SIRT1在香烟诱导的气道重构中的作用机制研究

Airway remodeling is a significant mechanism of progressive airflow limitation in chronic obstructive airway disease (COPD) patients. It has been proved that cigarette smoke induces airway epithelial to mesenchymal transition (EMT) in vivo and in vitro, which is the important mechanism of airway remodeling in COPD patients. Oxidative stress plays an important role in EMT. Recent studies proved that SIRT1 take part in the pulmonary oxidative stress induced by cigarette smoke. It is not clear whether SIRT1 is involved in EMT process. We presume SIRT1 plays an important role in cigarette smoke induced airway epithelial to mesenchymal transition. In this study, we plan to culture human bronchial epithelial cells（HBE）and use gene knockout mice, transgenic mice, siRNA and specific inhibitor and agonist, to explore: 1)the regulatory mechanism of SIRT1 in cigarette smoke induced oxidative stress, airway epithelial to mesenchymal transition; 2)the involvement of SIRT1 in EMT by exerting its epigenetic regulation to TGF/NF-κB signaling pathway; 3) the effect of targeted intervention of SIRT1 on CS-induced airway epithelial to mesenchymal transition.

气道重塑是引起慢性阻塞性肺疾病（COPD）患者气流受限逐渐进展的重要机制，研究证实COPD患者发生气道重塑的重要机制之一是香烟烟雾引起的气道上皮间充质转化（EMT）。氧化应激是上皮间充质转化发生的重要介导途径，研究证实SIRT1参与了香烟诱导的肺部氧化应激反应。但SIRT1是否调控EMT未阐明。我们推测SIRT1在香烟诱导的氧化应激所致气道上皮间充质转化过程中有重要调控作用。本研究拟通过培养人支气管上皮细胞，基因敲除小鼠，转基因小鼠，采用RNA干扰，细胞转染，特异性激动剂，抑制剂等方法，探讨：1）SIRT1在香烟诱导的氧化应激，气道上皮间充质转化中的调节作用；2）SIRT1通过对TGF/Smad3/ NF-κB信号通路的去乙酰化作用发挥表观遗传学调控在气道上皮间充质转化过程中的调控机制；3）对SIRT1进行特异性增强后靶向干预气道EMT的研究，为香烟引起的气道重塑提供新的治疗靶点。