吸烟是慢性阻塞性肺疾病（COPD）最主要的诱发因素，但其致病的分子机制尚未明确。我们最近开创性地研究了细胞自噬在COPD中的关键调控作用（PLoS ONE 2008与PNAS 2010），本课题在此基础上进一步探讨细胞自噬关键上游信号哺乳动物雷帕霉素靶蛋白（mTOR）在吸烟诱导的气道上皮细胞损伤和COPD中的调控作用及分子机制。体外研究拟利用香烟烟雾提取物处理人体气道上皮细胞系和小鼠原代气道上皮细胞，体内研究拟构建气道上皮细胞和肺泡II型上皮细胞mTOR特异性诱导敲除小鼠并给与烟雾暴露，通过测定mTOR相关信号通路分子的表达、细胞自噬与凋亡、炎症因子表达、气道炎症细胞浸润、粘液分泌以及小鼠肺平均内衬间隔（MLI）等因素，阐明mTOR信号通路在吸烟诱导的气道上皮细胞损伤和COPD分子发病机制中的关键调控作用，为有效预防和治疗吸烟诱导的气道炎症提供新思路，为开发新型COPD防治药物提供新靶点。

Cigarette smoking is the most risk factor of chronic obstructive pulmonary disease (COPD), while the detailed molecular mechanisms of the process remain unclear. Based on our recent studies that autophagy has been critically involved in lung epithelial injury and COPD development (PLoS ONE 2008 and PNAS 2010), we propose in the current project to explore the role and mechanisms of mTOR (mammalian target of rapamycin), a pivotal upstream signal of autophagy, in cigarette smoking induced airway epithelial injury and COPD pathogenesis. Human bronchial epithelial cells and primary mouse tracheal epithelial cells will be treated with cigarette smoking extract, and mice with mTOR specifically deleted in airway epithilium or aveolar type II cells will be exposed to cigarette smoke. The expression of mTOR related molecules, autophagy and apoptosis, production of inflammatory cytokines, airway inflammation, mucus hypersecretion and mean linear intercepts (MLI) of mouse lungs will be measured. These studies will identify an important role of mTOR in cigarette smoking induced airway epithelial injury and COPD development, which would shed new lights for prevention and treatment of chronic airway inflammation, and provide new therapeutic targets of durg development for COPD.