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.

概括： 以动脉粥样异常血症为特征的心脏代谢性疾病的患病率（血浆增加 甘油三酸酯（TG）水平（高甘油三酸酯血症），高密度脂蛋白（HDL）胆固醇（C）和 小胆固醇酯耗尽-TG富含低密度脂蛋白（LDL）），胰岛素抵抗（IR）和2型 糖尿病（T2DM）和非酒精性脂肪肝疾病（NAFLD）或其下游并发症，非 - 在过去25年中，酒精性脂肪性肝炎（NASH）增加了。金斯伯格博士领导了NHLBI- 资助实验室已有40多年的历史 人类中的脂蛋白水平，包括IR的作用，研究和分泌非常低的组装和分泌 培养的肝细胞中的密度脂蛋白（VLDL），用于NAFLD的小鼠模型，包括一些IR。博士 金斯伯格及其合作者的独特位置，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， 老鼠和人类。拟议的计划是三方，有明显的机会合并每个主要区域 调查。它们包括：对VLDL议会的大会和分泌的规定 分泌。在过去的25年中，金斯伯格实验室生产了一大批作品，证明了 APOB的新型生物学，并提供了确定调节潜在目标所需的见解 肝脏的动脉粥样硬化脂蛋白。基于最近的激动人心的数据，我们将重点进行肝瘤的实验 细胞以最大化备用APOB的分泌和或将TG加载到目标的方法 分泌。维持肝脂质稳态的机制。我们计划一系列 实验以确定（a）脂质诱导的ER应力的机制和（b）信号通路 在ER应力和ER自噬之间。影响血浆的人类突变的详细表型 脂蛋白代谢对肝脂质稳态有或没有影响。提出的研究 部分将结合Ginsberg博士一直是领导者数十年的领域，Tracer Kinetic 脂蛋白代谢的研究，该区域是Ginsberg实验室全新的，IPSC衍生的 肝细胞。我们未来工作的这一组成部分将与最近达成的合作进行 哥伦比亚博士，Kam Leong博士，Samuel Y Sheng生物医学工程学教授，也是 国家工程学院，再生医学和生物材料领域的领导者。我们将 患有单基因缺陷的个体与NAFLD和低脂血症有关。低脂血症 没有NAFLD，具有NAFLD的血脂异常。在同一个人中，没有实验室定义 突变在影响脂质和脂蛋白代谢的基因中突变的病理生理作用。 肝细胞和整个身体的水平。