The dynamics and mechanisms of autophagy in ethanol - induced liver pathogenesis

描述（由申请人提供）：酒精性肝病（ALD）以脂肪变性、炎症和纤维化为特征，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效应，影响多种细胞过程。虽然对乙醇诱导肝损伤的发病机制的理解已经取得了重大进展，但对细胞防御乙醇有害影响的了解还很多。我们最近发现急性乙醇处理可诱导巨噬，并对乙醇诱导的细胞凋亡和肝损伤具有显著的保护作用。巨噬是一种进化保守的细胞内降解机制，参与多种生物活性和许多疾病的发病机制。ALD是长期饮酒的结果。目前还不清楚乙醇是如何在长时间暴露中影响自噬功能的，而自噬功能反过来又会影响疾病。了解巨噬如何以及为什么可以抵消肝脏中乙醇的毒性以及这一过程的动力学是很重要的，这可能会导致进一步了解ALD的发病机制，更重要的是，找到治疗这种疾病的新方法。为此，我们制定了以下目标。目的1将研究长时间乙醇处理过程中自噬的动力学及其信号环境，以确定自噬在此过程中的功能状态，从而更深入地了解乙醇诱导的发病机制对细胞防御机制的影响。目的2将检验自噬改善氧化应激、脂肪毒性和内质网应激以防止细胞死亡和肝损伤的假设。这是基于对乙醇诱导的自噬的观察，其特点是对受损的线粒体和脂滴具有选择性。我们的研究应该提供自噬如何影响酒精性肝损伤发展的基本知识。结合Aim 2的研究，Aim 3将通过探索体内和体外系统中保守分子途径的参与来剖析肝细胞选择性自噬的机制。本研究将为今后在特定部位进行干预以控制乙醇引起的肝脏病理提供基础。总的来说，对ALD中自噬的探索代表了该领域的一个新方向，并将产生有关其发病机制和治疗的新信息。

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. ALD is the result of long-term alcohol consumption. It is also not clear how ethanol may affect the function of autophagy during the long exposure, which in turn can affect the disease. It would be important to understand how and why macroautophagy can counteract the toxicity of ethanol in the liver and the dynamics of this process, which could lead to a further understanding of the pathogenesis of ALD, and, more importantly, novel approaches to treat the disease. Toward that end, we have developed the following aims. Aim 1 will investigate the dynamics of autophagy and its signaling environment during a prolonged ethanol treatment to determine the function status of autophagy during this course, thus providing a deeper understanding of the ethanol-induced pathogenesis regarding the impact on a cellular defensive mechanism. Aim 2 will examine the hypothesis that autophagy ameliorates oxidative stress, lipotoxicity and ER stress to protect against cell death and liver injury. This is based on the observation that ethanol-induced autophagy is characterized by its selectivity toward damaged mitochondria and lipid droplets. Our studies should provide the essential knowledge of how autophagy can impact the development of alcoholic liver injury. In couple with the studies of Aim 2, Aim 3 will dissect the mechanisms of selective autophagy in hepatocytes by exploring the participation of a conserved molecular pathway in both in vivo and in vitro systems. This study in this aim will provide the basis for future intervention at a specific site to control ethanol-induced liver pathology. Overall, the exploration of autophagy in ALD represents a novel direction in the field and will generate novel information regarding the pathogenesis and therapy.