DNA甲基化调控下的Gadd45b/p38MAPK轴在COPD气道炎症及细胞衰老中的作用

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease with high morbidity and mortality, which associated with a heavy medical burden. Airway inflammation and cellular senescence are involved in COPD, but the pathogenesis is not fully elucidated. Recent studies imply that Growth arrest and DNA damage inducible 45b (Gadd45b) play an important role in the regulation of immunity response and cellular senescence. Furthermore, Gadd4b expression was reduced in the airway epithelium of COPD patients according to our pre-experimental results. Based on the above, this study aims to explore the role and mechanism of Gadd45b in the airway inflammation and cellular senescence in COPD. Firstly, we will detect Gadd45b expression in the bronchial epithelium in human, mice model and cellular model. Subsequently, we evaluate the impact of Gadd45b on smoking-induced airway inflammation and cellular senescence. Further more, we are going to investigate whether Gadd45b expression in the bronchial epithelium is regulated by promoter methylation. This study intense to provide a new target for treatment of COPD.

慢性阻塞肺疾病（COPD）是一种高发病率、高死亡率，给社会带来沉重医疗负担的慢性呼吸道炎症性疾病。气道炎症、细胞衰老等病理过程参与COPD发病，然而其机制未完全阐明。近期研究发现，生长阻滞及DNA损伤诱导蛋白45b（Gadd45b）在免疫反应和细胞衰老中发挥重要作用，我们预实验结果显示Gadd45b在COPD患者气道上皮表达降低。因此，本课题在国内外研究和预实验结果的基础上，从人体水平、动物水平和细胞水平，先探讨Gadd45b在COPD气道上皮细胞表达的变化，然后研究Gadd45b对COPD气道炎症和细胞衰老的影响及其机制，最后探究香烟是否通过改变Gadd45b启动子的甲基化程度来调节其表达。本研究旨在进一步阐明COPD的发病机理，为COPD的治疗提供新靶点。

慢性阻塞性肺病（COPD）是最普遍的呼吸道疾病，对健康构成极大威胁，同时也是全球第三大死亡原因，带来巨大的社会经济和医疗负担。目前认为，吸烟通过引起的异常炎症及加速的肺脏老化等机制导致COPD发病，然而其机制未完全阐明。. 近年研究发现，生长阻滞及DNA损伤诱导蛋白45b（Gadd45b）在炎症反应及细胞衰老中起重要作用。本课题在国内外研究的基础上，发现香烟烟雾提取物（CSE）可能通过降低Gadd45b启动子甲基化程度来上调气道上皮Gadd45b表达，后者表达升高后激活p38信号通路，促进气道炎症和细胞衰老，最终导致COPD发病。本研究进一步阐明COPD的发病机理，为COPD的治疗提供潜在新靶点。