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
- 批准号:10597680
- 负责人:
- 金额:$ 42.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptive TransferAllogenicAntigensApoptosisAutoimmuneAutoimmune DiseasesB Cell ProliferationB-LymphocytesBeta CellBiological ProcessCD8-Positive T-LymphocytesCell DeathCell SizeCell SurvivalCell divisionCell physiologyComplementComplexDataDevelopmentDiabetes MellitusDiabetes preventionDiseaseEIF4EBP1 geneEnvironmentFRAP1 geneGenderGlucoseGrowthGrowth FactorIGFBP2 geneIRS2 geneImmune TargetingImmune responseImmune systemIn VitroIncidenceInfiltrationInflammatoryInjuryInsulin ResistanceInsulin-Dependent Diabetes MellitusKnowledgeLipidsLymphocyteLymphocyte ActivationLymphoidMediatingMessenger RNAMetabolismModelingMolecularMolecular ProfilingMusNon-Insulin-Dependent Diabetes MellitusNutrientPathway interactionsPatientsPhenotypePhosphorylationPopulationPreventionProliferatingProteinsPublishingRegulationRegulatory T-LymphocyteRoleSCID MiceSelf ToleranceSignal TransductionSkin TransplantationSplenocyteT cell responseT-LymphocyteTestingTherapeuticTissuesTranslation InitiationTranslationsUp-Regulationadaptive immunityautoreactive T cellcell regenerationcytokinecytotoxicdesigndiabetes controldrug developmenteffector T cellhuman diseaseimmunoregulationinflammatory milieuinsightinsulin secretioninsulitisisletlymphocyte proliferationmalemouse modelnovelnovel therapeutic interventionnovel therapeuticspharmacologicpreservationpreventresponsesensorsexual dimorphism
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/摘要
1型糖尿病(T1 D)是一种毁灭性疾病,在世界范围内发病率增加。拟定治疗
这种疾病的治疗集中在β细胞的保存和免疫调节上。的mTOR
复合物1(mTORC 1)是一种营养传感器,通过作用于S6 K和4 E-
BPs是mTORC 1的两个主要下游靶点。4 E-BP被mTORC 1过度磷酸化,导致其
从eIF 4 E释放和促进翻译起始。通过4 E-BP 2激活4 E-BP 2/eIF 4 E途径
缺失通过上调IRS 2水平诱导β细胞扩增和增殖。除了β细胞,
mTORC 1/4 E-BP轴对适应性免疫的调节也至关重要。初步研究表明,4 E-
BP 2缺失在体外对β细胞具有促存活作用,对抗促炎细胞的细胞毒性作用。
细胞因子,T1 D中β细胞死亡的原因。在NOD中使用新产生的全球4 E-BP 2缺陷小鼠
背景(4 E-BP 2KONOD),初步研究表明,90%的雄性(非雌性)小鼠受到保护,
通过保留β细胞群来预防T1 D的发展。此外,NOD.scid小鼠的过继转移研究
结果显示,接受来自4 E-BP 2KONOD小鼠的脾细胞的小鼠比接受来自4 E-BP 2KONOD小鼠的脾细胞的小鼠患糖尿病的程度显著降低。
对照组接受来自WT小鼠的脾细胞。这表明抑制4 E-BP 2/eIF 4 E相互作用可以抑制4 E-BP 2/eIF 4 E相互作用。
通过潜在地保留功能性β细胞,减少细胞内的细胞毒性,
自身免疫损伤和增强β细胞再生。然而,4 E-BP 2缺失如何保护β细胞
从自身免疫损伤,并诱导免疫调节作用和潜在的性别二型性,这
表型未知。我们的假设是4 E-BP 2缺失通过两种不同的机制逆转T1 D:1. .
在T1 D炎症环境中增加存活和保存β细胞功能,以及2.调制
淋巴细胞产生免疫反应的能力。以下目标将检验这一假设:目标1。到
确定4 E-BP 2缺失对β细胞存活的贡献和介导的分子机制,
在T1 D和Aim 2的背景下发挥作用。揭示4 E-BP 2缺失如何诱导免疫调节作用
保护T1 D。此外,评估β细胞或免疫系统在性别中的作用的研究
糖尿病保护的双态表型将补充这些目标。拟议的研究将填补
重要的知识差距,通过提供对4 E-BP 2/eIF 4 E激活作为药理学靶点的见解,
T1 D治疗这样的结果将产生积极的影响,因为这一目标将作为一个平台,
新的治疗策略,以扩大糖尿病药物的开发。
项目成果
期刊论文数量(0)
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:
$ 42.36万 - 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:
10417417 - 财政年份:2022
- 资助金额:
$ 42.36万 - 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:
$ 42.36万 - 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:
$ 42.36万 - 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:
$ 42.36万 - 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:
$ 42.36万 - 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:
$ 42.36万 - 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:
$ 42.36万 - 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:
$ 42.36万 - 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:
$ 42.36万 - 项目类别:
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