The pathogenesis of insulin resistance in alcoholic liver disease

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。该申请旨在研究神经酰胺在早期酒精性肝病(ALD)的胰岛素抵抗中的作用，并将在以下实验室进行：Rexford Ahima博士，医学博士，内分泌学、糖尿病和代谢学部医学教授，糖尿病、肥胖和代谢研究所(IDOM)肥胖部主任，以及糖尿病和内分泌研究中心主任，小鼠表型、生理学和代谢核心。这项研究计划探索了一种新的假设，即Perilipin 2(Plin2)介导的脂滴生物发生和脂联素信号在酗酒者神经酰胺代谢和胰岛素敏感性中起关键作用 脂肪变性。这一假说将被以下相互关联的特定目的所追求：(1)确定抑制神经酰胺合成或Plin2表达是否改善了体内酒精性脂肪变性的胰岛素抵抗。(2)探讨神经酰胺对乙醇诱导的肝细胞胰岛素信号转导通路的损伤是否由Plin2机制介导。以及(3)确定脂联素在酒精性脂肪变性中对神经酰胺和Plin2的调节是否需要AMPK和神经酰胺酶的激活。为了实现这些特定的目标，我们将结合使用全面的体内代谢表型分析、脂质组学分析和体外建模方法，包括使用基因敲除模型。这些特定目标的成功实现将识别胰岛素信号的特定分子靶点 在酒精性脂肪变性，这可能导致开发新的治疗ALD的方法。与此同时，我将在一个咨询委员会的指导下完成一个职业发展计划，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NIH资助的研究人员组成。这一结构化的课程与专注于脂肪肝疾病管理的肝病临床经验相结合，将使我处于独特的地位，能够成为一名领先的内科科学家，能够在领先的学术中心进行NIH资助的独立研究。我计划监督我自己的实验室和研究项目，重点是开发一种脂肪信号，可以用来预测ALD和非酒精性脂肪肝患者的疾病预后，并确定胰岛素信号靶点 最终可以用于治疗。

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.