TAX1BP1通过RNF115/STX17途径调控线粒体自噬参与脓毒症心肌损伤的作用及机制研究

心肌损伤是脓毒症常见的重要并发症，然而其病理过程仍不明确。线粒体是维持心肌细胞正常生理功能的重要细胞器，我们和他人的研究证实脓毒症病理过程中心肌细胞线粒体自噬抑制导致的线粒体质量异常是心肌损伤的关键，但其分子机制尚不清楚。我们进一步的研究初步发现：自噬受体蛋白TAX1BP1通过调控线粒体自噬参与脓毒症导致的心肌损伤，且TAX1BP1可能是通过招募RNF115调控RNF115/STX17信号途径，影响线粒体自噬小体与溶酶体的融合进而参与心肌细胞线粒体自噬。本项目拟在前期研究基础上，通过建立在体和离体的脓毒症心肌损伤模型，利用靶基因过表达或干扰技术，进一步从分子、细胞及动物水平阐明TAX1BP1通过RNF115/STX17途径调控线粒体自噬参与脓毒症心肌损伤的作用及其分子机制。本项目一方面将进一步阐明脓毒症心肌损伤的分子机理，另一方面将为临床上防治脓毒症心肌损伤提供新的思路和理论支持。

Myocardial injury is a common and important complication of sepsis, but its pathologic process remains unclear. Mitochondria are important organelles to maintain the normal physiological functions of cardiomyocytes. It has been reported by our lab and others that abnormal quality of mitochondria caused by the inhibited mitophagy during sepsis is the key mechanism leading to myocardial injury, however, the specific molecular mechanism is still unclear. Our further study found that autophagy receptor protein TAX1BP1 was involved in sepsis-induced myocardial injury by regulating mitophagy, in addition, our preliminary data indicated that TAX1BP1 may regulate RNF115/STX17 pathway through recruiting RNF115 to influence mitophagosome-lysosome fusion, participating in mitophagy of cardiomyocytes. Based on our previous research, this project is designed to further clarify the role and molecular mechanism of TAX1BP1 mediated mitophagy to participate in sepsis-induced myocardial injury through RNF115/STX17 pathway from the molecular, cellular and animal levels by constructing a model of sepsis-induced myocardial injury and using target gene overexpression or interference techniques. On the one hand, this project will further illuminate the molecular mechanism of sepsis-induced myocardial injury, and on the other hand, it will provide novel ideas and theoretical support for the clinical management of sepsis-induced myocardial injury.