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 细胞死亡或胰岛素生成细胞凋亡的结果。虽然 β 细胞凋亡有多种已知的触发因素,但大多数都会进入导致 β 细胞中活性氧 (ROS) 生成增加的途径。 β细胞活性氧不受控制的积累会破坏细胞稳态,引起氧化损伤,并导致细胞凋亡。对 ROS 增加的典型适应性反应包括转录因子 NRF2 的激活,它会刺激细胞保护性抗氧化反应并恢复体内平衡。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 NRF2 的串联激活可将自噬与抗氧化反应结合起来,减少 β 细胞的 ROS,并 防止氧化损伤,增加体内 β 细胞的存活率。重要的是,我们发现 NRF2 在线粒体中的非典型作用与刺激线粒体自噬(自噬选择性降解线粒体)有关。总的来说,这些数据得出了我们的假设,即自噬和抗氧化反应在 β 细胞中耦合,并且这些过程的协调对于维持 β 细胞稳态和预防糖尿病至关重要。拟议的工作将结合使用培养的胰岛/β细胞的体外实验和小鼠的体内分析。我们将追求以下具体目标:1)确定控制NRF2线粒体易位的机制并确定其在β细胞中的作用 自噬/抗氧化反应耦合; 2) 确定自噬/抗氧化反应耦合对 β 细胞稳态的体内贡献。总的来说,这些实验将定义自噬/抗氧化反应耦合在应激适应性反应中的作用,并使我们能够确定在已知导致β细胞衰竭的条件下指导胰岛内信号事件的治疗靶点。我在 β 细胞生物学方面的背景以及印第安纳州糖尿病和代谢疾病中心的资源使我非常适合实现该项目的目标。

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:
    10210544
  • 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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