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
• 负责人: Ernesto Bernal-Mizrachi
• 金额: $ 39.82万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10417417
• 关键词: Address; Adoptive Transfer; Allogenic; Antigens; Apoptosis; Autoimmune; Autoimmune Diseases; B Cell Proliferation; B-Lymphocytes; Beta Cell; Biological Process; CD8-Positive T-Lymphocytes; Cell Death; Cell Size; Cell Survival; Cell division; Cell physiology; Complement; Complex; Data; Development; Diabetes Mellitus; Diabetes prevention; Disease; EIF4EBP1 gene; Environment; FRAP1 gene; Gender; Glucose; Growth; Growth Factor; IGFBP2 gene; IRS2 gene; Immune Targeting; Immune response; Immune system; In Vitro; Incidence; Infiltration; Inflammatory; Injury; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Knowledge; Lipids; Lymphocyte; Lymphocyte Activation; Lymphoid; Mediating; Messenger RNA; Metabolism; Modeling; Molecular; Molecular Profiling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphorylation; Population; Prevention; Proteins; Publishing; Regulation; Regulatory T-Lymphocyte; Role; SCID Mice; Self Tolerance; Signal Transduction; Skin Transplantation; Splenocyte; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Translation Initiation; Translations; Up-Regulation; adaptive immunity; autoreactive T cell; cell regeneration; cytokine; cytotoxic; design; diabetes control; drug development; effector T cell; human disease; immunoregulation; inflammatory milieu; insight; insulin secretion; insulitis; islet; lymphocyte proliferation; male; mouse model; novel; novel therapeutic intervention; novel therapeutics; preservation; prevent; response; sensor; sexual dimorphism

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.

项目摘要/摘要 1型糖尿病(T1D)是一种严重危害人类健康的疾病，在世界范围内发病率呈上升趋势。建议的治疗方法 这种疾病的治疗方法主要集中在保存β细胞和免疫调节上。MTOR 复合体1(MTORC1)是一种营养感受器，通过作用于S6K和4E-来调节β细胞的质量和增殖。 Bps，mTORC1的两个主要下游目标。4E-Bps被mTORC1过度磷酸化，导致其 从eIF4E中释放并促进翻译启动。4E-BP2激活4E-BP2/eIF4E通路 缺失通过上调IRS2水平来诱导β细胞的扩张和增殖。除了贝塔细胞， MTORC1/4E-BP轴对获得性免疫的调节也是至关重要的。初步研究表明，4E- BP2缺失在体外对β细胞的生存作用对抗促炎的细胞毒作用 细胞因子，这是T1D中β细胞死亡的原因。使用新产生的全球4E-BP2缺陷小鼠在NOT中 背景(4E-BP2KONOD)，初步研究表明，90%的雄性(非雌性)小鼠受到保护 通过保存β细胞团来发育T1D。此外，过继转移到NOD.SCID小鼠体内的研究 结果显示，接受4E-BP2KONOD小鼠脾细胞的小鼠患糖尿病的几率显著低于 对照组接受来自WT小鼠的脾细胞。这表明抑制4E-BP2/eIF4E相互作用可能 是一种有希望的治疗T1D的策略，通过潜在地保留功能的β细胞，减少 自身免疫损伤和促进β细胞再生。然而，4E-BP2缺失是如何保护β细胞的 从自身免疫损伤和诱导的免疫调节作用和潜在的性二型性 表型尚不清楚。我们的假设是，4E-BP2缺失通过两种不同的机制逆转了T1D：1。 在T1D炎症环境中增加存活和保护β细胞功能，以及2.调节 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.至 确定4E-BP2缺失对β细胞存活的贡献及其分子机制 4E-BP2缺失是如何诱导免疫调节效应的 以保护免受T1D的侵袭。此外，评估贝塔细胞或免疫系统在性别中的贡献的研究 糖尿病保护的两种表型将补充这些目标。拟议的研究将填补 通过提供对4E-BP2/eIF4E激活的洞察作为治疗的药理学靶点，提供重要的知识差距 T1D治疗。这样的结果将产生积极的影响，因为这一目标将成为设计 扩大糖尿病药物开发的新治疗策略。