Autophagy/antioxidant response coupling in pancreatic beta-cell homeostasis regulation

胰腺β细胞稳态调节中的自噬/抗氧化反应耦合

基本信息

项目摘要

The incidence of diabetes in the US population has been rapidly increasing over the past several decades. Type 1 diabetes is a result of β-cell death, or apoptosis of the insulin-producing cells in the pancreas. While there are a variety of known triggers for β-cell apoptosis, most feed into pathways that lead to increased generation of reactive oxygen species (ROS) in the β-cell. Unchecked accumulation of β-cell ROS can disrupt cellular homeostasis, cause oxidative damage, and lead to apoptosis. A typical adaptive response to increased ROS includes activation of the transcription factor NRF2, which stimulates the cell-protective antioxidant response and restores homeostasis. We recently found that tandem activation of interleukin-6 (IL-6) receptor signaling and NRF2 in the β-cell couples autophagy to the antioxidant response, reduces β-cell ROS, and protects against oxidative damage to increase β-cell survival in vivo. Importantly, we discovered that non-canonical actions of NRF2 in the mitochondria were associated with the stimulation of mitophagy, the selective degradation of mitochondria by autophagy. Collectively, these data lead to our hypothesis that autophagy and antioxidant response are coupled in the β-cell and that orchestration of these processes is essential for maintenance of β-cell homeostasis and diabetes prevention. The proposed work will incorporate both in vitro experiments using cultured islets/ β-cells and in vivo analyses in mice. We will pursue the following specific aims: 1) To identify the mechanism controlling NRF2 mitochondrial translocation and determine its role in β-cell autophagy/antioxidant response coupling; and 2) To determine the in vivo contributions of autophagy/antioxidant response coupling to β-cell homeostasis. Overall, these experiments will define the role of autophagy/antioxidant response coupling in the adaptive response to stress and allow us to identify therapeutic targets guiding the signaling events within the islet under conditions known to lead to β-cell failure. My background in β-cell biology and resources within the Indiana Center for Diabetes and Metabolic Diseases makes me uniquely suited to accomplish the aims of this project.
在过去的几年里,美国人口中糖尿病的发病率迅速增加。 几十年1型糖尿病是胰腺中β细胞死亡或胰岛素产生细胞凋亡的结果。虽然有多种已知的β细胞凋亡触发因子,但大多数进入导致β细胞中活性氧(ROS)产生增加的途径。β细胞ROS的不受控制的积累可破坏细胞内稳态,引起氧化损伤,并导致细胞凋亡。对增加的ROS的典型适应性反应包括转录因子NRF 2的激活,其刺激细胞保护性抗氧化反应并恢复稳态。我们最近发现,β细胞中白细胞介素-6(IL-6)受体信号传导和NRF 2的串联激活将自噬与抗氧化反应偶联,减少β细胞ROS, 保护免受氧化损伤以增加体内β细胞存活。重要的是,我们发现线粒体中NRF 2的非经典作用与线粒体自噬的刺激有关,线粒体自噬是通过自噬选择性降解线粒体。总的来说,这些数据导致我们的假设,即自噬和抗氧化反应在β细胞中偶联,并且这些过程的协调对于维持β细胞稳态和预防糖尿病是必不可少的。拟议的工作将包括使用培养的胰岛/ β细胞的体外实验和小鼠体内分析。本研究的具体目标如下:1)研究NRF 2在β细胞中的作用,探讨NRF 2在β细胞线粒体转位中的作用机制。 自噬/抗氧化反应偶联;和2)确定自噬/抗氧化反应偶联对β细胞稳态的体内贡献。总的来说,这些实验将定义自噬/抗氧化反应偶联在对应激的适应性反应中的作用,并使我们能够在已知导致β细胞衰竭的条件下确定指导胰岛内信号传导事件的治疗靶点。我在β细胞生物学和印第安纳州糖尿病和代谢疾病中心的资源背景使我特别适合完成这个项目的目标。

项目成果

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Amelia K Linnemann其他文献

Amelia K Linnemann的其他文献

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{{ truncateString('Amelia K Linnemann', 18)}}的其他基金

Autophagy/antioxidant response coupling in pancreatic beta-cell homeostasis regulation
胰腺β细胞稳态调节中的自噬/抗氧化反应耦合
  • 批准号:
    10371254
  • 财政年份:
    2021
  • 资助金额:
    $ 39.63万
  • 项目类别:
Autophagy/antioxidant response coupling in pancreatic beta-cell homeostasis regulation
胰腺β细胞稳态调节中的自噬/抗氧化反应耦合
  • 批准号:
    10570271
  • 财政年份:
    2021
  • 资助金额:
    $ 39.63万
  • 项目类别:
Functional and molecular characterization of the human islet interferon alpha response
人胰岛干扰素α反应的功能和分子特征
  • 批准号:
    10264921
  • 财政年份:
    2020
  • 资助金额:
    $ 39.63万
  • 项目类别:
Microscopy Core
显微镜核心
  • 批准号:
    10633134
  • 财政年份:
    2015
  • 资助金额:
    $ 39.63万
  • 项目类别:
Obesity induced cytokines and beta cell mass regulation
肥胖诱导的细胞因子和β细胞质量调节
  • 批准号:
    9211315
  • 财政年份:
    2015
  • 资助金额:
    $ 39.63万
  • 项目类别:

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