Mechanisms regulating autophagy in alcohol-induced liver injury

酒精性肝损伤中自噬的调节机制

基本信息

批准号：
8508766
负责人：
Wen-Xing Ding
金额：
$ 31.39万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508766
关键词：
Acetylation Acute Adenoviruses Affect Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcohols Animal Model Autophagocytosis BCL2 gene Binding Biological Assay Catabolic Process Cell Death Cell Survival Cells Deacetylase Dominant-Negative Mutation Ethanol Ethanol toxicity Excision Genes Genetic Genetic Transcription Goals Health Hepatocyte Hepatotoxicity Homeostasis Injection of therapeutic agent Injury Knockout Mice Knowledge Laboratories Lead Life Liver Liver diseases Mediating Mitochondria Molecular Mus Muscular Atrophy Nuclear Organelles Outcome Oxidative Stress Pathogenesis Pathway interactions Play Process Protein Family Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Reactive Oxygen Species Regulation Reporting Research Role Small Interfering RNA Stress Subfamily lentivirinae Testing Transgenic Organisms United States Up-Regulation Work alcohol abuse therapy alcohol exposure chromatin immunoprecipitation forkhead protein in vivo inhibitor/antagonist innovation liver injury novel novel therapeutic intervention novel therapeutics problem drinker programs promoter response small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Autophagy is a genetically programmed, evolutionarily conserved process that degrades long-lived cellular proteins and damaged organelles, including mitochondria, as a critical cell survival mechanism in response to stress. We recently reported that ethanol induces autophagy, which reduces ethanol-induced liver injury (Ding et al., 2010a). This is an important finding because alcohol abuse is a major cause of liver disease and a major health problem in the United States. Oxidative stress and mitochondrial damage play important roles in alcohol-induced hepatotoxicity. Cells may protect themselves by removing damaged mitochondria by mechanisms such as autophagy. Therefore modulating the autophagy process could offer new therapeutic treatments for alcoholic liver diseases. However, the mechanisms by which ethanol induces autophagy and how autophagy protects against ethanol-induced liver pathogenesis are not clear. Without such understanding, the potential to ultimately use autophagy in the treatment of alcohol-related liver disease will be limited. Our preliminary studies suggest that the forkhead transcription factor FoxO3a could play a major role in ethanol- induced autophagy. Therefore, the central hypothesis is that ethanol induces autophagy by activating FoxO3a, and autophagic removal of ethanol-induced damaged mitochondria is crucial to protect against ethanol- induced liver pathogenesis. To examine our hypothesis, three specific aims are proposed: 1) determine the mechanisms by which ethanol activates FoxO3a in hepatocytes, 2) determine how ethanol-activated FoxO3a induces autophagy in hepatocytes, and 3) determine the mechanisms by which removal of damaged mitochondria protects against ethanol-induced hepatotoxicity. The research proposed in this application is innovative in the concept that ethanol can activate autophagy as a protective mechanism against its known detrimental effects on the liver. Moreover, we will utilize novel genetic animal models such as GFP-LC3 transgenic and Atg5 liver-specific knockout mice to specifically study the role of autophagy in alcohol-induced liver injury. Furthermore, it focuses on the role of FoxO3a-mediated autophagy pathway in alcoholic liver disease, which has not been studied. The proposed research is significant because the results from this study will lead to the understanding of mechanisms and roles of autophagy in alcohol-induced liver pathogenesis. Ultimately, such knowledge has the potential of offering novel therapeutic approaches for treating alcoholic liver pathogenesis by modulating autophagy.

描述（由申请人提供）：自噬是一种遗传编程的，进化保守的过程，可降低长期寿命的细胞蛋白和包括线粒体在内的细胞器，作为响应压力的关键细胞存活机制。我们最近报道，乙醇诱导自噬，从而减少乙醇诱导的肝损伤（Ding等，2010a）。这是一个重要的发现，因为酗酒是美国肝病和主要健康问题的主要原因。氧化应激和线粒体损伤在酒精引起的肝毒性中起重要作用。细胞可以通过通过自噬等机制去除损坏的线粒体来保护自己。因此，调节自噬过程可以为酒精性肝脏疾病提供新的治疗治疗方法。但是，乙醇诱导自噬的机制以及自噬如何预防乙醇诱导的肝脏发病机理的机制尚不清楚。如果没有这样的了解，最终将自噬用于治疗与酒精有关的肝病的潜力将受到限制。我们的初步研究表明，叉状转录因子FOXO3A可能在乙醇诱导的自噬中起主要作用。因此，中心假设是乙醇通过激活FOXO3A诱导自噬，并且自噬去除乙醇诱导的受损线粒体对于预防乙醇诱导的肝脏发病机理至关重要。为了审查我们的假设，提出了三个具体目的：1）确定乙醇激活肝细胞中FoxO3A的机制，2）2）确定乙醇激活的FOXO3A如何在肝细胞中诱导自噬，而3）确定损坏的线粒体保护的机制。在本应用中提出的研究具有创新性，即乙醇可以激活自噬作为保护其对肝脏的已知有害影响的保护机制。此外，我们将利用新型的遗传动物模型，例如GFP-LC3转基因和ATG5肝特异性敲除小鼠，以专门研究自噬在酒精诱导的肝损伤中的作用。此外，它重点介绍了FOXO3A介导的自噬途径在尚未研究的酒精性肝病中的作用。拟议的研究很重要，因为这项研究的结果将导致对自噬在酒精诱导的肝发病机理中的机制和作用的理解。最终，这种知识具有提供新颖的治疗方法来通过调节自噬来治疗酒精性肝脏发病机理。