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制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) 适应性免疫的过度反应，最常见的是通过 CD4* T 辅助淋巴细胞 (TH2) 细胞； (2) 与异常细胞外基质相关的炎症缺乏解决，异常细胞外基质会放大炎症细胞的流入和激活； (3)产生过多的活性氧和氮，促进重塑。根据我们累积的发现，我们计划的统一假设是哮喘是由长期和过度的炎症（主要是 TH2）引起的，并且尝试解决和修复失败导致气道重塑。为了测试这一点，我们的计划通过 4 个项目组织了一个综合方法，旨在研究细胞外和细胞分子成分的相互关联作用，包括： 新发现的 IL-25（TH2 细胞因子）途径，依赖于泛素 iigase Act1 来介导过敏通过对气道上皮和 T 细胞的独立（且非冗余）影响而产生气道炎症（项目 2）；由于哮喘病理氧化状态下酪氨酸磷酸酶失活，气道上皮对 TH2 细胞因子的反应放大并持续（项目 1）；富含透明质酸的病理性细胞外基质的异常沉积增加，阻碍炎症消退（项目 3）；最近发现的嗜酸性粒细胞过氧化物酶催化的氨甲酰化蛋白修饰与烟草烟雾暴露有关，并且与适应性免疫无关，可诱导哮喘样表型。我们的多学科严谨的科学方法揭示了机制，并为成功转化为患者利益提供了最大的机会。三个科学核心（临床、生物样本库、动物模型）和一个管理核心通过提供专家服务和轻松获取器官型培养中明确的临床样本和原代细胞以及小鼠哮喘模型来加强每个项目并加快翻译速度。总的来说，转化研究整合在整个计划中，以 NIH 资助的研究人员的基本发现为基础，广泛利用克利夫兰诊所转化科学奖 (CTSA) 的支持，并受益于 FDA 对人类过敏原挑战模型的批准。总而言之，科学的范围和规模、高效和富有成效的研究人员以及一致的转化重点有望带来基础性的科学发现，这些发现将在该计划的多年来影响患者的护理。