Role of mTORC1 signaling in type 1 diabetes

mTORC1 信号在 1 型糖尿病中的作用

基本信息

项目摘要

Project Summary/Abstract Type 1 diabetes (T1D) is a devastating disease with increased incidence in the world. Proposed therapeutic therapies for this disease have focused on preservation of beta cells and immunomodulation. The mTOR complex 1 (mTORC1), a nutrient sensor, regulates beta cell mass and proliferation by acting on S6K and 4E- BPs, two major downstream targets of mTORC1. 4E-BPs are hyperphosphorylated by mTORC1 causing their release from eIF4E and promotion of translation initiation. Activation of 4E-BP2/eIF4E pathway by 4E-BP2 deletion induces beta cell expansion and proliferation by upregulation of IRS2 levels. In addition to beta cells, mTORC1/4E-BP axis is also crucial for the regulation of adaptive immunity. Preliminary studies suggest that 4E- BP2 deletion has prosurvival effects for the beta cell in vitro against the cytotoxic effects of pro-inflammatory cytokines, a cause of beta cell demise in T1D. Using a newly generated global 4E-BP2 deficient mice in the NOD background (4E-BP2KONOD), preliminary studies showed that 90% of male (not female) mice were protected from the development of T1D by preserving beta cell mass. In addition, adoptive transfer studies into NOD.scid mice showed that mice that received splenocytes from 4E-BP2KONOD mice developed significantly less diabetes than controls that received splenocytes from WT mice. This suggests that inhibition of 4E-BP2/eIF4E interaction could be a promising therapeutic strategy for T1D by potentially preserving functional beta cells, reduction in autoimmune injury and enhancing beta cell regeneration. However, how 4E-BP2 deletion protects beta cells from autoimmune injury and induces immunomodulatory effects and the potential sexual dimorphism of this phenotype is unknown. Our hypothesis is that 4E-BP2 deletion reverses T1D by two distinct mechanisms: 1. . Augmenting survival and conserving beta cell function in a T1D inflammatory environment, and 2. modulating the ability of lymphocytes to mount an immune response. The following aims will test this hypothesis: Aim 1. To determine the contribution and molecular mechanisms mediated by 4E-BP2 deletion on beta cell survival and function in the context of T1D and Aim 2. To uncover how 4E-BP2 deletion induces immunomodulatory effects to protect from T1D. In addition, studies assessing the contribution of beta cells or immune system in the gender dimorphic phenotype of diabetes protection will complement these aims. The proposed studies will fill an important knowledge gap by providing insights into the 4E-BP2/eIF4E activation as a pharmacological target for T1D treatment. Such results will have a positive impact because this target will serve as a platform for designing novel therapeutic strategies to expand drug development for diabetes.
项目总结/文摘

项目成果

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专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Ernesto Bernal-Mizrachi其他文献

Ernesto Bernal-Mizrachi的其他文献

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{{ truncateString('Ernesto Bernal-Mizrachi', 18)}}的其他基金

Amino acid sensing mechanisms in beta and alpha cells
β 和 α 细胞中的氨基酸传感机制
  • 批准号:
    10655636
  • 财政年份:
    2022
  • 资助金额:
    $ 39.82万
  • 项目类别:
Role of mTORC1 signaling in type 1 diabetes
mTORC1 信号在 1 型糖尿病中的作用
  • 批准号:
    10597680
  • 财政年份:
    2022
  • 资助金额:
    $ 39.82万
  • 项目类别:
AKT/mTOR signaling and regulation of cell cycle in B-cells
B 细胞中的 AKT/mTOR 信号传导和细胞周期调节
  • 批准号:
    10093016
  • 财政年份:
    2019
  • 资助金额:
    $ 39.82万
  • 项目类别:
AKT/mTOR signaling and regulation of cell cycle in B-cells
B 细胞中的 AKT/mTOR 信号传导和细胞周期调节
  • 批准号:
    9913511
  • 财政年份:
    2019
  • 资助金额:
    $ 39.82万
  • 项目类别:
AKT/mTOR signaling and regulation of cell cycle in B-cells
B 细胞中的 AKT/mTOR 信号传导和细胞周期调节
  • 批准号:
    10356793
  • 财政年份:
    2019
  • 资助金额:
    $ 39.82万
  • 项目类别:
mTORC1 signaling and regulation of alpha-cell mass and function.
mTORC1 信号传导以及α细胞质量和功能的调节。
  • 批准号:
    9231264
  • 财政年份:
    2016
  • 资助金额:
    $ 39.82万
  • 项目类别:
mTOR signaling and regulation of alpha-cell mass and function
mTOR 信号传导以及 α 细胞质量和功能的调节
  • 批准号:
    10455409
  • 财政年份:
    2016
  • 资助金额:
    $ 39.82万
  • 项目类别:
mTORC1 signaling and regulation of alpha-cell mass and function.
mTORC1 信号传导以及α细胞质量和功能的调节。
  • 批准号:
    8920270
  • 财政年份:
    2016
  • 资助金额:
    $ 39.82万
  • 项目类别:
mTOR signaling and regulation of alpha-cell mass and function
mTOR 信号传导以及 α 细胞质量和功能的调节
  • 批准号:
    10620230
  • 财政年份:
    2016
  • 资助金额:
    $ 39.82万
  • 项目类别:
mTOR signaling and regulation of alpha-cell mass and function
mTOR 信号传导以及 α 细胞质量和功能的调节
  • 批准号:
    9884855
  • 财政年份:
    2016
  • 资助金额:
    $ 39.82万
  • 项目类别:

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ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
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