γ-H2AX焦点形成延迟介导Ⅱ型肺上皮细胞再生阻遏对支气管肺发育不良的影响机制研究

支气管肺发育不良（BPD）是早产儿所特有的肺泡发育障碍性疾病，Ⅱ型肺上皮细胞（ATⅡ）作为肺泡化的祖细胞，其损伤后再生能力直接影响早产儿出生后的肺发育进程。课题组前期证实BPD中ATⅡ存在DNA双链断裂（DSB）及细胞再生受阻，近期发现组蛋白γ-H2AX焦点形成延迟、KPNA2入核障碍、DNA损伤累积，提示KPNA2/H2AX/DSB通路可能调控ATⅡ的细胞命运。本项目提出工作假说：γ-H2AX焦点形成延迟引发DNA损伤修复监视功能失调，在DNA损伤压力下，ATⅡ再生阻遏导致BPD的肺发育不良：拟阐明γ-H2AX焦点形成延迟对ATⅡ再生的影响；解析γ-H2AX焦点形成延迟对DNA损伤修复的影响规律；探索γ-H2AX焦点延迟形成的关键调控分子机制；验证KPNA2/H2AX/DSB对BPD病理结局的影响。旨在从新的角度认识BPD氧化应激损伤的发病机制，寻找基于改善DNA损伤为靶点的全新策略。

Bronchopulmonary dysplasia (BPD) is an alveolar dysplasia disorder in premature infants. Type II alveolar epithelial（ATII）cells, as the progenitor cells of alveolarization, its regeneration ability after injury directly influences pulmonary development. Our research team previously confirmed that DNA double-strand break (DSB) and cell regeneration disorder existed in ATII cells during BPD. Recently,DNA damage accumulation, delayed focal formation of histone γ-H2AX, and blocked KPNA2 nuclear translocation were found by us, suggesting that the KPNA2/H2AX/DSB pathway may regulate the cell fate of ATII cells in BPD. This project proposes the following hypothesis: delayed formation of γ-H2AX foci leads to the monitoring dysfunction of DNA damage repair. Regeneration of ATII cells are inhibited due to DNA damage, resulting in BPD. This project aims to clarify the effect of delayed γ-H2AX foci formation on ATII regeneration; To elucidate the effect of delayed γ-H2AX foci formation on DNA damage repair; To explore the key regulatory molecular mechanism of delayed γ-H2AX foci formation; To validate the impact of KPNA2/H2AX/DSB pathway on pathological outcomes of BPD. The project aims to understand the pathogenesis of oxidative stress injury in BPD from a novel perspective and to investigate new strategies for prevention and treatment of BPD based on improving DNA damage.