CYLD mRNA的m6A甲基化修饰在线粒体DNA介导ARDS内皮损伤中的作用及机制

肺微血管内皮细胞损伤是ARDS的重要病理生理改变。在损伤环境下，线粒体DNA(mtDNA)激活STING信号通路启动内皮损伤，去泛素化酶CYLD通过去除STING的多聚泛素化来稳定STING蛋白功能。预实验发现，mtDNA和ARDS病情严重程度呈正相关。ARDS时CYLD升高，CYLD mRNA上存在m6A甲基化修饰位点。推测CYLD mRNA m6A甲基化修饰，促进去泛素化酶CYLD表达，抑制STING蛋白泛素化，进而增强mtDNA介导ARDS内皮损伤。本项目将从临床、动物、细胞、分子水平，解析CYLD对评估ARDS患者疾病病因、病情严重程度及预后的价值，深入探讨CYLD mRNA m6A甲基化修饰在mtDNA启动ARDS内皮损伤中的作用，阐明CYLD mRNA m6A甲基化修饰在mtDNA介导ARDS内皮损伤中的分子机制，为ARDS内皮损伤治疗提供全新思路。

ARDS has a critical pathophysiological change of pulmonary microvascular endothelial cell dysfunction. In the injured environment, mitochondrial DNA(mtDNA) activates STING signaling pathway to initiate endothelial dysfunction, and STING protein stabilization can be kept via removing the polyubiquitination by deubiquitination enzyme CYLD. Preliminary experiments demonstrated that mtDNA was positively correlated with ARDS severity. CYLD was increased in ARDS, m6A modification sites existed on CYLD mRNA. It is speculated that CYLD mRNA m6A methylation promotes the expression of deubiquitin enzyme CYLD, which inhibits STING protein ubiquitination , and thus enhances mtDNA-mediated endothelial dysfunction in ARDS. The research will analysis CYLD values in assessment of ARDS etiology, severity and prognosis, discuss further effects of CYLD mRNA m6A methylation modification in the progress of mtDNA-initiated ARDS endothelial dysfunction, clarify the molecular mechanisms of CYLD mRNA m6A methylation modificationin in mtDNA-mediated ARDS endothelial dysfunction from clinical, animal, cell and molecular levels. Theses will provide a new thought for ARDS endothelial dysfunction treatment.