hOGG1通过DNA甲基化调控p55PIK在COPD气道炎症和重构中的作用及机制研究

外界环境因素通过氧化损伤形成DNA甲基化与COPD的发生发展密切相关。本课题组前期研究发现人8-羟基鸟嘌呤DNA糖苷酶1（hOGG1）可通过影响氧化损伤产物DNA加合物8-OHdG调控DNA甲基化，后者引起p55PIK的改变。因此我们推测：hOGG1通过DNA甲基化调控p55PIK，触发COPD气道炎症反应和气道重构的发生。在既往研究基础上，本研究从细胞、动物和人体水平探讨p55PIK活化及抑制，以及阻断其下游AKT和N24通路对气道炎症和气道重构的影响，明确p55PIK在COPD的关键作用；然后研究hOGG1作用于DNA加合物影响DNA甲基化来调控p55PIK的机制。旨在探讨hOGG1/p55PIK如何影响环境因素引起的COPD特异性气道炎症、细胞增殖和气道重构的发生，hOGG1从上游抑制p55PIK及阻断p55PIK下游通路在COPD中的治疗价值，从而为COPD的防治提供新的理论依据。

External environmental factors can form DNA methylation through oxidative damage, which is closely related to the occurrence and development of COPD. Our previous studies have found that human 8-hydroxyguanine DNA glycosidase 1 (hOGG1) can regulate DNA methylation by affecting oxidative damage products (DNA adduct 8-OHdG), which induces changes in p55PIK. Therefore, we speculate that hOGG1 regulates p55PIK through DNA methylation, which triggers airway inflammation and airway remodeling in COPD. On these bases, we will explore the activation and inhibition of p55PIK at cellular, animal and human levels respectively in this study, and the effects of airway inflammation and airway remodeling by blocking downstream AKT and N24 pathways, to define the key role of p55PIK in COPD. Then we will study the mechanism of hOGG1 regulating p55PIK by acting on DNA adducts to induce DNA methylation. To explore how hOGG1/p55PIK affects COPD-specific airway inflammation, cell proliferation and airway remodeling induced by environmental factors, and the therapeutic value of hOGG1 inhibiting p55PIK from upstream and blocking p55PIK downstream pathway in COPD. This provides a new theoretical basis for the prevention and treatment of COPD.