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，影响全球超过1.55亿人，其中美国约有2200万人。哮喘的慢性炎症很大程度上是由于肺结构细胞以及浸润的CD4+淋巴细胞、嗜酸性粒细胞、嗜碱性粒细胞和常驻肥大细胞产生的Th2淋巴细胞和Th2细胞因子/趋化因子的持续存在，导致肺功能的进行性丧失。最近的研究表明，IL-25是Th2反应的重要介质，位于经典Th2细胞因子反应的上游。我们最近报道了一种新的E3泛素连接酶Act1，它是IL-25信号传导的重要信号分子，在配体刺激下被招募到IL-25R上。上皮细胞缺乏Act1可减少il -25介导的过敏性肺部炎症，而T细胞缺乏Act1也可导致Th2反应减弱和肺部炎症。基于这些发现，我们假设IL-25诱导的Act1介导的信号通路通过对上皮细胞和T细胞室的不同影响，在Th2细胞反应和过敏性肺部炎症中发挥重要作用。为了验证这一假设，我们提出了两个具体目标：(1)研究il -25诱导的act1介导的信号通路在Th2反应和过敏性肺部炎症中的机制作用；(2)阐明Act1介导IL-25信号转导的分子机制，开发诱骗（抑制）肽作为变应性肺部炎症的潜在治疗策略。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哮喘治疗的新疗法的潜力。

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.