Phenotyping Genetic Disorders of Hepatic Lipid and Lipoprotein Metabolism in Cells, Mice, and Men

细胞、小鼠和男性肝脏脂质和脂蛋白代谢的表型遗传疾病

• 批准号: 10307631
• 负责人: HENRY N GINSBERG
• 金额: $ 95.39万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307631
• 关键词: Academy; Affect; Apolipoproteins B; Area; Autophagocytosis; Award; Biocompatible Materials; Biology; Biomedical Engineering; Cardiometabolic Disease; Cells; Cholesterol Esters; Collaborations; Complication; Cultured Cells; Data; Dyslipidemias; Engineering; Functional disorder; Funding; Future; Genes; Genetic; Genetic Diseases; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; Homeostasis; Human; Hypertriglyceridemia; Individual; Insulin Resistance; Investigation; Kinetics; Laboratories; Lipids; Lipoproteins; Liver; Liver diseases; Low-Density Lipoproteins; Maintenance; Metabolism; Molecular; Mus; Mutation; National Heart, Lung, and Blood Institute; Non-Insulin-Dependent Diabetes Mellitus; Phenotype; Plasma; Positioning Attribute; Prevalence; Productivity; Regenerative Medicine; Regulation; Research Personnel; Role; Series; Signal Pathway; Single-Gene Defect; Tracer; Triglycerides; Very low density lipoprotein; Work; base; clinical investigation; endoplasmic reticulum stress; experimental study; hepatoma cell; hypolipidemia; in vivo; induced pluripotent stem cell; innovation; insight; member; men; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; pre-clinical; professor; programs

Summary: The prevalence of cardiometabolic disorders characterized by an atherogenic dyslipidemia (increased plasma triglyceride (TG) levels (hypertriglyceridemia), low levels of high density lipoprotein (HDL) cholesterol (C), and small cholesteryl ester depleted-TG enriched low density lipoproteins (LDL)), insulin resistance (IR) and type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) or its downstream complication, non- alcoholic steatohepatitis (NASH), have increased over the past 25 years. Dr. Ginsberg, has led an NHLBI- funded laboratory for more than 40 years, progressing from in vivo studies on the regulation of plasma lipoprotein levels in humans, including the role of IR, to studies of the assembly and secretion of very low density lipoproteins (VLDL) in cultured liver cells, to mouse models of NAFLD, including some with IR. Dr. Ginsberg and his collaborators are uniquely positioned to conduct fully integrated studies of the pathophysiology of dyslipidemia and NAFLD at the genetic, molecular, and whole body levels in cultured cells, mice, and humans. The proposed program is tripartite, with clear opportunities for merging of each major area of investigation. They include: Regulation of the assembly and secretion of VLDL assembly and secretion. During the past 25 years, the Ginsberg laboratory produced a body of work demonstrating the novel biology of apoB and provided insights needed to identify potential targets for modulating the secretion of atherogenic lipoproteins from the liver. Based on recent exciting data, we will focus experiments in hepatoma cells on ways to maximize the secretion of spare apoB and or the loading of TG onto apoB targeted to secretion. Mechanisms for the maintenance of hepatic lipid homeostasis. We plan a series of experiments to determine (a) the mechanism for lipid induced ER stress and (b) the signaling pathway between ER stress and ER autophagy. Detailed phenotyping of human mutations affecting plasma lipoprotein metabolism with or without effects on hepatic lipid homeostasis. The studies proposed in this section will combine an area in which Dr. Ginsberg has been a leader for several decades, tracer kinetic studies of lipoprotein metabolism, with an area completely new to the Ginsberg laboratory, iPSC-derived hepatocytes. This component of our future work will be carried out in collaboration with a recent arrival at Columbia, Dr. Kam Leong, Samuel Y Sheng Professor of Biomedical Engineering and a member of the National Academy of Engineering, a leader in the field of regenerative medicine and biomaterials. We will study individuals with single gene defects the are associated with NAFLD and hypolipidemia; hypolipidemia without NAFLD, dyslipidemia with NAFLD. No laboratory has, in the same individual, defined the pathophysiologic effects of mutations in genes affecting lipid and lipoprotein metabolism at both the level of the hepatocyte and the whole body.

摘要： 以致动脉粥样硬化性血脂异常(血浆升高)为特征的心脏代谢紊乱的患病率 甘油三酯(TG)水平(高甘油三酯血症)，低水平的高密度脂蛋白胆固醇(C)，以及 小胆固醇酯耗竭-富含甘油三酯的低密度脂蛋白(LDL)、胰岛素抵抗(IR)和2型 糖尿病(T2 DM)和非酒精性脂肪性肝病(NAFLD)或其下游并发症，非 酒精性脂肪性肝炎(NASH)，在过去的25年里有所增加。金斯伯格博士领导了一项NHLBI- 资助实验室40多年，从血浆调节的体内研究进展 在人类脂蛋白水平中，包括IR的作用，对组装和分泌的研究很低 培养的肝细胞中的密度脂蛋白(VLDL)，到NAFLD的小鼠模型，包括一些IR。Dr。 金斯伯格和他的合作者处于独特的地位，可以对 培养细胞中遗传、分子和全身水平的血脂异常和NAFLD的病理生理学， 老鼠，还有人类。拟议的计划是三方的，每个主要领域都有明确的合并机会 调查的结果。它们包括：极低密度脂蛋白组装和分泌的调节 分泌物。在过去的25年里，金斯伯格实验室制作了一系列工作，证明了 载脂蛋白B的新生物学，并提供了识别调节载脂蛋白B分泌的潜在靶点所需的见解 来自肝脏的致动脉粥样硬化的脂蛋白。基于最近令人兴奋的数据，我们将专注于肝癌的实验 细胞研究如何最大限度地分泌多余的apoB和/或将TG加载到apoB上 分泌物。维持肝脏脂质平衡的机制。我们计划了一系列 确定(A)脂质诱导内质网应激的机制和(B)信号通路的实验 内质网应激和内质网自噬之间。影响血浆的人类突变的详细表型分析 脂蛋白代谢对肝脏脂平衡有或没有影响。在这篇文章中提出的研究 部分将结合金斯伯格博士几十年来一直是领导者的一个领域，示踪剂动力学 脂蛋白代谢的研究，这是金斯伯格实验室的一个全新领域，由IPSC衍生 肝细胞。我们未来工作的这一部分将与最近抵达的 美国哥伦比亚大学生物医学工程系教授梁锦松博士 美国国家工程院，再生医学和生物材料领域的领先者。我们会 研究有单基因缺陷的个体与NAFLD和低脂血症有关； 无NAFLD者，有NAFLD者血脂异常。没有一个实验室在同一个人身上定义了 影响脂和脂蛋白代谢的基因突变在两种疾病中的病理生理效应 肝细胞和全身的水平。