The role of PDK4 in alcohol-associated liver disease

PDK4 在酒精相关性肝病中的作用

• 批准号: 10283591
• 负责人: JIANGUO WU
• 金额: $ 18.19万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10283591
• 关键词: Abstinence; Academia; Acetaldehyde; Acetyl Coenzyme A; Acute Alcoholic Hepatitis; Address; Advisory Committees; Affect; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Animal Model; Apoptosis; Apoptotic; Arsenic; Biochemistry; Bioenergetics; Biological Assay; Biology; Cell Death; Cell Survival; Cells; Cellular Metabolic Process; Cessation of life; Chronic; Cirrhosis; Citric Acid Cycle; Data; Development; Diagnostic; Diethylnitrosamine; Disease; Drug Metabolic Detoxication; Economic Burden; Enzymes; Ethanol; Ethanol Metabolism; Ethanol toxicity; Event; Excision; Fatty Liver; Fibrosis; Gene Expression Regulation; Genes; Glucose; Goals; Health; Health Expenditures; Healthcare; Heavy Drinking; Hepatic; Hepatitis C virus; Hepatocyte; Histologic; Homeostasis; Human; Immune; Immunology; Impairment; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 beta; Intervention; Isoenzymes; Knowledge; Lead; Light; Link; Liver; Liver Cirrhosis; Liver Failure; Liver Regeneration; Liver diseases; Location; Malignant Neoplasms; Malignant neoplasm of liver; Marker Discovery; Mediating; Mediator of activation protein; Mentors; Methods; Mission; Mitochondria; Mitochondrial DNA; Mitochondrial Matrix; Molecular; Morbidity - disease rate; Morphology; Mus; National Institute on Alcohol Abuse and Alcoholism; Natural regeneration; Nuclear; Oxidative Stress; PDH kinase; Pathogenesis; Pathologic; Pathology; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Phenotype; Positioning Attribute; Proteins; Proteomics; Public Health; Publishing; Pyruvate; Pyruvate Dehydrogenase Complex; Regulation; Research; Resources; Role; Science; Scientist; Steatohepatitis; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Training; United States; alcohol abstinence; alcohol exposure; alcohol research; alcohol response; attributable mortality; base; career development; effective therapy; experience; experimental study; fatty acid metabolism; feeding; improved; inhibitor/antagonist; insulin sensitivity; interest; knock-down; lipid metabolism; liver injury; liver transplantation; macrophage; member; metabolomics; mitochondrial dysfunction; monocyte; mortality; mouse model; non-alcoholic fatty liver disease; novel marker; novel therapeutics; overexpression; prevent; prognostic; pyruvate dehydrogenase kinase 4; skills; socioeconomics; therapeutic target; therapeutically effective; welfare

ABSTRACT Alcohol-associated liver disease (ALD) is a major health problem and can lead to liver failure, liver cancer, and death, incurring enormous healthcare expenditures annually in the US. Few specific treatments are available for patients with ALD. Abstinence is difficult to achieve in many patients and cannot prevent the progression at later stages of ALD. Deciphering molecular mechanisms and identifying novel markers of ALD can lead to new therapeutic avenues and is of substantial interest to public health and welfare. Mitochondria, the central location for alcohol-metabolizing enzymes, are active mediators in response to alcohol toxicity. Mitochondrial alterations induced by alcohol are a hallmark of ALD, which have profound impacts on cell metabolism and associate with activation of inflammation, underlying the pathogenesis of ALD. Pyruvate dehydrogenase kinase 4 (PDK4) inactivates pyruvate dehydrogenase complex (PDC) in the mitochondrial matrix, thus suppressing the conversion of pyruvate to acetyl-CoA. PDK4 maintains mitochondrial homeostasis and has been implicated in the development of non-alcoholic fatty liver disease and apoptotic liver injury. However, little is known about the role of PDK4 in ALD. This proposal is to reveal how PDK4 coordinates mitochondrial dysfunction with activation of inflammation in the face of ethanol-induced liver injury. Our central hypothesis is that loss of PDK4 function impairs alcohol metabolism/detoxification and enhances pro-inflammatory response to promote the development of ALD. We aim to: (1) define the role PDK4 in liver injury in mouse models of ethanol feeding; (2) unravel the molecular mechanisms of PDK4 in ethanol-induced liver injury. Our proposed studies will conceptually and mechanistically reveal the connection between mitochondrial ethanol metabolism and inflammasome activation, which helps to open novel therapeutic avenues for the treatment of ALD. This K01 application will allow the applicant to acquire advanced knowledge and research skills in ALD by integrating interdisciplinary resources. The applicant has assembled an advisory committee composed of outstanding members, including Drs. Laura Nagy (mentor), Srinivasan Dasarathy, and Xiaoxia Li, who are renowned hepatologists or well-recognized scientists in fields of alcohol metabolism, inflammation, mitochondrial biology, gene expression and regulation, immunology, etc., with a formidable record of training junior scientists to be independent and successful in academia. They will direct the applicant's academic career development and provide full support to the implementation of proposed experiments.

抽象的 酒精相关肝病（ALD）是一个主要的健康问题，可能导致肝衰竭，肝癌和 死亡，每年在美国产生巨大的医疗支出。很少有具体的治疗 ALD患者。在许多患者中，难以戒酒，无法阻止以后的进展 Ald的阶段。解密的分子机制和识别ALD的新颖标记可能会导致新的 治疗途径，对公共卫生和福利具有很大的兴趣。线粒体，中心位置 对于酒精代谢酶，是响应酒精毒性的活性介质。线粒体改变 酒精诱导的是ALD的标志，它对细胞代谢产生了深远的影响，并与 炎症的激活，是ALD的发病机理的基础。丙酮酸脱氢酶激酶4（PDK4） 在线粒体基质中灭活丙酮酸脱氢酶络合物（PDC），从而抑制转化率 丙酮酸到乙酰辅酶A。 PDK4保持线粒体稳态，并与 非酒精性脂肪肝病和凋亡肝损伤的发展。但是，对角色知之甚少 Ald中的PDK4。该建议是揭示PDK4如何与激活激活的线粒体功能障碍坐标 面对乙醇引起的肝损伤的炎症。我们的中心假设是PDK4功能的丧失 损害酒精代谢/排毒并增强促炎反应以促进发展 Ald。我们的目标是：（1）在乙醇喂养的小鼠模型中定义PDK4的作用； （2）解开 PDK4在乙醇诱导的肝损伤中的分子机制。我们提出的研究将在概念上， 机械机械地揭示线粒体乙醇代谢和炎性体激活之间的联系， 这有助于打开新的治疗途径，以治疗ALD。此K01应用程序将允许 申请人通过整合跨学科资源来获取ALD的高级知识和研究技能。 申请人组建了一个由杰出成员组成的咨询委员会，包括博士。劳拉 Nagy（导师），Srinivasan Dasarathy和Siaoxia Li，他们是著名的肝病学家或众所周知的 酒精代谢，炎症，线粒体生物学，基因表达和调节领域的科学家， 免疫学等，培训初级科学家独立和成功的培训记录 学术界。他们将指导申请人的学术职业发展，并为 实施拟议的实验。