Asthma Inflammation Research (AIR)

描述（由申请人提供）： 哮喘是世界上最常见的慢性疾病之一。本研究组的协同和机制研究对确定哮喘炎症和重塑的基本致病过程做出了重大贡献，包括：（1）获得性免疫的过度反应，最常见的是通过CD 4 * T辅助淋巴细胞（TH 2）细胞;（2）与异常细胞外基质相关的炎症缺乏消退，异常细胞外基质放大了炎症细胞的流入和活化;和（3）产生促进重塑的过量活性氧和氮物质。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，主要是TH 2的炎症引起的，而解决和修复的尝试失败导致气道重塑。为了验证这一点，我们的计划组织了一个全面的方法，通过4个项目，旨在研究细胞外和细胞分子组分的相互关联的作用，包括：（TH 2细胞因子）途径，其依赖于泛素连接酶Act 1经由独立途径介导过敏性气道炎症。对气道上皮细胞和T细胞的影响（和非冗余）（项目2）;由于病理性氧化状态下酪氨酸磷酸酶的失活，气道上皮细胞对TH 2细胞因子的反应的放大和持续哮喘（项目1）;病理性富含透明质酸的细胞外基质的增加和异常沉积阻碍炎症的消退（项目3）;以及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，其与烟草烟雾暴露相关，并且独立于适应性免疫，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，生物储存库，动物模型）和一个行政核心加强每个项目，并通过提供专家服务和方便地获得明确的临床样本和器官型培养中的原代细胞以及小鼠哮喘模型来加快翻译。总的来说，转化研究在整个项目中得到了整合，建立在我们NIH资助的研究人员所做的基本发现的基础上，广泛利用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，高效和富有成效的调查人员，以及一贯的翻译重点，承诺将影响多年的病人护理计划的基础科学发现。

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.