Testing; Therapeutic; Time; Translational Research; Travel; Universities; Up-Regulation; Wisconsin; Work; abstracting; airway inflammation; airway remodeling; allergic airway inflammation; allergic response; asthmatic airway; base; clinical practice; cytokine; design; eosinophil; eosinophilic inflammation; experience; human TGFB1 protein; human subject; in vivo; in vivo Model; innovation; insight; interest; mRNA Stability; macrophage; mepolizumab; mouse model; next generation; novel; periostin; programs; public health relevance; 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）功能的理解，前期资助周期完成的初步数据和研究为EOS通过增强气道炎症和重塑在哮喘病理生理中发挥关键作用的假设奠定了基础。本次PPG更新申请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，全面地和互动地解决EOS在使用过敏性气道炎症中的作用