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 酒精相关性肝病 (ALD) 是一个主要的健康问题，可导致肝功能衰竭、肝癌和 死亡，每年在美国产生巨额医疗支出。很少有具体的治疗方法 酒精性肝病（ALD）患者。许多患者很难实现戒断，并且无法阻止后期病情进展 ALD 的阶段。破译 ALD 的分子机制并鉴定新的标记物可以带来新的发现 治疗途径，对公众健康和福利具有重大意义。线粒体，中心位置 对于酒精代谢酶来说，是响应酒精毒性的活性介质。线粒体改变 酒精诱导是 ALD 的一个标志，它对细胞代谢产生深远影响，并与 炎症的激活是 ALD 发病机制的基础。丙酮酸脱氢酶激酶 4 (PDK4) 使线粒体基质中的丙酮酸脱氢酶复合物 (PDC) 失活，从而抑制转化 丙酮酸转化为乙酰辅酶A。 PDK4 维持线粒体稳态并与 非酒精性脂肪肝和凋亡性肝损伤的发展。但对于这个角色却知之甚少 ALD 中的 PDK4。该提案旨在揭示 PDK4 如何通过激活来协调线粒体功能障碍 面对乙醇引起的肝损伤时出现炎症。我们的中心假设是 PDK4 功能丧失 损害酒精代谢/解毒并增强促炎反应以促进发育 酒精性肝病。我们的目标是：（1）明确PDK4在乙醇喂养小鼠模型肝损伤中的作用； (2) 解开 PDK4在乙醇诱导的肝损伤中的分子机制。我们提出的研究将从概念上和 从机制上揭示线粒体乙醇代谢与炎症小体激活之间的联系， 这有助于为 ALD 的治疗开辟新的治疗途径。此 K01 应用程序将允许 申请人通过整合跨学科资源获得ALD的先进知识和研究技能。 申请人组建了一个由杰出成员组成的咨询委员会，其中包括博士。劳拉 Nagy（导师）、Srinivasan Dasarathy、李晓霞，均为著名肝病专家或公认的肝病专家 酒精代谢、炎症、线粒体生物学、基因表达和调控领域的科学家， 免疫学等，在培训年轻科学家独立并成功地从事相关领域方面有着令人印象深刻的记录 学术界。他们将指导申请人的学术职业发展并为申请人提供全力支持 实施拟议的实验。