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The pathogenesis of insulin resistance in alcoholic liver disease

酒精性肝病胰岛素抵抗的发病机制

基本信息

批准号：
9272766
负责人：
ROTONYA M CARR
金额：
$ 19.47万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272766
关键词：
5&apos -AMP-activated protein kinase AKT inhibition Adipose tissue Advisory Committees Alcohol consumption Alcoholic Liver Diseases Alcohols Alpha Cell Antisense Oligonucleotides Biogenesis Cells Ceramidase Ceramides Cessation of life Clinical Closure by clamp Development Diabetes Mellitus Diet Disease Disease Progression Disease Resistance Doctor of Medicine Doctor of Philosophy Endocrinology Enzymes Ethanol Ethanol Metabolism Expenditure Fatty Liver Fibrosis Funding Genetic Healthcare Hepatic Hepatocyte Hepatology High Fat Diet Impairment Incubated Injectable Innovative Therapy Institutes Insulin Insulin Resistance International 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 Pharmacology Phenotype Phosphorylation Physicians Physiology Positioning Attribute Prevention Process Program Development Protein Kinase Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Public Health Radioisotopes Recombinants Regulation Research Research Personnel Resistance Role STK11 gene Saline Scientist Signal Transduction Signaling Protein Small Interfering RNA Specificity Sphingolipids Sphingomyelins Steatohepatitis Structure Therapeutic Uses Tracer Training Programs United States United States National Institutes of Health Universities adipokines adiponectin career development chronic alcohol ingestion cost experience experimental study impaired glucose tolerance improved in vitro Model in vivo inhibitor/antagonist insight insulin sensitivity insulin sensitizing drugs insulin signaling intraperitoneal lipid biosynthesis lipid metabolism mRNA Expression metabolic phenotype non-alcoholic fatty liver novel novel therapeutics outcome forecast perilipin prevent problem drinker professor programs protein expression public health relevance receptor synthetic enzyme translational approach

项目摘要

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）：本申请概述了一个全面的五年指导培训计划，并过渡到独立。该应用研究了神经酰胺在早期酒精性肝病 (ALD) 胰岛素抵抗中的作用，并将在内分泌、糖尿病和代谢科医学教授 Rexford Ahima 博士的实验室进行；糖尿病、肥胖和代谢研究所 (IDOM) 肥胖科主任；糖尿病和内分泌研究中心小鼠表型、生理学和代谢核心主任。该研究计划探索了新的假设，即 Perilipin 2 (Plin2) 介导的脂滴生物合成和脂联素信号在酒精性酒精中毒的神经酰胺代谢和胰岛素敏感性中至关重要。脂肪变性。该假设将通过以下相互关联的具体目标来实现：(1)确定神经酰胺合成或Plin2表达的抑制是否改善体内酒精性脂肪变性的胰岛素抵抗。 (2) 确定乙醇处理的肝细胞中神经酰胺对胰岛素信号传导的损害是否是由 Plin2 机制介导的。 (3) 确定 AMPK 和神经酰胺酶激活是否是脂联素对酒精性脂肪变性中神经酰胺和 Plin2 的调节所必需的。为了实现这些具体目标，我们将结合使用全面的体内代谢表型、脂质组学分析和体外建模方法，包括使用基因敲除模型。成功实现这些特定目标将确定胰岛素信号传导的特定分子靶点酒精性脂肪变性可能会导致 ALD 新疗法的开发。同时，我将在咨询委员会的指导下完成职业发展计划，该委员会由来自宾夕法尼亚大学和托马斯杰斐逊大学的国际公认的美国国立卫生研究院资助的研究人员组成。这个结构化的计划与专注于脂肪肝疾病管理的肝病学临床经验相结合，将使我成为一名领先的医师科学家，能够在领先的学术中心进行 NIH 资助的独立研究。我计划监督自己的实验室和研究项目，重点是开发脂质特征，该特征可用于预测 ALD 和非酒精性脂肪肝患者的疾病预后，并确定胰岛素信号传导目标最终可以用于治疗。