A METABOLIC BIOMARKER OF HEPATIC NADH/NAD+ RATIO

肝脏 NADH/NAD 比率的代谢生物标志物

• 批准号: 10221676
• 负责人: Russell Paul Goodman
• 金额: $ 17.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221676
• 关键词: Advisory Committees; Animal Model; Animals; Biochemistry; Biological Markers; Clinical; Clinical Research; Complex; Coupled; Development; Diglycerides; Disease; Ensure; Environment; FDA approved; Fatty Liver; Foundations; Functional disorder; Genes; Genetic; Genetic Epistasis; Genetic Polymorphism; Genetic Variation; Hepatic; Hepatocyte; Human; Hydroxybutyrates; In Vitro; Institutes; Institution; Insulin Resistance; Joints; Knowledge; Lead; Link; Lipids; Liver; Liver diseases; Measures; Mentors; Metabolic; Metabolism; Molecular Biology; Morbidity - disease rate; NADH; Oxidation-Reduction; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Physicians; Physiology; Play; Reaction; Reporter; Research; Research Personnel; Resources; Risk; Role; Scientist; Signal Transduction; Testing; Tissues; Work; career; career development; chronic liver disease; circulating biomarkers; early detection biomarkers; experience; experimental study; genetic risk factor; global health; improved; in vivo; innovation; lipid biosynthesis; liver metabolism; liver transplantation; metabolomics; mortality; mouse model; non-alcoholic fatty liver disease; novel; novel strategies; oxidation; prevent; resistance mechanism; success; tool

PROJECT ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and is an increasing cause of significant morbidity and mortality. Despite its growing impact on global health there are currently no FDA-approved therapies for treatment. While the pathophysiology of NAFLD is complex, increasing evidence supports a direct role of alterations in hepatic NADH/NAD+ levels. However, testing the role of NADH/NAD+ in hepatic physiology is challenging given the limitations of existing tools with which to manipulate it in a precise manner, and the lack of circulating biomarkers for NADH/NAD+ which, as unstable intracellular metabolites, would be impractical to measure in most clinical and human research settings. The Mootha lab has developed a genetically encoded metabolic tool, called LbNOX, to directly and precisely manipulate cellular NADH/NAD+ in different tissues and cellular compartments. In preliminary work, I have used this tool both in vitro and in vivo to identify that a circulating metabolite, α-hydroxybutyrate (αHB) is sensitive to alterations in hepatic NADH/NAD+. αHB, has previously been shown to be a biomarker of insulin resistance and sensitive to polymorphisms in the gene GCKR, which in turn has been associated with NAFLD. Our preliminary work also shows LbNOX improves hepatic insulin resistance in vivo, and that GCKR influences hepatocyte NADH/NAD+. These findings link GCKR, NAFLD, αHB, and hepatic NADH/NAD+. The central hypothesis of this proposal is that αHB is a circulating biomarker of hepatic NADH/NAD+ which is causally linked to hepatic insulin resistance and steatosis, and that genetic modulators of hepatic NADH/NAD+ influence hepatic steatosis and insulin resistance In this proposal, I will use a combination of in vitro and in vivo hepatic LbNOX expression to further define the causal connection between hepatic insulin resistance, hepatic steatosis, and hepatic NADH/NAD+. I will define the mechanism by which LbNOX improves hepatic insulin resistance, and the mechanism by which GCKR influences hepatic NADH/NAD+. I am a clinical and research hepatologist dedicated to a research career as a physician scientist specializing in metabolic aspects of liver disease. The proposed research plan will allow me to develop new knowledge and expertise in metabolism, metabolomics, and hepatic physiology, and provide experience with animal models of chronic liver disease. Throughout the proposed research I will be guided by a formal research advisory committee comprised of outstanding mentors and experts in metabolism, NAFLD, and hepatic physiology, all in the setting of a stellar research environment comprised of MGH, the Broad Institute, and affiliated institutions. The research proposed, along with the guidance of my mentors and collaborators in this research, will help ensure my successful transition to scientific independence.

项目摘要 非酒精性脂肪肝病（NAFLD）是世界上最常见的慢性肝病，是一种 显着发病率和死亡率的增加原因。尽管它对全球健康的影响越来越大，但 目前尚无 FDA 批准的治疗方法。虽然 NAFLD 的病理生理学很复杂， 越来越多的证据支持肝脏 NADH/NAD+ 水平变化的直接作用。然而，测试 鉴于现有工具的局限性，NADH/NAD+ 在肝脏生理学中的作用具有挑战性。 以精确的方式操纵它，并且缺乏 NADH/NAD+ 的循环生物标志物，这些生物标志物不稳定 细胞内代谢物，在大多数临床和人类研究环境中测量是不切实际的。 Mootha 实验室开发了一种基因编码代谢工具，称为 LbNOX，可以直接、精确地 操纵不同组织和细胞区室中的细胞 NADH/NAD+。在前期工作中，我有 使用该工具在体外和体内鉴定循环代谢物 α-羟基丁酸 (αHB) 对肝脏 NADH/NAD+ 的变化敏感。 αHB，先前已被证明是胰岛素的生物标志物 对 GCKR 基因的多态性具有耐药性和敏感性，而 GCKR 基因又与 NAFLD 相关。 我们的初步工作还表明 LbNOX 改善体内肝脏胰岛素抵抗，并且 GCKR 影响 肝细胞 NADH/NAD+。这些发现将 GCKR、NAFLD、αHB 和肝脏 NADH/NAD+ 联系起来。中央 该提议的假设是 αHB 是肝脏 NADH/NAD+ 的循环生物标志物， 与肝脏胰岛素抵抗和脂肪变性有因果关系，并且肝脏的遗传调节剂 NADH/NAD+影响肝脂肪变性和胰岛素抵抗 在本提案中，我将结合体外和体内肝脏 LbNOX 表达来进一步定义 肝脏胰岛素抵抗、肝脏脂肪变性和肝脏 NADH/NAD+ 之间的因果关系。我将定义 LbNOX 改善肝脏胰岛素抵抗的机制以及 GCKR 的机制 影响肝脏 NADH/NAD+。 我是一名临床和研究肝病学家，致力于作为一名医学科学家的研究生涯，专门从事 肝脏疾病的代谢方面。拟议的研究计划将使我能够发展新知识并 代谢、代谢组学和肝脏生理学方面的专业知识，并提供动物模型的经验 慢性肝病。在整个拟议的研究过程中，我将受到正式研究咨询的指导 委员会由代谢、NAFLD、肝脏生理学领域的杰出导师和专家组成 由麻省总医院、博德研究所和附属机构组成的一流研究环境。 拟议的研究以及我的导师和合作者在这项研究中的指导将有助于 确保我成功过渡到科学独立。