PINK1/Parkin介导线粒体自噬保护胃黏膜上皮细胞免于乙醇诱导氧化损伤的作用机制研究

Alcohol abuse is detrimental to gastric epithelium cells and consequently can induce gastritis and gastric ulcer. Researches have shown that it is caused by ethanol-induced oxidative stress. Autophagy is a regulation mechanism, and mitophagy, as a part of it, plays an important role in the anti-oxidative effect, although the regulation mechanism of ethanol-induced gastric epithelium injuries still remains unknown. Recently, we find that oxidative stress of gastric epithelium cells could be induced by ethanol and it could cause mitophagy with inhibition of autophagy aggravating oxidative damages. This involves the activation of PINK1/Parkin pathway. Combined with current research progress, we hypothesize that ethanol can cause oxidative stress, which results in mitochondria damage. By activating PINK1/Parkin pathway, it can cause mitophagy to mitigate the damage. This project aims at building a model of ethanol-induced gastric mucosa damages with methods such as RT-PCR, Western blot, transmission electron microscopy, confocal laser scanning microscope to detect the underlying mechanisms and the role of PINK1/Parkin pathway in oxidative stress induced mitophagy. By doing so, we could figure out mechanisms of protective role that mitophagy plays in gastric epithelium cells. It may contribute to a novel therapeutic option in the prevention and treatment of ethanol-induced gastritis and gastric ulcer.

过量饮酒损害胃黏膜上皮细胞并可引发胃炎及胃溃疡，研究显示这源于乙醇导致的氧化应激。自噬作为一种自我调控机制，其中线粒体自噬在抗氧化损伤中发挥重要作用，但其在酒精性胃黏膜损伤中的作用机制仍不清楚。本项目组近期发现乙醇可以引起胃黏膜上皮细胞氧化应激并诱导线粒体自噬，抑制线粒体自噬加重细胞氧化损伤，而这涉及PINK1/Parkin通路活化。结合当前研究进展我们提出假设：乙醇诱导胃黏膜上皮细胞氧化应激并导致线粒体损伤，通过激活PINK1/Parkin通路，引起线粒体自噬以减缓损伤。本项目拟建立酒精性胃黏膜损伤模型，利用RT-PCR、western blot、透射电镜、激光共聚焦等方法检测自噬在乙醇诱导胃黏膜上皮细胞损伤中的作用机制及PINK1/Parkin通路对氧化应激引起线粒体自噬的调控作用，以阐明线粒体自噬在胃黏膜上皮细胞中的保护性机制，将为酒精性胃炎及胃溃疡的预防和诊治提供新思路与新靶点。

背景：过量饮酒是造成胃黏膜上皮细胞损伤并导致胃炎及胃溃疡的重要原因，虽然对于饮酒危害的研究较多，但是探讨胃损伤的机制研究以及治疗策略依然匮乏。方法：我们通过建立乙醇诱导的胃黏膜损伤的细胞和动物模型，收集临床组织样本，利用相关实验技术检测细胞增殖、凋亡、氧化应激、自噬以及PINK1/Parkin通路等各项指标的调控与改变，来探讨乙醇的损伤机制。结果：乙醇能够诱导胃黏膜上皮细胞氧化应激，并导致细胞凋亡增加、增殖活性降低，而胃黏膜上皮细胞可以在乙醇干预下通过激活PINK1/Parkin通路来活化线粒体自噬，以清除细胞内氧化应激产物，从而减弱乙醇损伤的作用。结论：PINK1/Parkin通路可以介导自噬途径保护胃黏膜上皮细胞免于乙醇诱导的氧化损伤，调控细胞自噬有望成为酒精性胃炎乃至胃溃疡预防与治疗过程中的新策略。