Regulation of Liver Growth and Function

肝脏生长和功能的调节

基本信息

项目摘要

DESCRIPTION (provided by applicant): Nutrient intake in excess of energy expenditure is a major contributing factor to the world-wide epidemic of obesity and type 2 diabetes. Traditionally nutrients have been considered to be precursors for the biosynthesis of macromolecules and as substrates for the production of molecules involved in energy metabolism. However, they are now understood to act through signal transduction cascades to regulate various cellular processes including protein synthesis. The nutrient-sensing pathways are not only interconnected at multiple levels but are tightly coupled to the insulin receptor signaling pathway. Thus, nutrient-sensing and insulin receptor signaling pathways do not function in isolation, but rather as components of a larger, integrated system of intracellular communication. The project proposed herein focuses on the liver, which is an especially important organ in regards to the body's response to nutrient intake because of its position in relation to the gastrointestinal tract, affording it immediate access to the products of digestion appearing in the portal vein. The project also focuses on protein synthesis because the liver, in combination with the gastrointestinal tract, accounts for 25% of the whole body protein synthetic response to a mixed meal. Finally, the project focuses on translational control mechanisms, an area of research for which the expertise of the PI's laboratory is well recognized and one becoming increasingly recognized as playing a prominent role in the regulation of gene expression. The project will employ non-diabetic and diabetic mice maintained on four different diets designed to increase both the fat and caloric intake. The hypothesis to be tested is that chronic nutrient excess and diabetes, alone and in combination, acting through translational control mechanisms, cause both global and specific changes in hepatic protein expression patterns that contribute to pathologies associated with maladapted metabolism. The hypothesis will be tested by pursuing the three following specific aims: (1) define the effects of different dietary regimens and diabetes, alone and in combination, on global and specific changes in protein expression patterns, the translational control mechanisms mediated by eIF2 and eIF4F, and the activation state of nutrient- sensing and insulin receptor signaling pathways in the liver of nondiabetic and diabetic mice; (2) quantitate expression of the mTORC1 repressor REDD1 in the liver of nondiabetic and diabetic mice in response to nutrient excess, define regulatory mechanisms contributing to its upregulated expression, and define its mechanisms of action; and (3) elucidate the signaling pathways and molecular mechanisms through which diabetes-induced hyperglycemia and nutrient excess mediate increased hepatic expression of the translational repressor 4E-BP1. Overall, the project is expected to produce new knowledge that will provide insight into designing strategies for the treatment of pathologies resulting from the maladapted whole body metabolism associated with obesity and diabetes.
描述(申请人提供):营养素摄入量超过能量消耗是肥胖症和2型糖尿病在全球流行的一个主要因素。传统上,营养素被认为是大分子生物合成的前体,也被认为是产生参与能量代谢的分子的底物。然而,它们现在被认为是通过信号转导级联来调节包括蛋白质合成在内的各种细胞过程。营养感知通路不仅在多个水平上相互连接,而且与胰岛素受体信号通路紧密耦合。因此,营养感应和胰岛素受体信号通路并不是孤立地发挥作用,而是作为一个更大的、集成的细胞内交流系统的组成部分发挥作用。这里提出的项目侧重于肝脏,这是人体对营养摄入的反应的一个特别重要的器官,因为它相对于胃肠道的位置,使它能够立即获得门静脉出现的消化产物。该项目还将重点放在蛋白质合成上,因为肝脏和胃肠道结合在一起,占全身蛋白质合成反应的25%。最后,该项目将重点放在翻译控制机制上,这是PI实验室的专业知识得到广泛认可的一个研究领域,并且越来越多地被认为在基因表达调控中发挥着突出的作用。该项目将使用非糖尿病和糖尿病小鼠,通过四种不同的饮食来增加脂肪和卡路里的摄入量。需要检验的假设是,慢性营养过剩和糖尿病,单独和联合作用,通过翻译控制机制,导致肝脏蛋白质表达模式的全局和特定变化,从而导致与适应不良代谢相关的病理变化。该假说将通过追求以下三个具体目标来验证:(1)确定不同饮食方案和糖尿病单独和联合对蛋白质表达模式的全局和特异性变化的影响,eIF2和eIF4F介导的翻译调控机制,以及非糖尿病和糖尿病小鼠肝脏营养感知和胰岛素受体信号通路的激活状态;(2)定量非糖尿病和糖尿病小鼠肝脏对营养过剩的反应,确定其上调表达的调控机制,并确定其作用机制;(3)阐明糖尿病高血糖和营养过剩介导肝脏翻译抑制因子4E-BP1表达增加的信号通路和分子机制。总体而言,该项目预计将产生新的知识,为设计治疗肥胖和糖尿病相关的全身代谢失调所致疾病的战略提供洞察力。

项目成果

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LEONARD S JEFFERSON其他文献

LEONARD S JEFFERSON的其他文献

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{{ truncateString('LEONARD S JEFFERSON', 18)}}的其他基金

Research Training in Physiological Adaptations to Stress
压力生理适应研究培训
  • 批准号:
    9308987
  • 财政年份:
    2014
  • 资助金额:
    $ 38.96万
  • 项目类别:
Research Training in Physiological Adaptations to Stress
压力生理适应研究培训
  • 批准号:
    8742892
  • 财政年份:
    2014
  • 资助金额:
    $ 38.96万
  • 项目类别:
Regulation of Liver Growth and Function
肝脏生长和功能的调节
  • 批准号:
    7847817
  • 财政年份:
    2009
  • 资助金额:
    $ 38.96万
  • 项目类别:
Regulation of Skeletal Muscle Metabolism
骨骼肌代谢的调节
  • 批准号:
    8006688
  • 财政年份:
    2009
  • 资助金额:
    $ 38.96万
  • 项目类别:
Regulation of Liver Growth and Function
肝脏生长和功能的调节
  • 批准号:
    6868588
  • 财政年份:
    1996
  • 资助金额:
    $ 38.96万
  • 项目类别:
RESEARCH TRAINING IN PHYSIOLOGICAL ADAPTATION TO STRESS
压力生理适应研究培训
  • 批准号:
    6914341
  • 财政年份:
    1996
  • 资助金额:
    $ 38.96万
  • 项目类别:
Regulation of Liver Growth and Function
肝脏生长和功能的调节
  • 批准号:
    9304191
  • 财政年份:
    1996
  • 资助金额:
    $ 38.96万
  • 项目类别:
Regulation of Liver Growth and Function
肝脏生长和功能的调节
  • 批准号:
    7564038
  • 财政年份:
    1996
  • 资助金额:
    $ 38.96万
  • 项目类别:
Regulation of Liver Growth and Function
肝脏生长和功能的调节
  • 批准号:
    7784653
  • 财政年份:
    1996
  • 资助金额:
    $ 38.96万
  • 项目类别:
Regulation of Liver Growth and Function
肝脏生长和功能的调节
  • 批准号:
    8053755
  • 财政年份:
    1996
  • 资助金额:
    $ 38.96万
  • 项目类别:

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利用和增强花生和坚果 2S 白蛋白的 IgE 结合表位
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利用和增强花生和坚果 2S 白蛋白的 IgE 结合表位
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  • 批准号:
    17H02202
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Studies on Asymmetric Nitroaldol Reaction using mutant albumins
突变体白蛋白不对称硝醛醇反应的研究
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SPIN LABELING STUDIES OF NORMAL RECOMBINANT & MUTANT HUMAN SERUM ALBUMINS
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  • 批准号:
    6118869
  • 财政年份:
    1999
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    $ 38.96万
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COPPER BINDING OF COMMERCIAL, NORMAL RECOMBINANT, & MUTANT HUMAN SERUM ALBUMINS
商业、正常重组的铜结合,
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    6118864
  • 财政年份:
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Structure and Metabolism of the Serum Albumins Characteristic of Bisalbuminemia in Fowl
家禽双清蛋白血症血清白蛋白的结构与代谢特征
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  • 财政年份:
    1967
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  • 项目类别:
Structure and Metabolism of the Serum Albumins Characteristic of Bisalbuminemia
双清蛋白血症血清白蛋白的结构和代谢特征
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    1965
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