The pathogenesis of insulin resistance in alcoholic liver disease

酒精性肝病胰岛素抵抗的发病机制

• 批准号: 8681286
• 负责人: ROTONYA M CARR
• 金额: $ 17.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681286
• 关键词: 5' -AMP-activated protein kinase; Adipose tissue; Advisory Committees; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Antisense Oligonucleotides; Binding; Biogenesis; Cells; Ceramidase; Ceramides; Cessation of life; Clinical; Development; Diabetes Mellitus; Diet; Disease; Disease Progression; Doctor of Medicine; Doctor of Philosophy; Endocrinology; Enzymes; Ethanol; Ethanol Metabolism; Expenditure; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Funding; Genetic; Healthcare; Hepatic; Hepatocyte; Hepatology; Impairment; Incubated; Innovative Therapy; Institutes; Insulin; Insulin Resistance; Investigation; Knock-out; Knockout Mice; Laboratories; Laboratory Research; Lead; Lipids; Liquid substance; Liver; Liver Failure; Liver diseases; Malignant neoplasm of liver; Mass Spectrum Analysis; Measures; Mediating; Medicine; Mentors; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular Target; Mus; Obesity; Pathogenesis; Pathology; Pathway interactions; Patients; Pennsylvania; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physicians; Physiology; Positioning Attribute; Prevention; Process; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; Public Health; Recombinants; Regulation; Research; Research Personnel; Resistance; Role; STK11 gene; Saline; Scientist; Signal Transduction; Signaling Protein; Small Interfering RNA; Specificity; Sphingolipids; Sphingomyelins; Steatohepatitis; Structure; Tracer; Training Programs; United States; United States National Institutes of Health; Universities; adiponectin; career development; ceramide-activated protein phosphatase; chronic alcohol ingestion; cost; experience; feeding; impaired glucose tolerance; improved; in vitro Model; in vivo; inhibitor/antagonist; insight; insulin sensitivity; insulin signaling; lipid biosynthesis; lipid metabolism; mRNA Expression; non-alcoholic fatty liver; novel; novel therapeutics; outcome forecast; perilipin; prevent; problem drinker; professor; programs; protein expression; public health relevance; receptor; research study; synthetic enzyme; translational approach

DESCRIPTION (provided by applicant): This application outlines a comprehensive five-year mentored training program with a transition to independence. The application investigates the role of ceramides in insulin resistance in early alcoholic liver disease (ALD) and will be carried out in the laboratory of Dr. Rexford Ahima, M.D., Ph.D., Professor of Medicine, Division of Endocrinology, Diabetes, & Metabolism; Director of Obesity Unit, Institute for Diabetes, Obesity and Metabolism (IDOM); and Director of Diabetes and Endocrinology Research Center Mouse Phenotyping, Physiology and Metabolism Core. The research plan explores the novel hypothesis that Perilipin 2 (Plin2)- mediated lipid droplet biogenesis and adiponectin signaling are critically involved mechanistically in ceramide metabolism and insulin sensitivity in alcoholic steatosis. This hypothesis will be pursued by the following interrelated Specific Aims: (1) To determine if inhibition of ceramide synthesis or Plin2 expression ameliorates insulin resistance in alcoholic steatosis in vivo. (2) To determine whether ceramide's impairment of insulin signaling is mechanistically mediated by Plin2 in ethanol-treated hepatocytes. and (3) To determine if AMPK and ceramidase activation are required for adiponectin's regulation of ceramides and Plin2 in alcoholic steatosis. To accomplish these Specific Aims, we will use a combination of comprehensive in vivo metabolic phenotyping, lipidomics analyses, and in vitro modeling approaches, including the use of genetic knockout models. Successful accomplishment of these Specific Aims will identify specific molecular targets of insulin signaling in alcoholic steatosis which may lead to the development of new therapeutics for ALD. Concurrently, I will complete a career development program under the guidance of an advisory committee with internationally recognized NIH-funded researchers from the University of Pennsylvania and Thomas Jefferson University. This structured program combined with clinical experience in hepatology that focuses on the management of fatty liver diseases will make me uniquely positioned to become a leading physician-scientist capable of NIH-funded independent investigation at a leading academic center. I plan to oversee my own laboratory and research program focused on developing a lipid signature that can be used to predict disease prognosis in patients with both ALD and non-alcoholic fatty liver and identify insulin signaling targets that can ultimately be used therapeutically.

描述（由申请人提供）：这份申请概述了一个全面的五年指导培训计划，并过渡到独立。该应用程序研究神经酰胺在早期酒精性肝病（ALD）胰岛素抵抗中的作用，将在Rexford Ahima博士的实验室进行，他是内分泌、糖尿病和代谢学部的医学教授；糖尿病、肥胖和代谢研究所（IDOM）肥胖组主任；糖尿病和内分泌学研究中心小鼠表型、生理和代谢核心主任。该研究计划探索了一个新的假设，即Perilipin 2 （Plin2）介导的脂滴生物形成和脂联素信号传导在酒精神经酰胺代谢和胰岛素敏感性中起着关键的机制作用