cGAS-STING信号通路在哮喘发病中的作用及其机制

项目名称： cGAS-STING信号通路在哮喘发病中的作用及其机制

项目编号： No.81470215

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 颜伏归

作者单位： 浙江大学

项目金额： 75万元

中文摘要： 过敏原诱导的气道上皮凋亡常见于哮喘，但其是否介导哮喘发病尚未明确。最近发现凋亡细胞DNA可通过胞浆DNA识别信号通路的核心STING介导炎症性疾病的发生，而激活STING的关键分子是胞浆DNA感受器cGAS。我们研究发现卵白蛋白（OVA）依赖cGAS诱导气道上皮细胞IL-25的合成，因此提出cGAS-STING可能通过识别过敏原攻击所产生的凋亡气道上皮细胞DNA进而促进气道上皮细胞合成驱动Th2优势免疫的细胞因子以介导哮喘发病。本课题拟OVA体外干预cGAS/STING敲除气道上皮细胞，检测干预后细胞凋亡及IL-25等驱动Th2优势免疫的细胞因子表达。体内以OVA攻击气道上皮细胞/II 型肺泡上皮细胞cGAS/STING特异性敲除小鼠，检测攻击后小鼠IL-25等因子表达，评估肺组织炎症、气道黏液及气道高反应性。本课题拟阐明气道上皮凋亡介导哮喘发病的机制，为筛选新的哮喘治疗靶点提供理论依据。

中文关键词： 过敏性哮喘；cGAS；STING；细胞凋亡

英文摘要： Allergen-induced apoptosis of airway epithelial cells is common in asthma,but which is whether to mediate the pathophysiology of asthma remains unclear.A recent study showed that apoptotic cell DNA could mediate inflammatory disease through stimulator of interferon genes(STING) which is the core molecule of DNA sensor signaling pathway,and the key molecule activating STING is a newly identified cytosolic DNA sensor cyclic GMP-AMP synthase(cGAS).Our preliminary studies confirmed ovalbumin(OVA)-induced IL-25 production was dependent on cGAS in airway epithelial cells,so we hypothesize that the cGAS-STING signaling pathway can recognize allergen-induced apoptotic DNA of airway epithelial cells, then increase the production of cytokines driven-Th2 predominant immune response,and finally cause the development of asthma.We will use OVA to stimulate the cGAS/STING knockdown airway epithelial cells and examine cell apoptosis and cytokines driven-Th2 predominant immune response such as IL-25,IL-33 et al.Furthermore, we will utilize OVA to challenge mice with cGAS/STING specific knockdown in airway epithelial cells and alveolar type II epithelial cells, examine cytokines driven-Th2 predominant immune response in BALF and lung tissues, and evaluate the inflammation and mucins of lung tissues and airway hyperreactivity.We are aimed to elucidae the mechanisms by which apoptosis damage of airway epithelial cells mediates the pathophysiology of asthma,and provide preliminary theoretical basis for screening new effective therapy target in asthma.

英文关键词： asthma;cGAS;STING;cell apoptosis