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.

项目概要/摘要 1 型糖尿病 (T1D) 是一种毁灭性的疾病，在世界范围内发病率不断上升。建议治疗 这种疾病的治疗重点是保存β细胞和免疫调节。 mTOR 复合物 1 (mTORC1) 是一种营养传感器，通过作用于 S6K 和 4E- 来调节 β 细胞质量和增殖 BPs，mTORC1 的两个主要下游靶标。 4E-BP 被 mTORC1 过度磷酸化，导致其 eIF4E 的释放和翻译起始的促进。 4E-BP2 激活 4E-BP2/eIF4E 通路 缺失通过上调 IRS2 水平诱导 β 细胞扩增和增殖。除了β细胞外， mTORC1/4E-BP 轴对于适应性免疫的调节也至关重要。初步研究表明 4E- BP2 缺失对体外 β 细胞具有抗促炎细胞毒性作用的促存活作用 细胞因子，T1D 中 β 细胞死亡的一个原因。在 NOD 中使用新生成的全局 4E-BP2 缺陷小鼠 背景（4E-BP2KONOD），初步研究表明 90% 的雄性（非雌性）小鼠受到保护 通过保留 β 细胞量来预防 T1D 的发展。此外，对 NOD.scid 小鼠的过继转移研究 结果表明，接受 4E-BP2KONOD 小鼠脾细胞的小鼠患糖尿病的几率明显低于接受 4E-BP2KONOD 小鼠的脾细胞的小鼠 对照组接受来自 WT 小鼠的脾细胞。这表明抑制 4E-BP2/eIF4E 相互作用可以 通过潜在地保留功能性 β 细胞、减少 自身免疫损伤和增强β细胞再生。然而，4E-BP2 缺失如何保护 β 细胞 免受自身免疫损伤并诱导免疫调节作用和潜在的性别二态性 表型未知。我们的假设是 4E-BP2 缺失通过两种不同的机制逆转 T1D： 1. . 增强 T1D 炎症环境中的存活率并保护 β 细胞功能，以及 2. 调节 淋巴细胞发起免疫反应的能力。以下目标将检验这一假设： 目标 1. 确定 4E-BP2 缺失对 β 细胞存活的贡献和分子机制 在 T1D 背景下发挥作用，目标 2：揭示 4E-BP2 缺失如何诱导免疫调节作用 预防 T1D。此外，还有评估 β 细胞或免疫系统对性别的贡献的研究 糖尿病保护的二态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 激活作为药理学靶点的见解，弥补了重要的知识差距 T1D 治疗。这样的结果将产生积极的影响，因为该目标将作为设计的平台 扩大糖尿病药物开发的新治疗策略。