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
• 负责人: Ernesto Bernal-Mizrachi
• 金额: $ 42.36万
• 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/10597680
• 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; Phenotype; Phosphorylation; Population; Prevention; Proliferating; 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; pharmacologic; 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）是一种毁灭性疾病，世界上发病率增加。拟议的治疗性 该疾病的疗法集中于保存β细胞和免疫调节。 mtor 养分传感器的复合物1（MTORC1）通过作用于S6K和4E-- BPS，MTORC1的两个主要下游目标。 4e-bps通过MTORC1过度磷酸化，从而导致其 从EIF4E释放和促进翻译启动。 4E-BP2激活4E-BP2/EIF4E途径 缺失通过IRS2水平的上调诱导β细胞扩张和增殖。除了β细胞， MTORC1/4E-BP轴对于调节适应性免疫也至关重要。初步研究表明4E- BP2缺失在体外对β细胞具有利用效果，以对促炎的细胞毒性作用 细胞因子，T1D中β细胞灭亡的原因。在点头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，有90％的雄性（非雌性）小鼠受到保护 通过保留β细胞量来开发T1D。此外，对小鼠的收养转移研究 表明从4e-bp2konod小鼠接受脾细胞的小鼠患糖尿病明显少于 从WT小鼠接收脾细胞的对照。这表明抑制4e-bp2/eif4e相互作用可能 通过潜在地保留功能性β细胞，减少功能性β细胞，成为T1D的有希望的治疗策略 自身免疫性损伤和增强β细胞再生。但是，4E-BP2缺失如何保护β细胞 自身免疫性损伤并诱导免疫调节作用以及潜在的性二态性 表型未知。我们的假设是4E-BP2删除将T1D逆转到两种不同的机制：1。 在T1D炎症环境中增强生存和保存β细胞功能，并调节2。 淋巴细胞安装免疫反应的能力。以下目的将检验以下假设：目标1。 确定由4E-BP2缺失介导的β细胞存活和 在T1D和AIM 2的背景下功能。发现4E-BP2缺失如何诱导免疫调节作用 防止T1D。此外，研究评估β细胞或免疫系统在性别中的贡献 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4E-BP2/EIF4E激活作为药理学目标的重要知识差距 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平台 扩大糖尿病药物开发的新型治疗策略。