Control of beta cell identity by the mitochondrial life cycle

通过线粒体生命周期控制 β 细胞身份

基本信息

  • 批准号:
    10454761
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

Diabetes results from insufficient functional pancreatic β-cell mass to meet peripheral insulin demands. β-cell failure can occur in T2D due to loss of β-cell identity or de-differentiation, with recent studies suggesting that loss of the mitochondrial gene expression program heralds the immature β-cell state. β-cells rely upon mitochondrial respiration to generate the energy necessary for the metabolic demands of insulin biosynthesis, processing, and secretion. Indeed, defects in mitochondrial structure, function, and DNA levels have been reported in the β-cells of patients with type 2 diabetes (T2D). Defects in mitochondrial structure and function are characteristic of impairments in the mitochondrial life cycle, which maintains functional mitochondrial mass via a balance of biogenesis and turnover. It is not clear, however, if impaired mitochondria are necessary and sufficient to directly induce β-cell immaturity. Interestingly, our preliminary data suggest that genetic loss of biogenesis or mitophagy reduces β-cell maturity and mass, which is not due to impaired β-cell replication or survival. Therefore, our goal is to dissect the mechanistic contribution of mitochondrial biogenesis and turnover to β-cell maturity and elucidate their contribution to diabetes pathogenesis. The central hypothesis to be tested is that defects in the mitochondrial life cycle induce a retrograde signaling cascade that impairs β-cell identity. We will test this hypothesis by the following approach: Specific Aim 1 will elucidate the effect of metabolic overload on the mitochondrial life cycle and its control of β-cell identity. Specific Aim 2 will determine the contribution of mitochondria derived oxidative damage to the development of β-cell immaturity. Specific Aim 3 will delineate the role of the integrated stress response to consolidate retrograde signals inducing β-cell immaturity following mitochondrial dysfunction. We anticipate obtaining a clear understanding of the importance and translational relevance of the mitochondrial life cycle by revealing the key effectors that mediate mito-nuclear crosstalk and impact β-cell identity. These results should re-define the role of mitochondria in diabetes pathogenesis and could open new possibilities to re-program immature β-cells back to a mature state to treat diabetes in Veterans.
糖尿病是由于胰腺β细胞不能满足周围胰岛素需求而引起的。β细胞

项目成果

期刊论文数量(0)
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Scott Soleimanpour其他文献

Scott Soleimanpour的其他文献

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{{ truncateString('Scott Soleimanpour', 18)}}的其他基金

Type 2 diabetes risk variant effects on mitochondrial (patho)physiology
2 型糖尿病风险变异对线粒体(病理)生理学的影响
  • 批准号:
    10717519
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Control of beta cell identity by the mitochondrial life cycle
通过线粒体生命周期控制 β 细胞身份
  • 批准号:
    10619610
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Control of beta cell identity by the mitochondrial life cycle
通过线粒体生命周期控制 β 细胞身份
  • 批准号:
    9890737
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Mediators of mitophagy in the regulation of beta cell function
线粒体自噬调节β细胞功能的介质
  • 批准号:
    9237051
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Mediators of mitophagy in the regulation of beta cell function
线粒体自噬调节β细胞功能的介质
  • 批准号:
    9761533
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Endosomal regulation of GLP-1 receptor function in beta cells by Clec16a
Clec16a 对 β 细胞中 GLP-1 受体功能的内体调节
  • 批准号:
    9086362
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Endosomal regulation of GLP-1 receptor function in beta cells by Clec16a
Clec16a 对 β 细胞中 GLP-1 受体功能的内体调节
  • 批准号:
    8949507
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
The Role of Clec16a in the Pancreatic Islet
Clec16a 在胰岛中的作用
  • 批准号:
    8394578
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
The Role of Clec16a in the Pancreatic Islet
Clec16a 在胰岛中的作用
  • 批准号:
    8242336
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
The Role of Clec16a in the Pancreatic Islet
Clec16a 在胰岛中的作用
  • 批准号:
    8984302
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:

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