DNA损伤和核苷酸切除修复（NER）通路关键基因DDB2/XPE在慢阻肺细胞衰老中的作用及调控方式

慢性阻塞性肺疾病（简称慢阻肺）是全球“四大慢性疾病”之一，在我国具有高患病率、高死亡率、高疾病负担的特点，随着人口老龄化的急速加剧，我国慢阻肺防治面临严峻形势。吸烟是慢阻肺最重要的危险因素，而吸烟介导的DNA损伤，可导致细胞凋亡、衰老、炎症及突变的形成。在慢阻肺中，多个DNA损伤修复通路存在不同程度的上调或下调，研究表明，核苷酸切除修复（NER）通路随着慢阻肺临床严重程度增加而下调程度尤为明显，其关键蛋白DDB2/XPE表达下降，但其下游细胞衰老情况、炎症反应及病理改变尚未被探讨。.本研究拟通过临床、动物及细胞研究，探究在慢阻肺中，NER通路表达程度的改变对细胞衰老的影响，及下游炎症反应、病理改变的情况。并探讨ATM对慢阻肺中NER通路的调控。该研究探讨了DNA修复关键通路NER通路的下调导致的细胞衰老,并检测了下游炎症表达，为慢阻肺发病机制的研究提供了较为完整的线索。

Chronic obstructive pulmonary disease (COPD) is one of the four major chronic diseases in the world, defined by WHO. It has high prevalence, high mortality and leading to high disease burden in China. With rapid aging of the population in China, we are facing a severe situation in prevention and treatment of COPD. As the most significant risk factor for COPD, smoking causes DNA damage in cells, leading to cell apoptosis, senescence, inflammation and mutation. In COPD, multiple DNA damage repair pathways are up-regulated or down-regulated to varying degrees. Previous study has shown that the nucleotide excision repair (NER) pathway is particularly down-regulated as the clinical severity of COPD increases. Expression of DDB2/XPE, a key protein of NER pathway, decreased in COPD, but the downstream mechanism of this hasn’t been explored, including cell senescence, inflammatory response and pathological changes. .In our study, we intend to investigate the effect of changes in the expression of NER pathway on cell senescence in COPD through clinical, animal and cellular studies, as well as downstream inflammation and pathological changes. Meanwhile, we will explore the regulation of ATM on NER pathway in COPD. This study will explore the cell senescence caused by the down-regulation of the NER pathway, a key pathway of DNA repair, and detect the expression of downstream inflammation, providing a complete clue for the pathogenesis of COPD.