mTOR信号通路在哮喘发病中的调控作用及分子机制

Asthma is one of the most popular chronic diseases. The pathogenesis of asthma is complex, of which most remain unclear, such as the mechanisms of allergen-induced epithelial injury and eosinophil differentiation. Based on our previous work, we proposed that mTOR (mammalian target of rapamycin) plays pivotal roles in allergen-induced epithelial injury as well as in eosinophil differentiation during asthma development. Human bronchial epithelial cells and primary mouse tracheal epithelial cells will be treated with ovabulmin (OVA), and the expression of mTOR related molecules and the released cytokines will be determined. Non adhere mononuclear cells from bone marrow will be used for in vitro eosinophil differentiation. Mice with mTOR specifically deleted in airway epithilium and Lysm-Cre-mTOR mice will be subjected for OVA sensitization and challenge. The mTOR related molecules, production of inflammatory cytokines, airway inflammation, mucus hypersecretion and airway hyperresponsiveness will be measured. These studies will identify the differential roles of mTOR in OVA-induced airway epithelial injury and eosinophil differentiation during asthma development, which would provide new therapeutic targets of durg development for asthma.

哮喘是全球最常见的慢性疾病之一，其发病机制错综复杂，许多关键机制如过敏原诱导的气道上皮细胞损伤机制以及嗜酸性粒细胞分化过程的调控机制等仍未阐明。本项目拟在前期工作基础上分别从气道上皮细胞损伤和嗜酸性粒细胞分化的角度探讨哺乳动物雷帕霉素靶蛋白（mTOR）在哮喘发生发展中的调控作用及分子机制。体外研究拟采用卵蛋白（OVA）刺激人体气道上皮细胞系和小鼠原代气道上皮细胞并检测mTOR相关信号通路分子的表达和炎症因子释放，同时分离小鼠骨髓非粘附单核细胞进行嗜酸性粒细胞分化研究；体内研究拟构建气道上皮细胞和骨髓来源粒细胞mTOR特异性诱导敲除小鼠哮喘模型，通过检测mTOR信号通路分子表达、炎症因子、气道炎症细胞浸润、粘液分泌和气道高反应性，阐明mTOR信号通路在过敏原诱导的气道上皮细胞损伤以及哮喘发生发展过程中嗜酸性粒细胞分化中的关键调控作用，为开发新型哮喘治疗药物提供新靶点和实验依据。

哮喘是全球最常见的慢性疾病之一，其发病机制错综复杂，许多关键机制如过敏原诱导的气道上皮细胞的损伤机制以及嗜酸性粒细胞分化过程的调控机制等仍不清楚。本项目拟在前期工作的基础上分别从气道上皮细胞损伤和嗜酸性粒细胞分化的角度探讨哺乳动物雷帕霉素靶蛋白（mTOR）在哮喘发生发展中的调控作用及分子机制。体外研究拟利用卵蛋白（OVA）处理人体气道上皮细胞系和小鼠原代气道上皮细胞，或者分离小鼠骨髓非粘附单核细胞进行嗜酸性粒细胞分化，体内研究拟构建气道上皮细胞和骨髓来源粒细胞 mTOR 特异性诱导敲除小鼠哮喘模型，通过测定 mTOR 相关信号通路分子的表达、炎症因子、气道炎症细胞浸润、粘液分泌和气道高反应性等因素，阐明 mTOR 信号通路在过敏原诱导的气道上皮细胞损伤以及哮喘发生发展过程中嗜酸性粒细胞分化中的关键调控作用，为有效预防和治疗这一慢性气道炎症提供新思路，为开发新型哮喘防治药物提供新靶点和实验依据。