eIF2α乙酰化修饰在尿毒症小鼠心肌缺血再灌注损伤中的作用机理研究

尿毒症增加心肌缺血再灌注（I/R）损伤易感性，真核细胞翻译启始因子2α（eIF2α）乙酰化修饰是影响心肌I/R损伤的潜在关键靶点，然而其在尿毒症心肌损伤中的作用及机制尚不明确。前期研究显示，eIF2α去乙酰化明显减轻心肌I/R损伤；尿毒症心肌eIF2α乙酰化水平明显上调，而去乙酰化酶Sirt1表达显著下调，基于此，本项目提出“eIF2α乙酰化靶向修饰显著减轻尿毒症心肌I/R损伤”的科学设想。拟借助5/6肾切除构建小鼠尿毒症模型，从细胞和整体水平，采用心肌特异性eIF2α乙酰化位点突变及免疫共沉淀等技术，观察I/R损伤后ATF4/CHOP信号通路介导的心肌细胞凋亡，明确eIF2α乙酰化修饰的上游调控靶点，阐明eIF2α乙酰化修饰在尿毒症心肌I/R损伤中的作用机理。本项目将从eIF2α乙酰化修饰这一全新角度，揭示尿毒症增加心肌I/R损伤易感性的机制，为尿毒症心肌保护提供有效干预靶点。

Uremia increases the susceptibility to myocardial ischemia reperfusion (I/R) injury, and acetylation of eukaryotic initiation factor 2α (eIF2α) is a potential key target for myocardial I / R injury. However, its role and mechanism in uremic myocardium injury are not clear. Previous studies showed that eIF2αdeacetylation significantly reduced myocardial I / R injury; eIF2α acetylation in uremic myocardium was significantly increased, and Sirt1 expression was significantly reduced. We presumed that targeting eIF2α acetylation modification might significantly reduce uremic myocardial I / R injury. The uremia model was constructed in mice by 5/6 subtotal nephrectomy. By myocardial specific eIF2α acetylation site mutation and co-immunoprecipitation techniques, we will observe the ATF4/CHOP signal pathway mediated myocardial apoptosis after I/R injury, explore the upstream regulatory target of eIF2α acetylation modification, and clarify the mechanism of eIF2α acetylation modification in uremic myocardial I / R injury. This project will reveal the mechanism of increased susceptibility to myocardial I / R injury in uremic myocardium from the new perspective of eIF2α acetylation modification, and provide an effective intervention target for uremic myocardial protection.