Mechanism and role of selective autophagy in ethanol-induced liver injury

描述（由申请人提供）：酒精性肝病（ALD）的特征是脂肪变性、炎症和纤维化，可导致终末期肝硬化和多种并发症。乙醇具有非常广泛的生物学效应，影响多种细胞过程。虽然关于乙醇诱导的肝损伤的发病机制的理解已经取得了显着的进展，但关于细胞防御乙醇的有害影响还有待了解。我们最近发现，大自噬是由急性乙醇处理诱导的，并对乙醇诱导的细胞凋亡和肝损伤具有显着的保护作用。宏自噬是一种进化上保守的细胞内降解机制，参与多种生物活动和许多疾病的发病机制。因此，重要的是要了解巨自噬如何以及为什么可以抵消乙醇在肝脏中的毒性，这可能会导致对ALD发病机制的进一步了解，更重要的是，治疗这种疾病的新方法。我们已经发现乙醇诱导的自噬的特征在于其对受损线粒体和脂滴的选择性，而不是一般蛋白质。因此，我们假设，这一特点必须与自噬如何影响乙醇诱导的毒性。本项目的目的一是研究乙醇条件下自噬体识别受损线粒体和脂滴的机制，以及乙醇处理过程中自噬的动力学，以确定自噬功能是否以及如何在此过程中发生变化，从而为制定可能的治疗策略提供重要信息。本项目的目的2将检验这样的假设，即自噬通过去除受损的线粒体和减少总细胞脂质含量，最终减少ROS产生，脂质过氧化， 和急诊室压力我们预计，这项研究将导致重要的和系统的发现，如何自噬可能在乙醇诱导的发病机制。自噬是否以及如何影响ALD的进展是一个新的、关键的问题，但研究不够，尽管 广泛认识到疾病（ALD）和机制（肝脏自噬）的重要性。因此，该项目可以为开发治疗ALD的新方法提供重要信息。

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is characterized by steatosis, inflammation and fibrosis, which can lead to end stage cirrhosis and multiple complications. Ethanol has very broad biological effects affecting multiple cellular processes. While significant progresses have been made regarding the understanding of the pathogenesis of ethanol induced liver injury, much has yet to be learnt about the cellular defense against the detrimental effects of ethanol. We recently find that macroautophagy is induced by acute ethanol treatment and has significant protective effects against ethanol-induced apoptosis and liver injury. Macroautophagy is an evolutionarily conserved intracellular degradation mechanism involved in diverse biological activities and in the pathogenesis of many diseases. It would thus be important to understand how and why macroautophagy can counteract the toxicity of ethanol in the liver, which could lead to a further understanding of the pathogenesis of ALD, and, more importantly, novel approaches to treat the disease. We have found that ethanol-induced autophagy is characterized by its selectivity toward damaged mitochondria and lipid droplets, but not general proteins. We thus hypothesize that this feature must be related to how autophagy affects ethanol-induced toxicity. Aim 1 of this project will investigate the mechanisms involved in the recognition of the damaged mitochondria and lipid droplets by the autophagosome in the ethanol conditions, and the dynamics of autophagy during a prolonged ethanol treatment to determine whether and how the function of autophagy may change during this course, thus providing important information for forge a possible therapeutic strategy to enhancing autophagy function. Aim 2 of this project will examine the hypothesis that autophagy reduces ethanol-induced cell death and liver injury by removing damaged mitochondria and reducing total cellular lipid content, culminating in decreased ROS generation, lipid peroxidation, and ER stress. We anticipate that this study will result in important and systemic findings of how autophagy may function in ethanol-induced pathogenesis. The subject of whether and how autophagy may affect the progression of ALD is novel, critical, but insufficiently studied, despite the wide recognition of the importance of both the disease (ALD) and the mechanism (autophagy in the liver). This project could thus yield important information for the development of a novel approach toward the treatment of ALD.