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

乙醇诱导的肝脏发病过程中自噬的动态和机制

• 批准号: 9112813
• 负责人: HIDEKAZU TSUKAMOTO
• 金额: $ 41.87万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112813
• 关键词: Acute; Address; Affect; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Apoptosis; Autophagocytosis; Autophagosome; Biological; Cell Death; Cell physiology; Cessation of life; Chronic; Cirrhosis; Defense Mechanisms; Development; Disease; Disease Progression; Environment; Ethanol; Ethanol toxicity; Fibrosis; Future; Goals; Health; Hepatocyte; Hepatotoxicity; Human; In Vitro; Inclusion Bodies; Inflammation; Intervention; Knowledge; Lead; Learning; Lipids; Liver; Liver diseases; Lysosomes; Mediating; Membrane; Metabolism; Mitochondria; Modeling; Molecular; Oral; Organelles; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Process; Regulation; Research Subjects; Role; Signal Transduction; Site; Staging; Stress; System; Therapeutic; Translating; alcohol effect; alcohol exposure; base; drinking; effective therapy; functional status; in vivo; liver injury; novel; novel strategies; novel therapeutic intervention; parkin gene/protein; problem drinker; protective effect

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.

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，这可能导致末期肝硬化和多种并发症。乙醇具有影响多种细胞过程的非常广泛的生物学作用。尽管在理解乙醇诱导的肝损伤的发病机理方面取得了重大进展，但有关乙醇有害作用的细胞防御尚未了解。我们最近发现，大藻酚是通过急性乙醇处理诱导的，并且对乙醇诱导的凋亡和肝损伤具有显着的保护作用。大量噬菌体是一种进化保守的细胞内降解机制，涉及多种生物学活性和许多疾病的发病机理。 ALD是长期饮酒的结果。尚不清楚乙醇在长期暴露期间如何影响自噬的功能，这反过来会影响疾病。重要的是要了解大型噬菌学如何以及为什么可以抵消乙醇在肝脏中的毒性以及该过程的动态，这可能会进一步了解ALD的发病机理，更重要的是，更重要的是治疗疾病的新方法。为此，我们开发了以下目标。 AIM 1将在长时间的乙醇处理过程中研究自噬及其信号传导环境的动力学，以确定本课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理，这些发病机理对对细胞防御机制的影响。 AIM 2将研究以下假设：自噬可以改善氧化应激，脂肪毒性和ER应激，以防止细胞死亡和肝损伤。这是基于这样的观察结果，即乙醇诱导的自噬的特征是其对线粒体和脂质液滴的选择性。我们的研究应提供有关自噬如何影响酒精肝损伤发展的基本知识。与AIM 2的研究隔间，AIM 3将通过探索保守分子途径在体内和体外系统中的参与来剖析肝细胞中选择性自噬的机制。这项目的的这项研究将为在特定部位的未来干预提供控制乙醇引起的肝脏病理学的基础。总体而言，ALD中自噬的探索代表了该领域的新方向，并将产生有关发病机理和治疗的新信息。