基于PINK1/Parkin介导的线粒体自噬研究HO-1在电针刺对内毒素海马损伤中的作用

Endotoxin-induced hippocampal injury is often manifested as cognitive dysfunction. Electro-acupuncture can improve the function of hippocampal neurons, but its mechanism is unknown. It has been suggested that HO-1 participated in the protective effect of electro-acupuncture on hippocampal neurons, and moreover, HO-1 could regulate mitophagy in endotoxin-induced liver injury. Pink1/Parkin-mediated mitophagy is an important regulatory pathway in the process of quality control of damaged mitochondria. Our previous studies have confirmed that HO-1 participated in maintaining mitochondrial morphology and functional stability, which protects the endotoxin-induced lung injury. Electro-acupuncture could up-regulate the expression of HO-1 and regulate the mitochondrial dynamics to protect the damaged lungs of endotoxemia. However, it is not clear whether HO-1 participates in the protective effect of electro-acupuncture on mitophagy of neurons by endotoxin-induced hippocampus injury. We hypothesize that electro-acupuncture may regulate Pink1/Parkin-mediated mitophagy to protect function of hippocampal neurons by HO-1 during endotoxemia. We propose to explore the related mechanism of electro-acupuncture by regulating PINK1/Parkin-mediated mitophagy through HO-1 to protect hippocampal neurons during endotoxemia, by means of silencing gene expression, immunofluorescence technique, plasmid transfection etc., both in vivo and in vitro, which may provide new theoretical basis of electro-acupuncture for prevention of endotoxemia.

内毒素海马损伤常表现为认知功能障碍。电针刺可改善海马神经元功能，但机制不明。研究认为HO-1参与电针刺对海马神经元的保护作用。此外，HO-1可调节内毒素肝损伤线粒体自噬。PINK1/Parkin介导的线粒体自噬在损伤的线粒体质量控制过程中具有重要作用。前期研究证实：HO-1参与维持线粒体形态和功能稳定，保护内毒素血症肺损伤。并且电针刺能上调HO-1表达、可调控线粒体运动平衡保护内毒素血症受损脏器，但HO-1是否参与电针刺调控内毒素海马损伤神经元线粒体自噬发挥保护作用尚不清楚。为此我们假设：电针刺可通过HO-1作用于PINK1/Parkin介导的线粒体自噬以发挥内毒素海马损伤的保护作用。我们拟通过基因沉默、转染质粒、免疫荧光等方法，从在体和离体不同角度，验证HO-1参与电针刺调节PINK1/Parkin介导的线粒体自噬，对内毒素海马损伤发挥保护作用，为防治内毒素海马损伤提供新思路。

内毒素海马损伤常表现为认知功能障碍。电针刺可改善海马神经元功能，但机制不明。前期研究结果证实：电针刺能上调HO-1表达，调控线粒体运动平衡保护内毒素血症受损脏器。报道称PINK1/Parkin介导的线粒体自噬在损伤的线粒体质量控制过程中具有重要作用。因此，本课题假设：电针刺可通过HO-1作用于PINK1/Parkin介导的线粒体自噬以发挥内毒素海马损伤的保护作用。我们利用基因沉默、基因敲除技术，采用免疫荧光、形态、功能和分子生物学等方法，从动物和细胞水平层面观察神经元线粒体形态、功能、标志蛋白和线粒体自噬的变化，阐明HO-1参与电针刺调节PINK1/Parkin介导的线粒体自噬，对内毒素海马损伤发挥保护作用，为电针刺防治内毒素海马损伤的而应用提供新的分子靶点。