lncRNA GAS5调控miR-223/p120/NF-κB信号轴对COPD的作用及机制研究

慢性阻塞性肺疾病（COPD）已成为全球第三大死亡原因。气道上皮屏障破坏和持续的炎症反应与COPD的发生发展密切相关。本人既往研究发现香烟烟雾提取物刺激的人气道上皮细胞中粘附分子p120表达下调，并通过RhoA激活NF-κB信号通路促进气道炎症；且前期研究发现miR-223可直接靶向作用于p120 mRNA的3’UTR区域，负性调节p120蛋白表达。晚近，本人研究发现COPD肺组织中GAS5表达水平降低；且在气道上皮细胞中敲低GAS5可以降低单层细胞跨膜电阻，提示GAS5可能参与了COPD的发病过程。据此推测GAS5通过调控miR-223/p120/NF-κB信号轴维持气道上皮屏障的完整性并抑制炎症因子及粘蛋白产生影响COPD发生发展。本项目将利用临床COPD病人肺组织标本，体外培养气道上皮细胞，以及体内香烟烟雾诱导COPD小鼠动物模型进行相关机制研究，有望为COPD防治提供新靶点。

Chronic obstructive pulmonary disease (COPD) has become the third leading cause of death worldwide. Airway epithelial barrier disruption and persistent inflammatory response are closely associated with the development of COPD. In my previous studies, I found that the expression of adhesion molecule p120 was down-regulated in epithelial cells stimulated by cigarette smoke extract and promoted airway inflammation through RhoA by activation of NF-κB signaling pathway; and previous studies found that miR-223 could directly target the 3'UTR region of p120 mRNA and negatively regulate p120 protein expression. Recently, I found that expression level of GAS5 was reduced in COPD lung tissues, and knocking down GAS5 in airway epithelial cells could reduce the transmembrane resistance of monolayer cells, suggesting that GAS5 may be involved in the pathogenesis of COPD. It is hypothesized that GAS5 maintains the integrity of the airway epithelial barrier and inhibits inflammatory factors and mucin production by modulating the miR-223/p120/NF-κB signaling axis to influence the development of COPD. This project will use lung tissue specimens from clinical COPD patients, in vitro airway epithelial cells culture and in vivo cigarette smoke induced COPD mouse models to study the related mechanism, which is expected to provide new targets for COPD control.