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）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。自噬是一种进化上保守的细胞内降解机制，参与多种生物学活动和多种疾病的发病机制。ALD是长期饮酒的结果。目前还不清楚乙醇在长期暴露期间如何影响自噬功能，从而影响疾病。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以及这个过程的动力学，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。为此，我们制定了以下目标。目的1将研究乙醇处理过程中自噬的动态变化及其信号环境，以确定乙醇处理过程中自噬的功能状态，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的观察。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。结合目标2的研究，目标3将通过探索体内和体外系统中保守分子通路的参与来剖析肝细胞中选择性自噬的机制。本研究将为将来在特定部位进行干预以控制乙醇诱导的肝脏病理提供基础。总体而言，ALD中自噬的探索代表了该领域的新方向，并将产生关于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.