Molecular Mechanisms for IL-25-mediated Th2 Responses

IL-25 介导的 Th2 反应的分子机制

• 批准号: 7989486
• 负责人: Xiaoxia Li
• 金额: $ 35.9万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989486
• 关键词: Adult asthma; Affect; Allergens; Allergic; Asthma; Basophils; Boxing; Bronchial Hyperreactivity; CCL17 gene; CD4 Positive T Lymphocytes; Cells; Childhood Asthma; Chronic; Dendritic Cells; Development; Eosinophilia; Eotaxin; Epidemic; Epithelial; Epithelial Cells; Event; Extrinsic asthma; Family; Goals; Hyperplasia; IgE; Immune; Immunity; Infiltration; Inflammation; Inflammatory; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Knowledge; Ligands; Lung; Lung Inflammation; Lung diseases; Lymphocyte; MAP Kinase Gene; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinase Kinases; Modeling; Molecular; Mus; Pathway interactions; Peptides; Phenotype; Play; Pneumonia; Pulmonary Eosinophilia; RANTES; Receptor Signaling; Recombinants; Recruitment Activity; Reporting; Research; Respiratory physiology; Role; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle; Staging; Symptoms; T-Lymphocyte; TRAF6 gene; TSLP gene; Testing; Th2 Cells; Therapeutic; Ubiquitination; United States; adaptive immunity; allergic response; base; cell type; chemokine; cytokine; environmental allergen; eosinophil; improved; inhibitor/antagonist; insight; interleukin-17E; mast cell; member; neutrophil; novel; novel therapeutics; public health relevance; receptor; response; tool; transcription factor; ubiquitin-protein ligase

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.

描述（由申请人提供）：哮喘已成为一种流行病，影响着世界上超过 1.55 亿人，其中包括约 2200 万人在美国。哮喘中的慢性炎症主要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，Act1 是一种新型 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至 IL-25R。上皮细胞中 Act1 的缺乏会减少 IL-25 介导的过敏性肺部炎症，而 T 细胞中 Act1 的缺乏也会导致 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 细胞区室的独特影响，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 信号传导的分子机制，并开发诱饵（抑制）肽作为过敏性肺部炎症的潜在治疗策略。拟议的研究将为引发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：哮喘已成为一种流行病，影响着世界上超过 1.55 亿人，其中包括美国约 2200 万人。超过 90% 的儿童哮喘和超过 65% 的成人哮喘是对多种环境过敏原（特应性哮喘）过敏的结果。拟议的 IL-25 信号研究将为引发和维持哮喘表型的事件提供更多见解。随着理解的加深，有可能开发出这些途径的特异性抑制剂，甚至可能开发出治疗哮喘的新疗法。