Asthma Inflammation Research (AIR)

描述(由申请人提供)： 哮喘是世界上最常见的慢性病之一。我们团队的协同和机制研究在很大程度上有助于确定哮喘炎症和重塑的基本致病过程，包括：(1)适应性免疫过度反应，通常通过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未能消退，后者放大炎症细胞的流入和激活；以及(3)产生过量的活性氧和氮物质，促进重塑。根据我们的累积发现，我们项目的统一假设是，哮喘是由长期和过度的炎症(主要是TH2)引起的，试图解决和修复失败会导致气道重塑。为了验证这一点，我们的计划通过4个项目组织了一个全面的方法，旨在研究细胞外和细胞-分子组件的相互关联的作用，包括：新发现的IL-25(TH2细胞因子)途径，依赖泛素Iigase Act1，通过对气道上皮和T细胞的独立(和非冗余)作用来介导过敏性气道炎症(项目2)；由于酪氨酸磷酸酶失活，哮喘病理氧化状态中TH2细胞因子的放大和持续(项目1)；富含透明质酸的细胞外基质增加和异常沉积，阻碍炎症的消退(项目3)；最近发现的嗜酸性粒细胞过氧化物酶催化的氨甲基化蛋白修饰与烟草烟雾暴露有关，并且不依赖适应性免疫，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，并为成功的翻译提供了最大的机会，使患者受益。三个科学核心(临床、生物库、动物模型)和一个管理核心通过提供专家服务和方便地获取明确定义的临床样本和器官培养的原代细胞以及小鼠哮喘模型，加强了每个项目并加快了翻译速度。总的来说，转化研究被整合到整个计划中，建立在我们由NIH资助的研究人员所做的基本发现的基础上，广泛利用了克利夫兰临床转化科学奖(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、高效和多产的研究人员以及始终如一的翻译重点保证了基础性的科学发现，这些发现将在该计划的多年中影响患者护理。

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.