Molecular Mechanisms for IL-25-mediated Th2 Responses

描述（由申请人提供）：哮喘已成为一种流行病，影响世界上超过1.55亿人，其中包括美国约2200万人。哮喘中的慢性炎症主要是由于Th 2淋巴细胞和Th 2细胞因子/趋化因子的持续存在，这些细胞因子由肺的结构细胞以及浸润的CD 4+淋巴细胞、嗜酸性粒细胞和嗜碱性粒细胞以及驻留的肥大细胞产生，导致肺功能的进行性丧失。最近的研究表明，IL-25作为Th 2应答的重要介质发挥作用，并且位于经典Th 2细胞因子应答的上游。我们最近报道，Act 1，一种新的E3泛素连接酶，是IL-25信号传导的重要信号分子，在配体刺激后被募集到IL-25 R。上皮细胞中的Act 1缺陷减少了IL-25介导的过敏性肺部炎症，而T细胞中的Act 1缺陷也导致Th 2应答和肺部炎症减少。基于这些发现，我们假设IL-25诱导的Act 1介导的信号通路通过对上皮细胞和T细胞区室的不同影响在Th 2细胞应答和过敏性肺部炎症中起重要作用。为了验证这一假设，我们提出了两个具体的目标：（1）研究IL-25诱导的Act 1介导的信号通路在Th 2应答和变应性肺炎中的作用机制;（2）阐明Act 1介导IL-25信号通路的分子机制，并开发诱饵（抑制）肽作为变应性肺炎的潜在治疗策略。拟议的研究将为启动和维持哮喘表型的事件提供重要的见解，从而增加开发这些途径的特异性抑制剂和治疗哮喘的新疗法的潜力。 公共卫生相关性：哮喘已经成为一种流行病，影响世界上超过1.55亿人，包括美国约2200万人。超过90%的儿童哮喘和超过65%的成人哮喘是对各种环境过敏原致敏的结果（特应性哮喘）。拟议的IL-25信号转导研究将提供额外的洞察事件，启动和维持哮喘表型。随着对这些通路的理解的加深，有可能开发出这些通路的特异性抑制剂，也许还有治疗哮喘的新疗法。

DESCRIPTION (provided by applicant): Asthma has become an epidemic affecting more than 155 million people in the world including ~22 million people in the United States. The chronic inflammation in asthma is due largely to the persistence of Th2 lymphocytes and Th2 cytokines/chemokines produced by both the structural cells of the lung as well as the infiltrating CD4+ lymphocytes, eosinophils, and basophils and the resident mast cells, leading to progressive loss of lung function. Recent studies have shown that IL-25 functions as an important mediator of Th2 responses and lies upstream of the classical Th2 cytokine responses. We recently reported that Act1, a novel E3 ubiquitin ligase, is an essential signaling molecule for IL-25 signaling, recruited to IL-25R upon ligand stimulation. Act1 deficiency in epithelial cells reduced IL-25-mediated allergic pulmonary inflammation, while Act1 deficiency in T cells also resulted in diminished Th2 responses and lung inflammation. Based on these findings, we hypothesize that the IL-25 induced Act1- mediated signaling pathway plays essential roles in Th2 cell responses and allergic pulmonary inflammation through the distinct impact on epithelial and T cell compartment. To test this hypothesis, we propose two Specific Aims: (1) Investigate the mechanistic role of IL-25-induced Act1-mediated signaling pathway in Th2 responses and allergic pulmonary inflammation; (2) Elucidate the molecular mechanism by which Act1 mediates IL-25 signaling and develop decoy (inhibitory) peptides as a potential therapeutic strategy for allergic pulmonary inflammation. The proposed research will provide significant insight into the events that both initiate and maintain the asthmatic phenotype, leading to increased potential to develop specific inhibitors of these pathways and novel therapeutics for the treatment of asthma. PUBLIC HEALTH RELEVANCE: Asthma has become an epidemic affecting more than 155 million people in the world including ~22 million people in the United States. Greater than 90% of childhood asthma and greater than 65% of adult asthma is the result of sensitization to a variety of environmental allergens (atopic asthma). The proposed study on IL-25 signaling will provide additional insight into the events that both initiate and maintain the asthmatic phenotype. With this improved understanding comes the potential to develop specific inhibitors of these pathways and perhaps novel therapeutics for the treatment of asthma.