Vesicle Translocation and the Metabolic Syndrome

囊泡易位和代谢综合征

基本信息

  • 批准号:
    9116816
  • 负责人:
  • 金额:
    $ 37.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-08-01 至 2019-07-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The regulation of glucose homeostasis is a complex process, which is disrupted in disease states such as type 2 diabetes. Insulin is the primary hormone regulating glucose homeostasis. Insulin stimulates glucose uptake in muscle and fat by causing the movement of GLUT4 glucose transporters out of intracellular membranes and to the cell surface. This effect of insulin is impaired in the setting of overnutrition, inactivity, ad genetic predisposition, resulting in insulin resistance and contributing to the development of diabetes. Therefore, to understand the pathogenesis of metabolic disease, it is necessary to understand the molecular mechanisms that control the targeting of GLUT4 among intracellular membranes, and by which this targeting is modulated by insulin. Previous work by this project identified the TUG protein as a regulator of GLUT4 targeting and glucose uptake in muscle, as in fat, and showed that this mechanism controls energy expenditure in mice. The data support a model in which GLUT4 is specifically retained within cells not stimulated by insulin by a protein complex containing TUG. Insulin then mobilizes GLUT4, in part by triggering TUG endoproteolytic cleavage. Cleavage may coordinate the regulation of glucose uptake with other effects on physiology and metabolism, which can result from the action of proteins that are produced by cleavage or co-regulated with GLUT4. This project focuses on the cleavage mechanism itself, and on how the ability of insulin to stimulate cleavage may be modulated to control insulin sensitivity. Aim 1 will define the relationship between TUG-bound vesicles and the insulin-responsive GLUT4 storage vesicles, and will study how TUG interacts with vesicle proteins, particularly IRAP, and undergoes proteolytic cleavage. To understand the physiologic role of TUG in the regulation in muscle, we will create muscle-specific TUG knockout mice and study glucose homeostasis in these animals. Aim 2 will study how acetylation of the TUG protein affects insulin sensitivity. We will test the hypothesis that acetylation modulates the interaction of the TUG carboxyl terminus with ACBD3, a protein present at the Golgi matrix, to control the size of an insulin-responsive pool of GLUT4. We will further study if a sirtuin protein regulates this acetylation to control insulin sensitivity in muscle, using knockout mice. We anticipate that, together, these studies will result in an improved understanding of molecular mechanisms regulating glucose metabolism and energy expenditure, with implications for the prediction, prevention, and treatment of diabetes and the metabolic syndrome.
 描述(申请人提供):葡萄糖稳态的调节是一个复杂的过程,在疾病状态下会被破坏,如2型糖尿病。胰岛素是调节血糖动态平衡的主要激素。胰岛素通过促使GLUT4葡萄糖转运体从细胞内膜移动到细胞表面来刺激肌肉和脂肪中的葡萄糖摄取。胰岛素的这种作用在营养过剩、缺乏活动和遗传易感性的情况下受到损害,导致胰岛素抵抗,并导致糖尿病的发生。因此,为了了解代谢性疾病的发病机制,有必要了解控制GLUT4在细胞内膜上靶向的分子机制,以及这种靶向受胰岛素调控的分子机制。该项目之前的工作发现,TUG蛋白是肌肉和脂肪中GLUT4靶向和葡萄糖摄取的调节因子,并表明这一机制控制小鼠的能量消耗。这些数据支持这样一种模型,即GLUT4被含有TUG的蛋白质复合体特异性地保留在不受胰岛素刺激的细胞内。然后,胰岛素动员GLUT4,部分是通过触发TRAG内切蛋白分解。裂解可以协调葡萄糖摄取的调节以及对生理和新陈代谢的其他影响,这可能是由裂解产生的蛋白质或与GLUT4共同调节的蛋白质的作用造成的。本项目的重点是裂解机制本身,以及如何调节胰岛素刺激裂解的能力来控制胰岛素敏感性。目的1确定TUG结合的小泡与胰岛素反应的GLUT4存储小泡之间的关系,并将研究TUG如何与囊泡蛋白,特别是IRAP相互作用,并经历蛋白水解性切割。为了了解TUG在肌肉调节中的生理作用,我们将建立肌肉特异性的TUG基因敲除小鼠,并研究这些动物的葡萄糖稳态。目的2将研究TUG蛋白的乙酰化如何影响胰岛素敏感性。我们将测试这一假设,即乙酰化调节TUG羧基末端与ACBD3的相互作用,ACBD3是一种存在于高尔基体中的蛋白质,以控制GLUT4胰岛素响应池的大小。我们将进一步研究一种sirtuin蛋白 在基因敲除小鼠中,调节这种乙酰化以控制肌肉中的胰岛素敏感性。我们预计,这些研究将有助于更好地理解调节葡萄糖代谢和能量消耗的分子机制,并对糖尿病和代谢综合征的预测、预防和治疗产生影响。

项目成果

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JONATHAN BOGAN其他文献

JONATHAN BOGAN的其他文献

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{{ truncateString('JONATHAN BOGAN', 18)}}的其他基金

Vesicle Translocation and the Metabolic Syndrome
囊泡易位和代谢综合征
  • 批准号:
    10452851
  • 财政年份:
    2022
  • 资助金额:
    $ 37.46万
  • 项目类别:
Vesicle Translocation and the Metabolic Syndrome
囊泡易位和代谢综合征
  • 批准号:
    10592402
  • 财政年份:
    2022
  • 资助金额:
    $ 37.46万
  • 项目类别:
Vesicle Translocation and the Metabolic Syndrome
囊泡易位和代谢综合征
  • 批准号:
    10161017
  • 财政年份:
    2020
  • 资助金额:
    $ 37.46万
  • 项目类别:
Regulation of insulin sensitivity by TUG acetylation
通过 TUG 乙酰化调节胰岛素敏感性
  • 批准号:
    8386145
  • 财政年份:
    2012
  • 资助金额:
    $ 37.46万
  • 项目类别:
Regulation of insulin sensitivity by TUG acetylation
通过 TUG 乙酰化调节胰岛素敏感性
  • 批准号:
    8516944
  • 财政年份:
    2012
  • 资助金额:
    $ 37.46万
  • 项目类别:
Vesicle translocation and the metabolic syndrome
囊泡易位和代谢综合征
  • 批准号:
    8297209
  • 财政年份:
    2012
  • 资助金额:
    $ 37.46万
  • 项目类别:
Vesicle translocation and the metabolic syndrome
囊泡易位和代谢综合征
  • 批准号:
    8518317
  • 财政年份:
    2012
  • 资助金额:
    $ 37.46万
  • 项目类别:
Insulin stimulated ubiquitin-like modification
胰岛素刺激的泛素样修饰
  • 批准号:
    7260014
  • 财政年份:
    2007
  • 资助金额:
    $ 37.46万
  • 项目类别:
Insulin stimulated ubiquitin-like modification
胰岛素刺激的泛素样修饰
  • 批准号:
    7631186
  • 财政年份:
    2007
  • 资助金额:
    $ 37.46万
  • 项目类别:
Insulin stimulated ubiquitin-like modification
胰岛素刺激的泛素样修饰
  • 批准号:
    8066936
  • 财政年份:
    2007
  • 资助金额:
    $ 37.46万
  • 项目类别:

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