Asthma Inflammation Research (AIR)

哮喘炎症研究 (AIR)

• 批准号: 8686052
• 负责人: Serpil C. Erzurum
• 金额: $ 262.03万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-02 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686052
• 关键词: Allergens; Animal Model; Asthma; Award; Carbohydrates; Caring; Cells; Chronic; Chronic Disease; Clinic; Clinical; Clinical Research; Deposition; Diagnostic; Environmental Risk Factor; Epithelial; Extracellular Matrix; Funding; Generations; Genetic; Goals; Helper-Inducer T-Lymphocyte; Human; Hyaluronan; Image; Inflammation; Inflammatory; Investigation; Lead; Link; Mediating; Modeling; Molecular; Monitor; Mucous body substance; Mus; Nitrogen; Oxygen; Pathologic; Pathway interactions; Patient Care; Patients; Phenotype; Post-Translational Protein Processing; Process; Prognostic Marker; Protein Tyrosine Phosphatase; Research; Research Personnel; Resolution; Role; Sampling; Science; Services; Smoke; T-Lymphocyte; Testing; Time; Tobacco; Translating; Translational Research; Translations; Ubiquitin; United States National Institutes of Health; adaptive immunity; airway epithelium; airway inflammation; airway remodeling; allergic airway inflammation; asthmatic patient; base; biobank; cytokine; design; eosinophil peroxidase; extracellular; improved; innovation; programs; repaired; response; tool

DESCRIPTION (provided by applicant): Asthma is one of the most common chronic diseases in the world. Synergistic and mechanistic research by our group has contributed substantially to define fundamental pathogenic processes underlying asthma inflammation and remodeling, including: (1) excessive response of adaptive immunity, most often via CD4* T helper lymphocyte (TH2) cells; (2) lack of resolution of inflammation related to abnormal extracellular matrix that amplifies influx and activation of inflammatory cells; and (3) generation of excessive reactive oxygen and nitrogen species that promotes remodeling. Based upon our cumulative findings, the unifying hypothesis of our Program is that asthma results from prolonged and excessive, predominantly TH2, inflammation with failed attempts at resolution and repair leading to airway remodeling. To test this, our Program organizes a comprehensive approach through 4 projects designed to study inter-related roles of extracellular and cellular-molecular components, including: the newly discovered IL-25 (TH2 cytokine) pathway that relies on ubiquitin iigase Act1 to mediate allergic airway inflammation via independent (and non-redundant) effects on airway epithelium and T cells (project 2); the amplification and persistence of airway epithelial response to TH2 cytokines due to inactivation of tyrosine phosphatase in the pathologic oxidative state of asthma (project 1); increased and aberrant deposition of pathological hyaluronan-rich extracellular matrix that impedes resolution of inflammation (project 3); and the recently uncovered eosinophil peroxidase-catalyzed protein modification of carbamylation that is linked to tobacco-smoke exposure, and independent of adaptive immunity induces an asthma-like phenotype. Our multi-disciplinary rigorous scientific approaches reveal mechanisms, and offer the greatest opportunities for successful translation to patient benefits. Three scientific Cores (Clinical, Biorepository, Animal Model) and an Administrative Core strengthen each project and expedite translation by providing expert service and easy access to well-defined clinical samples and primary cells in organotypic culture, and murine asthma models. Collectively, translational research is integrated throughout the Program, builds upon the fundamental discoveries made by our NIH-funded investigators, capitalizes extensively on support from the Cleveland Clinic Translational Science Award (CTSA), and benefits from FDA approval in place for human allergen challenge models. Altogether, the scope and scale of the science, the efficient and productive investigators, and the consistent translational focus promises fundamental scientific discoveries that will impact patient care over the years of the Program.

描述（由申请人提供）： 哮喘是世界上最常见的慢性疾病之一。我们小组的协同和机械研究为定义哮喘炎症和重塑的基本致病过程做出了重大贡献，包括：（1）自适应免疫的过度反应，通常通过CD4* T Helper淋巴细胞（TH2）细胞。 （2）缺乏与异常的细胞外基质有关的炎症分辨率，从而扩大了炎症细胞的流入和激活； （3）产生促进重塑的过量活性氧和氮种。基于我们的累积发现，我们计划的统一假设是，哮喘是由于长时间和过度，主要是Th2引起的，炎症是由于解决和修复的尝试失败而导致气道重塑。 To test this, our Program organizes a comprehensive approach through 4 projects designed to study inter-related roles of extracellular and cellular-molecular components, including: the newly discovered IL-25 (TH2 cytokine) pathway that relies on ubiquitin iigase Act1 to mediate allergic airway inflammation via independent (and non-redundant) effects on airway epithelium and T cells (project 2);由于哮喘的病理氧化态在病理氧化态中灭活，气道上皮反应对Th2细胞因子的扩增和持久性（项目1）；富含病理性透明质酸的细胞外基质的增加和异常沉积会阻碍炎症的分辨率（项目3）；最近发现的嗜酸性粒细胞过氧化物酶催化的蛋白质的蛋白质修饰与烟草烟相关，并且独立于适应性免疫会诱导哮喘样的表型。我们的多学科严格科学方法揭示了机制，并为成功转化为患者福利提供了最大的机会。三个科学核心（临床，生物术，动物模型）和一个行政核心通过提供专家服务并轻松访问器官型培养中定义明确定义的临床样本和原代细胞，并加强了每个项目的核心，以及鼠类哮喘模型。总的来说，转化研究遍及整个计划，建立在我们NIH资助的研究人员的基本发现的基础上，并大量利用了克利夫兰诊所转化科学奖（CTSA）的支持，并获得了人类过敏原挑战模型的FDA批准。总的来说，科学的范围和规模，高效和生产的研究人员以及一致的翻译重点有望在计划多年来影响患者护理的基本科学发现。