GRIM19适度下调通过线粒体自噬调控干细胞存活的作用机制研究

MSCs移植是促进梗死心肌修复和功能重建的重要手段，然而因缺氧、炎症导致的氧化应激会引起移植细胞大规模凋亡，严重影响MSCs的移植疗效。线粒体复合物I是维持细胞能量稳态的重要组分，也是ROS产生的主要位点之一。申请人前期证实线粒体复合物I亚基GRIM19适度下调能减少缺血再灌注过程中氧化应激损伤和凋亡，有效保护心肌组织，该过程可能由于GRIM19适度下调产生的电子泄露促进ROS少量持续表达，增强心肌细胞对于缺血再灌注损伤的耐受。同是申请人发现GRIM19适度下调也能调控MSCs对抗氧化应激损伤，其分子机制是否通过促进ROS少量持续表达来激活线粒体自噬。本项目将深入探讨GRIM19适度下调通过线粒体自噬调控MSCs对抗氧化应激损伤的作用及分子机制，通过心肌梗死模型，揭示GRIM19在MSCs存活及心肌修复中的作用机制，为提高干细胞移植疗效，促进损伤心肌组织修复及功能重建提供借鉴。

MSCs transplantation is an important means to promote repair and functional reconstruction of infarcted myocardium. However, hypoxia/inflammation-induced oxidative stress can cause large-scale apoptosis of transplanted cells, which seriously affects MSCs transplantation. Mitochondrial complex I is an important component to maintain cell energy homeostasis, and is also one of the main sites of ROS production. We preliminarily confirm that moderate down-regulation of mitochondrial complex I subunit GRIM19 can reduce oxidative stress-induced apoptosis during reperfusion, and effectively protect the myocardium, which is probably due to the electron leakage after moderate down-regulation of GRIM19 to promote a small and consistent ROS expression, enhancing myocardial tolerance in ischemia reperfusion injury. Meanwhile, we find that moderate down-regulation of GRIM19 can also protect MSCs against oxidative stress injury, and whether mitophagy activation through ROS expression remains to be elucidated. This project will study the effect and mechanism of moderate down-regulation of GRIM19 on MSCs survival against oxidative stress injury through mitophagy. Based on myocardial infarction model, this project will reveal the mechanism of GRIM19 in MSCs survival and myocardial repair, in order to improve the effect of stem cell transplantation, and provide a basis for promoting cardiac repair and functional reconstruction of infarcted myocardium.