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(由申请人提供):葡萄糖稳态的调节是一个复杂的过程,在疾病状态如2型糖尿病中会被破坏。胰岛素是调节葡萄糖稳态的主要激素。胰岛素通过使GLUT4葡萄糖转运蛋白从细胞内膜移出并到达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、不活动、遗传易感性的情况下受损,导致胰岛素抵抗并促进糖尿病的发展。因此,为了了解代谢疾病的发病机制,有必要了解控制GLUT 4在细胞内膜中靶向的分子机制,以及胰岛素通过该机制调节这种靶向。该项目先前的工作确定了TUG蛋白作为肌肉中GLUT4靶向和葡萄糖摄取的调节剂,如脂肪中,并表明这种机制控制小鼠的能量消耗。这些数据支持一种模型,其中GLUT4特异性地保留在细胞内,而不是通过含有TUG的蛋白质复合物被胰岛素刺激。然后胰岛素动员GLUT 4,部分通过触发TUG内切蛋白水解裂解。裂解可以协调葡萄糖摄取的调节与对生理学和代谢的其他影响,这可能是由裂解产生或与GLUT 4共调节的蛋白质的作用引起的。该项目的重点是裂解机制本身,以及胰岛素刺激裂解的能力如何调节以控制胰岛素敏感性。目的1将定义TUG结合囊泡和胰岛素响应性GLUT4储存囊泡之间的关系,并将研究TUG如何与囊泡蛋白,特别是IRAP相互作用,并进行蛋白水解切割。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TUG基因敲除小鼠并研究这些动物中的葡萄糖稳态。目的2研究TUG蛋白乙酰化修饰对胰岛素敏感性的影响。我们将测试的假设,乙酰化调节的TUG的羧基末端与ACBD 3,蛋白质存在于高尔基体基质,以控制胰岛素响应池的GLUT 4的大小的相互作用。我们将进一步研究沉默调节蛋白 利用基因敲除小鼠调节这种乙酰化作用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了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:
    8516944
  • 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:
    8386145
  • 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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