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。