基于PINK1/Parkin介导的线粒体自噬/焦亡途径探讨肿节风阻遏脓毒症心肌病的机制

线粒体自噬调控的细胞焦亡对心肌炎症微环境有至关重要的影响，与脓毒症心肌病（sepsis-induced cardiomyopathy，SIC）进程密切相关。前期研究发现，肿节风具有抑炎改善脓毒症小鼠心功能的作用；而PINK1/Parkin信号轴介导线粒体自噬的活化，抑制细胞焦亡，调控炎症微环境。我们推测：肿节风通过激活线粒体自噬，清除损伤线粒体，抑制心肌细胞焦亡，改善炎症微环境，阻遏SIC进展，且可能与PINK1/Parkin通路相关。为进一步验证假说，本项目拟：（1）建立SIC小鼠模型，借助二维超声斑点跟踪和RNAscope原位杂交等技术，评价肿节风对SIC小鼠心功能的改善及作用机制；（2）分离原代心肌细胞，建立LPS损伤模型，阐明肿节风调控线粒体自噬，保护损伤心肌细胞的分子机制。本研究的开展将有利于探讨肿节风改善心肌炎症微环境和修复损伤心肌的机制，并探索SIC的治疗新靶点。

Cell pyrotosis regulating by mitochondrial autophagy plays a keyword role in the imbalance of the cardiac inflammatory microenvironment, and becomes a dominant factor during the process of sepsis induced cardiomyopathy (SIC). Previous studies have shown that sarcandra glabra could inhibit inflammation and improve cardiac function in the mouse model of Sepsis and the PINK1/Parkin signal axis could mediate the activation of mitochondrial autophagy, inhibit pyrotosis and improve the inflammatory microenvironment. We speculated that Sarcandra glabra could attenuate the process of SIC by regulating mitochondrial autophagy, activating the clearance of the damaged mitochondria, inhibiting cell pyrotosis and improving the inflammatory microenvironment via the PINK1/Parkin pathway. The mouse model of SIC would be established and the cardiac function would be evaluated by two-dimensional speckle tracking imaging and RNAscope in situ hybridization in vivo. The primary cardiomyocytes would be isolated and stimulated by LPS-stress to elucidate the mechanism of mitochondrial autophagy regulation and improvement of SIC in vitro. This study will elucidate the mechanism of Sarcandra Glabra on regulating inflammatory microenvironment and injury carciac repaire, consequently providing a promising theraeputic target for the prevention and treatment of SIC.