乙醛脱氢酶2通过调控线粒自噬治疗脓毒症心肌损伤的作用机制研究

To elucidate the role and the underlying mechanisms of aldehyde dehydrogenase 2 （ALDH2） in the pathogenesis and treatment of sepsis-induced myocardial injury, the present study was designed to examine the effects of ALDH2 activation, ALDH2 overexpression, ALDH2 inhibition and ALDH2 knockdown on sepsis-induced myocardial injury in C57BL/6 mice which be intraperitoneally injected with lipopolysaccharide ( LPS ). Thereafter, the effects of ALDH2 activation, ALDH2 overexpression, ALDH2 inhibition and ALDH2 knockdown on cell mitophagy, apoptosis, oxidative stress, inflammatory response and mitophagy-depended signaling pathways in LPS-induced C57BL/6 mice myocardial cells, in an attempt to clarify the role of ALDH2 in regulating myocardial cells and its molecular mechanisms. This project will result in a better understanding of the mechanisms of mitophagy underlying the pathogenesis of sepsis-induced myocardial injury, which may provide novel therapeutic targets for the prevention and treatment of this disease.

为了阐明乙醛脱氢酶2（aldehyde dehydrogenase 2，ALDH2）在脓毒症心肌损伤发病和干预中的作用及其分子机制，本课题首先在脓毒症心肌损伤C57BL/6小鼠中观察脓毒症对心肌细胞ALDH2活性及表达的影响，观察ALDH2激活、ALDH2过表达、ALDH2抑制以及ALDH2沉默对小鼠脓毒症心肌损伤的作用。然后，在脂多糖培养的小鼠心肌细胞中观察ALDH2激活、ALDH2过表达、ALDH2抑制以及ALDH2沉默对细胞线粒体自噬、凋亡、氧化应激和炎症反应影响以及对下游线粒体自噬信号通路的调控，明确ALDH2对心肌细胞的作用及其分子机制。本课题的实施将为脓毒症心肌损伤的防治提供新的靶点。

主要研究内容：本课题采用体内实验的方法研究乙醛脱氢酶2( aldehyde dehydrogenase 2,ALDH2)在脓毒症心肌损伤中的作用及其机制.在脂多糖（lipopolysaccharide，LPS）诱导的脓毒症心肌损伤小鼠中，采用药物或基因干预的手段增加ALDH2的活性或增加（减少）ALDH2的表达量，观察对脓毒症小鼠心脏功能、心肌细胞凋亡、线粒体结构、线粒体自噬、氧化应激、炎症反应以及下游线粒体自噬信号通路的影响，从正反两个方面明确ALDH2在脓毒症心肌损伤发生和发展中所起的作用，探讨ALDH2调控线粒体自噬对脓毒症心肌损伤的作用及其分子机制。.重要结果：ALDH2能够通过抑制PINK1/Parkin介导的线粒体自噬改善脓毒症心肌损伤。.科学意义：本课题研究成果揭示了ALDH2在脓毒症心肌损伤中的作用及对线粒体自噬的调控机制，为脓毒症心肌损伤的防治提供新的理论依据，具有重要的现实意义和临床实用价值。