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): Diabetes mellitus and obesity, major epidemics that affect more than 5-8% and 20-25% of the US population, respectively, are manifestations of dysregulated metabolism. A tissue prominently involved in these disorders is the liver which must adapt rapidly to large variations in macronutrient availability and the associated fluctuations in anabolic and catabolic hormones in order to act in coordination with other tissues of the body to maintain metabolic homeostasis. Adaptation by the liver to either an influx of nutrients or nutrient deprivation is accomplished by multiple biochemical processes mediated by transcriptional, translational, and posttranslational mechanisms. Of these, the least is presently known about translational mechanisms, i.e., the process of translating mRNA into protein, an area of research in which the expertise of the PI's laboratory is well-recognized. Therefore, the overall objective of the proposed project is to gain an understanding of how translational control mechanisms in the liver and the signaling pathways that regulate them respond to variations in macronutrients and the hormones insulin and glucagon, and in so doing provide insight into designing strategies for the treatment of disorders involving dysregulated metabolism. The general hypothesis to be tested is that nutrients and hormones activate both distinct and redundant cell signaling pathways in the liver, thus altering molecular mechanisms that mediate the regulation of mRNA translation, a process that contributes to the highly coordinated gene-expression patterns required to respond to fluctuations in the metabolic demands imparted on the tissue in a variety of physiological conditions. To test this hypothesis we propose the following specific aims: (1) identify the mechanisms that are responsible for mediating the action of glucagon to repress and the actions of free fatty acids and the branched-chain amino acid leucine to activate signaling through the mammalian target of rapamycin (mTOR) pathway to produce a change in the translational control of gene expression; (2) identify the mechanisms and signaling pathways that are responsible for producing a change in the translational control of gene expression in response to amino acid imbalance or unphysiologically low or high glucose concentrations; and (3) identify the molecular mechanism(s), the signaling pathways(s), and the nutritional and hormonal inputs through which translation of the albumin mRNA is derepressed in response to food intake. We expect to identify novel targets for therapeutic intervention under conditions in which the liver contributes to dysregulated metabolism.
描述(申请人提供):糖尿病和肥胖症,分别影响超过5-8%和20-25%的美国人口的主要流行病,是代谢失调的表现。与这些疾病密切相关的组织是肝脏,它必须迅速适应大量营养素供应的巨大变化以及与之相关的合成代谢和分解代谢激素的波动,以便与身体其他组织协调行动,维持代谢平衡。肝脏对营养物质流入或营养缺乏的适应是由转录、翻译和翻译后机制介导的多种生化过程完成的。其中,目前最不为人所知的是翻译机制,即将mRNA翻译成蛋白质的过程,这是PI实验室的专业知识广为人知的研究领域。因此,拟议项目的总体目标是了解肝脏中的翻译控制机制和调节它们的信号通路如何应对大量营养素以及胰岛素和胰高血糖素激素的变化,从而为设计治疗涉及代谢失调的疾病的策略提供洞察力。需要检验的一般假设是,营养和激素激活了肝脏中不同的和多余的细胞信号通路,从而改变了调节mRNA翻译的分子机制,这一过程有助于形成高度协调的基因表达模式,以响应在各种生理条件下赋予组织的代谢需求的波动。为了验证这一假说,我们提出了以下具体目标:(1)确定负责介导胰高血糖素抑制作用的机制,以及自由脂肪酸和支链氨基酸亮氨酸通过哺乳动物目标雷帕霉素(MTOR)途径激活信号以产生基因表达翻译控制变化的作用;(2)确定导致基因表达翻译控制改变的机制和信号通路,以响应氨基酸失衡或非生理性的低或高糖浓度;以及(3)确定白蛋白基因翻译受食物摄入影响的分子机制(S)、信号转导途径(S)以及营养和激素输入。我们期望在肝脏导致代谢失调的情况下,为治疗干预找到新的靶点。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

LEONARD S JEFFERSON其他文献

LEONARD S JEFFERSON的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
    $ 42.58万
  • 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:
    $ 42.58万
  • 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:
    $ 42.58万
  • 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:
    $ 42.58万
  • 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:
    $ 42.58万
  • 项目类别:
Regulation of Liver Growth and Function
肝脏生长和功能的调节
  • 批准号:
    8442901
  • 财政年份:
    1996
  • 资助金额:
    $ 42.58万
  • 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:
    $ 42.58万
  • 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:
    $ 42.58万
  • 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:
    $ 42.58万
  • 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:
    $ 42.58万
  • 项目类别:

相似海外基金

ROLE OF CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
细胞粘附在生物信号转导中的作用
  • 批准号:
    6238317
  • 财政年份:
    1997
  • 资助金额:
    $ 42.58万
  • 项目类别:
CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
生物信号转导中的细胞粘附
  • 批准号:
    3732412
  • 财政年份:
  • 资助金额:
    $ 42.58万
  • 项目类别:
ROLE OF CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
细胞粘附在生物信号转导中的作用
  • 批准号:
    5210031
  • 财政年份:
  • 资助金额:
    $ 42.58万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了