Them1-Mediated Metabolic Regulation and Pathogenic Role in NAFLD

Them1 介导的 NAFLD 代谢调节和致病作用

基本信息

  • 批准号:
    10433907
  • 负责人:
  • 金额:
    $ 68.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-07-05 至 2023-03-13
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Insulin resistance due to obesity is central to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). This research proposal addresses the unanswered question of how molecular mechanisms that normally promote energy conservation become maladaptive and contribute to NAFLD. The long-term goal of this research is to understand the regulatory relationships between cellular lipid molecules and metabolism, particularly as they present therapeutic opportunities. The objective of this research is to understand fundamental mechanisms for the regulation of energy homeostasis and nutrient metabolism. Our central hypothesis is that Them1 conserves energy by limiting thermogenesis in brown and beige adipose tissue through its functions both as a lipid-regulated enzyme that reduces rates of fatty acid oxidation and as a transcriptional coregulator. In obesity, we postulate that Them1 becomes maladaptive. In addition to limiting energy expenditure in thermogenic adipose tissue, high fat diet-induced Them1 upregulation in liver leads to steatosis and excess gluconeogenesis and in white adipose tissue to inflammation and insulin resistance. The rationale for the proposed research is that the mechanisms by which Them1 limits energy expenditure, while promoting hepatic steatosis and insulin resistance, will reveal specific new targets for the management of NAFLD. Guided by extensive preliminary data, the central hypothesis will be tested in three specific aims: 1) To define the maladaptive mechanisms whereby Them1 promotes obesity and NAFLD; 2) To determine the cellular mechanisms for suppression of thermogenesis by Them1; and 3) To elucidate regulation of Them1 activity by the lipid-binding START domain. In Aim 1, genetically engineered mice will be used to test the hypothesis that increased Them1 expression in white adipose tissue promotes inflammation, which leads to insulin resistance, hepatic inflammation and endoplasmic reticulum stress, and in beige adipose tissue reduces thermogenesis. Aim 2 will test the hypothesis that Them1 in brown adipose tissue organizes into membrane- less organelles (puncta) that conserve energy by suppressing fatty acid oxidation, except during peak energy demand, when Them1 is directed to the nucleus to support thermogenesis by suppressing lipogenic gene expression. We will visualize puncta by 3-D electron microscopy and elucidate the phase transition that promotes their formation, and will characterize Them1-mediated transcriptional regulation. Aim 3 will test the hypothesis that lipids bound to the START domain allosterically regulate the enzymatic domains. Our approach will include detailed structural analysis of Them1 lipid-binding and catalysis using complementary biophysical approaches, along with the development of small molecule inhibitors, which could also prove to be of therapeutic value in NAFLD. Overall, this proposal will elucidate Them1-mediated metabolic regulation, which is significant because mechanisms that conserve energy in health may promote disease under conditions of overnutrition. These studies are expected to identify therapeutic opportunities for the management of NAFLD.
项目概要/摘要 肥胖引起的胰岛素抵抗是非酒精性脂肪肝 (NAFLD) 发病机制的核心。 这项研究提案解决了一个尚未解答的问题,即通常情况下的分子机制如何 提倡节能会导致适应不良并导致 NAFLD。本次活动的长远目标 研究是为了了解细胞脂质分子与代谢之间的调节关系, 特别是因为它们提供了治疗机会。这项研究的目的是了解 调节能量稳态和营养代谢的基本机制。我们的中央 假设 Them1 通过限制棕色和米色脂肪组织的生热作用来保存能量 通过其作为降低脂肪酸氧化速率的脂质调节酶和作为 转录共调节因子。在肥胖症中,我们假设 Them1 变得适应不良。除了限制之外 产热脂肪组织中的能量消耗,高脂肪饮食诱导的肝脏 Them1 上调导致 脂肪变性和过度糖异生以及白色脂肪组织中的炎症和胰岛素抵抗。这 拟议研究的基本原理是 Them1 限制能量消耗的机制,而 促进肝脂肪变性和胰岛素抵抗,将揭示治疗肝脂肪变性的具体新目标 非酒精性脂肪性肝病。在广泛的初步数据的指导下,中心假设将在三个具体目标上进行检验:1) 明确 Them1 促进肥胖和 NAFLD 的适应不良机制; 2)确定 Them1 抑制产热的细胞机制; 3) 阐明它们的监管1 脂质结合 START 结构域的活性。在目标 1 中,将使用基因工程小鼠来测试 假设白色脂肪组织中 Them1 表达增加会促进炎症,从而导致 胰岛素抵抗、肝脏炎症和内质网应激,以及米色脂肪组织中的减少 生热作用。目标 2 将检验棕色脂肪组织中的 Them1 组织成膜的假设 通过抑制脂肪酸氧化来节省能量的细胞器(puncta)较少,峰值能量期间除外 当 Them1 被定向到细胞核以通过抑制脂肪生成基因来支持生热作用时,需求 表达。我们将通过 3D 电子显微镜可视化斑点并阐明相变 促进它们的形成,并将表征 Them1 介导的转录调控。目标 3 将测试 假设与 START 结构域结合的脂质可以变构调节酶结构域。我们的方法 将包括使用补充生物物理学对 Them1 脂质结合和催化进行详细的结构分析 方法,以及小分子抑制剂的开发,这也可能被证明是 NAFLD 的治疗价值。总体而言,该提案将阐明 Them1 介导的代谢调节, 是重要的,因为在健康中保存能量的机制可能会在以下条件下促进疾病: 营养过剩。这些研究有望确定 NAFLD 管理的治疗机会。

项目成果

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DAVID E. COHEN其他文献

DAVID E. COHEN的其他文献

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{{ truncateString('DAVID E. COHEN', 18)}}的其他基金

Research Training in Gastrointestinal and Hepatic Diseases
胃肠道和肝脏疾病研究培训
  • 批准号:
    10628491
  • 财政年份:
    2023
  • 资助金额:
    $ 68.05万
  • 项目类别:
Them1 Inhibitors for the Management of Non-Alcoholic Fatty Liver Disease
Them1 治疗非酒精性脂肪肝的抑制剂
  • 批准号:
    10666090
  • 财政年份:
    2023
  • 资助金额:
    $ 68.05万
  • 项目类别:
Phospholipid-Mediated Metabolic Control in the Pathogenesis of NAFLD
NAFLD 发病机制中磷脂介导的代谢控制
  • 批准号:
    10543224
  • 财政年份:
    2021
  • 资助金额:
    $ 68.05万
  • 项目类别:
Phospholipid-Mediated Metabolic Control in the Pathogenesis of NAFLD
NAFLD 发病机制中磷脂介导的代谢控制
  • 批准号:
    10589147
  • 财政年份:
    2021
  • 资助金额:
    $ 68.05万
  • 项目类别:
Multidisciplinary Research Training in Gastroenterology and Hepatology
胃肠病学和肝病学多学科研究培训
  • 批准号:
    9922266
  • 财政年份:
    2019
  • 资助金额:
    $ 68.05万
  • 项目类别:
Them1-Mediated Metabolic Regulation and Pathogenic Role in NAFLD
Them1 介导的 NAFLD 代谢调节和致病作用
  • 批准号:
    8964017
  • 财政年份:
    2015
  • 资助金额:
    $ 68.05万
  • 项目类别:
Them1-Mediated Metabolic Regulation and Pathogenic Role in NAFLD
Them1 介导的 NAFLD 代谢调节和致病作用
  • 批准号:
    10836136
  • 财政年份:
    2015
  • 资助金额:
    $ 68.05万
  • 项目类别:
Them1-Mediated Metabolic Regulation and Pathogenic Role in NAFLD
Them1 介导的 NAFLD 代谢调节和致病作用
  • 批准号:
    9103123
  • 财政年份:
    2015
  • 资助金额:
    $ 68.05万
  • 项目类别:
Them1-Mediated Metabolic Regulation and Pathogenic Role in NAFLD
Them1 介导的 NAFLD 代谢调节和致病作用
  • 批准号:
    9353773
  • 财政年份:
    2015
  • 资助金额:
    $ 68.05万
  • 项目类别:
Them1-Mediated Metabolic Regulation and Pathogenic Role in NAFLD
Them1 介导的 NAFLD 代谢调节和致病作用
  • 批准号:
    10206113
  • 财政年份:
    2015
  • 资助金额:
    $ 68.05万
  • 项目类别:

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  • 批准号:
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  • 批准号:
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  • 财政年份:
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酰基辅酶 A 的分子生物学:胆固醇酰基转移酶
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    08044304
  • 财政年份:
    1996
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