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; 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 越来越多的发病率和死亡率的原因。尽管它对全球健康的影响越来越大 目前尚无FDA批准的治疗疗法。虽然NAFLD的病理生理学很复杂，但 越来越多的证据支持肝NADH/NAD+水平改变的直接作用。但是，测试 NADH/NAD+在肝生理学中的作用受到了挑战，这是现有工具的局限性 以精确的方式操纵它，并且缺乏NADH/NAD+的循环生物标志物，这是不稳定的 在大多数临床和人类研究环境中，测量细胞内代谢物是不切实际的。 Mootha Lab开发了一种普遍编码的代谢工具，称为LBNOX，直接，精确地 在不同组织和细胞室中操纵细胞NADH/NAD+。在初步工作中，我有 在体外和体内都使用此工具来确定循环代谢物α-羟基丁酸（αHb）为 对肝NADH/NAD+的改变敏感。 αHb以前已被证明是胰岛素的生物标志物 基因GCKR中多态性的抗性和敏感性，而基因GCKR又与NAFLD有关。 我们的初步工作还显示LBNOX在体内改善了肝胰岛素抵抗，而GCKR会影响 肝细胞NADH/NAD+。这些发现将GCKR，NAFLD，αHb和肝NADH/NAD+链接。中央 该提议的假设是αHb是肝NADH/NAD+的循环生物标志物 与肝胰岛素抵抗和脂肪变性的因果关系，以及肝的遗传调节剂 NADH/NAD+影响肝脂肪变性和胰岛素抵抗 在此提案中，我将使用体外和体内肝LBNOX表达的组合来进一步定义 肝胰岛素抵抗，肝脂肪变性和肝NADH/NAD+之间的因果关系。我会定义 LBNOX改善肝胰岛素抵抗的机制以及GCKR的机制 影响肝炎NADH/NAD+。 我是一名临床和研究肝病学家，致力于研究职业，从事专门研究的身体科学家 肝病的代谢方面。拟议的研究计划将使我能够发展新知识和 代谢，代谢组学和肝物理学方面的专业知识，并提供了动物模型的经验 慢性肝病。通过拟议的研究，我将受到正式研究咨询的指导 委员会完成了新陈代谢，NAFLD和肝生理学的杰出心理和专家 MGH，Broad Institute和会员机构完成了出色的研究环境的设置。 该研究提出的，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性。