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：
8161101
负责人：
Wen-Xing Ding
金额：
$ 33.75万
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/8161101
关键词：
Acetylation Acute Adenoviruses Affect Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcohols Animal Model Autophagocytosis 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 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. PUBLIC HEALTH RELEVANCE: Alcohol abuse and consumption are major causes of liver disease and is a major health problem in the United States and around the world. Autophagy has been shown to be able to regulate mitochondria homeostasis and cell death, which are important in alcoholic liver disease. Elucidating the molecular mechanisms of how autophagy, mitochondria homeostasis and cell death are integrated in alcoholic liver disease will help to generate novel therapeutic strategies.

描述（由申请人提供）：自噬是一种基因编程的、进化上保守的过程，可降解长寿的细胞蛋白质和受损的细胞器（包括线粒体），作为应对压力的关键细胞生存机制。我们最近报道乙醇会诱导自噬，从而减少乙醇引起的肝损伤（Ding et al., 2010a）。这是一个重要的发现，因为酗酒是导致肝脏疾病的主要原因，也是美国的一个主要健康问题。氧化应激和线粒体损伤在酒精引起的肝毒性中发挥重要作用。细胞可以通过自噬等机制去除受损的线粒体来保护自身。因此，调节自噬过程可以为酒精性肝病提供新的治疗方法。然而，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制尚不清楚。如果没有这样的了解，最终使用自噬治疗酒精相关肝病的潜力将受到限制。我们的初步研究表明叉头转录因子 FoxO3a 在乙醇诱导的自噬中发挥重要作用。因此，中心假设是乙醇通过激活 FoxO3a 诱导自噬，而自噬清除乙醇诱导的受损线粒体对于防止乙醇诱导的肝脏发病机制至关重要。为了检验我们的假设，提出了三个具体目标：1）确定乙醇激活肝细胞中 FoxO3a 的机制，2）确定乙醇激活的 FoxO3a 如何诱导肝细胞中的自噬，以及 3）确定去除受损线粒体的保护机制对抗乙醇引起的肝毒性。本申请中提出的研究具有创新性，其概念是乙醇可以激活自噬作为一种保护机制，对抗其已知的对肝脏的有害影响。此外，我们将利用GFP-LC3转基因小鼠和Atg5肝脏特异性敲除小鼠等新型遗传动物模型来专门研究自噬在酒精性肝损伤中的作用。此外，其重点关注FoxO3a介导的自噬途径在酒精性肝病中的作用，但尚未有研究。这项研究意义重大，因为这项研究的结果将有助于了解自噬在酒精诱导的肝脏发病机制中的机制和作用。最终，这些知识有可能为通过调节自噬来治疗酒精肝发病机制提供新的治疗方法。公共卫生相关性：酗酒和饮酒是导致肝病的主要原因，也是美国和世界各地的一个主要健康问题。自噬已被证明能够调节线粒体稳态和细胞死亡，这在酒精性肝病中很重要。阐明自噬、线粒体稳态和细胞死亡在酒精性肝病中如何整合的分子机制将有助于产生新的治疗策略。