Mitogenic Signal Transduction in Pancreatic Beta-Cells

胰腺β细胞中的有丝分裂信号转导

基本信息

  • 批准号:
    8492069
  • 负责人:
  • 金额:
    $ 32.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1998
  • 资助国家:
    美国
  • 起止时间:
    1998-09-30 至 2015-06-30
  • 项目状态:
    已结题

项目摘要

It has now been realized that type-2 diabetes is a disease of insulin insufficiency. Type-2 diabetes is associated with a decrease in functional pancreatic ss-cell mass that no longer compensates for the peripheral insulin resistance. As such, maintaining an optimal ss-cell population for the insulin secretory demand, especially by promoting ss-cell survival, is key for delaying the onset of type-2, as well as type-1, diabetes. In this regard, IRS-2 has been shown to play a pivotal role in ss-cell growth and survival. Increased IRS-2 expression promotes ss-cell growth and survival, whereas insufficient IRS-2 expression leads to spontaneous ss-cell apoptosis. Although IRS-2 protein and mRNA half-life is short in islet ss-cells, this is countered by efficient and highly regulated control of IRS-2 expression, predominately mediated at the transcriptional level. Under basal conditions, ss-cell IRS-2 gene transcription is controlled by a FoxO transcription factor via an insulin response element (IRE) in the IRS-2 promoter. When IRS-2/PI3K/PKB signaling is activated in ss-cells, FoxO transcription factors are consequently inactivated and IRS-2 expression is reduced, in what appears to be a temporal negative feedback mechanism to prevent IRS-2 signaling from being sustained. However, IRS-2 expression can be independently controlled in ss-cells by alternative means. Glucose, in the physiologically relevant range, is a major regulator of ss-cell IRS-2 gene transcription. This requires glucose metabolism and is Ca2+-dependent. It likely provides a mechanism to preserve ss-cell well-being during acute changes in metabolic demand, and is important since other factors, like incretins, only increae IRS-2 expression in ss-cells in a glucose-dependent fashion. However, these early findings need substantiating. This proposal means to gain a better insight into the control of IRS-2 expression in pancreatic ss-cells at the molecular level. It is intended to better characterize control of IRS-2 gene transcription under basal conditions with an emphasis on identifying which particular FoxO transcription factor downstream of PI3K/PKB signaling increases IRS-2 expression. In addition, we will pinpoint which particular secondary signals emanating from increased glucose metabolism in ss-cells link to increased IRS-2 expression (especially via Ca2+/CaMK). It is intended to define a glucose-regulatory cis-element(s) (GREs) in the IRS-2 gene promoter and then identify a trans-acting factor(s) that specifically associates with the GRE glucose-regulatory manner. Thus, a much deeper insight into the molecular mechanism that controls IRS-2 expression in normal, obese and type-2 diabetic primary ss-cells will emerge from these proposed studies. Obesity-linked type-2 diabetes is a major health problem in the US and caused by loss of pancreatic ss-cells that produce insulin. Novel therapeutic approaches are needed which are aimed at protecting the endogenous ss-cell population to produce enough insulin to delay, perhaps indefinitely, the onset of diabetes. IRS-2 is a gene key to ss-cell survival, and it is anticipated that new insight into the control of IRS-2 expression will lead to a novel means of maintaining adequate ss-cell numbers and sufficient insulin production in vivo, that in turn will alleviate, or perhaps even prevent, symptoms of type-2 diabetes.
现在已经认识到,2型糖尿病是一种胰岛素不足的疾病。2型糖尿病是

项目成果

期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
IGF-I and GH post-receptor signaling mechanisms for pancreatic beta-cell replication.
Increased phagocyte-like NADPH oxidase and ROS generation in type 2 diabetic ZDF rat and human islets: role of Rac1-JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet.
  • DOI:
    10.2337/db11-0809
  • 发表时间:
    2011-11
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Syed I;Kyathanahalli CN;Jayaram B;Govind S;Rhodes CJ;Kowluru RA;Kowluru A
  • 通讯作者:
    Kowluru A
Specific glucose-induced control of insulin receptor substrate-2 expression is mediated via Ca2+-dependent calcineurin/NFAT signaling in primary pancreatic islet β-cells.
  • DOI:
    10.2337/db11-0341
  • 发表时间:
    2011-11
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Demozay D;Tsunekawa S;Briaud I;Shah R;Rhodes CJ
  • 通讯作者:
    Rhodes CJ
Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation.
  • DOI:
    10.1371/journal.pone.0018146
  • 发表时间:
    2011-04-26
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Tanabe K;Liu Y;Hasan SD;Martinez SC;Cras-Méneur C;Welling CM;Bernal-Mizrachi E;Tanizawa Y;Rhodes CJ;Zmuda E;Hai T;Abumrad NA;Permutt MA
  • 通讯作者:
    Permutt MA
Stimulation of pancreatic beta-cell proliferation by growth hormone is glucose-dependent: signal transduction via janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) with no crosstalk to insulin receptor substrate-mediated mit
生长激素对胰腺 β 细胞增殖的刺激是葡萄糖依赖性的:通过 janus 激酶 2 (JAK2)/信号转导器和转录激活剂 5 (STAT5) 进行信号转导,与胰岛素受体底物介导的 mit 没有串扰
  • DOI:
  • 发表时间:
    1999
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Cousin,SP;Hügl,SR;MyersJr,MG;White,MF;Reifel-Miller,A;Rhodes,CJ
  • 通讯作者:
    Rhodes,CJ
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Christopher J Rhodes其他文献

Who knew? PPARs may act in the brain too
谁知道?
  • DOI:
    10.1038/s42255-022-00625-6
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    20.8
  • 作者:
    R. Seeley;Christopher J Rhodes
  • 通讯作者:
    Christopher J Rhodes

Christopher J Rhodes的其他文献

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{{ truncateString('Christopher J Rhodes', 18)}}的其他基金

Central Control of Pancreatic Islet Function
胰岛功能的中央控制
  • 批准号:
    9096773
  • 财政年份:
    2015
  • 资助金额:
    $ 32.09万
  • 项目类别:
Central Control of Pancreatic Islet Function
胰岛功能的中央控制
  • 批准号:
    8963982
  • 财政年份:
    2015
  • 资助金额:
    $ 32.09万
  • 项目类别:
Central Control of Pancreatic Islet Function
胰岛功能的中央控制
  • 批准号:
    9271963
  • 财政年份:
    2015
  • 资助金额:
    $ 32.09万
  • 项目类别:
An Interdisciplinary Molecular Metabolism Training Program
跨学科分子代谢培训计划
  • 批准号:
    8515773
  • 财政年份:
    2010
  • 资助金额:
    $ 32.09万
  • 项目类别:
An Interdisciplinary Molecular Metabolism Training Program
跨学科分子代谢培训计划
  • 批准号:
    7869732
  • 财政年份:
    2010
  • 资助金额:
    $ 32.09万
  • 项目类别:
An Interdisciplinary Molecular Metabolism Training Program
跨学科分子代谢培训计划
  • 批准号:
    8712473
  • 财政年份:
    2010
  • 资助金额:
    $ 32.09万
  • 项目类别:
An Interdisciplinary Molecular Metabolism Training Program
跨学科分子代谢培训计划
  • 批准号:
    8293342
  • 财政年份:
    2010
  • 资助金额:
    $ 32.09万
  • 项目类别:
An Interdisciplinary Molecular Metabolism Training Program
跨学科分子代谢培训计划
  • 批准号:
    8091288
  • 财政年份:
    2010
  • 资助金额:
    $ 32.09万
  • 项目类别:
Western Region Islet Study Group
西域岛研究小组
  • 批准号:
    6792587
  • 财政年份:
    2001
  • 资助金额:
    $ 32.09万
  • 项目类别:
Western Region Islet Study Group
西域岛研究小组
  • 批准号:
    6948786
  • 财政年份:
    2001
  • 资助金额:
    $ 32.09万
  • 项目类别:
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知道了