香烟烟雾诱导PLAC8 m6A修饰促进自噬介导COPD中性粒细胞胞外诱捕网形成的机制研究

香烟烟雾（CS）暴露是COPD最重要危险因素，申请人前期发现中性粒细胞胞外诱捕网（NETs）是CS致病的重要介质，但其如何调控NETs形成尚不清楚。鉴于m6A修饰在环境因素致病中的“桥梁”作用，申请人通过生物信息学分析和预实验发现COPD患者诱导痰和CS刺激的中性粒细胞中甲基化酶ALKBH5下调，而阅读蛋白IGF2BP2和自噬相关基因PLAC8上调。且ALKBH5可降低PLAC8 m6A甲基化和表达水平，因此提出CS介导ALKBH5诱导PLAC8 m6A修饰，同时调控阅读蛋白IGF2BP2表达，增强PLAC8的mRNA稳定性，共同促进细胞自噬介导NETs形成，加速气道炎症及COPD进展的科学假设。本课题拟以ALKBH5介导的PLAC8 m6A甲基化为中心，从临床、动物、细胞、分子多维度揭示CS促进NETs形成和COPD进程的机制，为今后靶向NETs的COPD治疗策略开发提供新思路。

Cigarette smoke (CS) exposure is the most important risk factor for chronic obstructive pulmonary disease (COPD). The applicant previously discovered that neutrophil extracellular traps (NETs) are important mediators of CS causing COPD, but how it regulates the formation of NETs is still unclear. Given the "bridge" role of m6A modification in the pathogenesis of environmental factors, the applicant found through bioinformatics analysis and pre-experiments that the methylase ALKBH5 was down-regulated in neutrophils stimulated by sputum and CS in COPD patients while reading protein IGF2BP2 and autophagy-related gene PLAC8 were up-regulated. Besides, ALKBH5 could reduce the m6A methylation modification and expression level of PLAC8. Thus, it is proposed that CS-mediated ALKBH5 induces PLAC8 m6A modification, regulates the expression of the reading protein IGF2BP2, enhances the mRNA stability of PLAC8, jointly promoting the formation of NETs mediated by autophagy, promoting the airway inflammation, and accelerating COPD progression. This project intends to focus on ALKBH5-mediated PLAC8 m6A methylation, revealing the mechanism of CS promoting the formation of NETs and the process of COPD from multiple dimensions such as clinical, animal, cell, and molecule, and provide new ideas for developing COPD treatment strategies targeting NETs in the future.