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
• 负责人: Ernesto Bernal-Mizrachi
• 金额: $ 44.66万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-11 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093016
• 关键词: Amino Acids; Anabolism; Apoptosis; Autophagocytosis; Award; B Cell Proliferation; B-Lymphocytes; Beta Cell; Binding Proteins; Calcium; Cell Cycle Regulation; Cell Size; Cell Survival; Cells; Complex; Coupling; Cytokine Receptors; Defect; Diabetes Mellitus; Eukaryotic Initiation Factors; FRAP1 gene; Failure; Feedback; Funding; Glucose; Goals; Growth; Growth Factor; Human; IGFBP2 gene; IRS1 gene; IRS2 gene; Individual; Insulin; Insulin Resistance; Knowledge; Link; MAPK10 gene; Mediating; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Overnutrition; Pathway interactions; Pharmacology; Play; Process; Proinsulin; Proto-Oncogene Proteins c-akt; Publishing; Raptors; Receptor Protein-Tyrosine Kinases; Regulation; Research; Ribosomal Protein S6 Kinase; Role; SH2B gene; Signal Pathway; Signal Transduction; Sirolimus; Stimulus; TSC1 gene; TSC1/2 gene; Testing; Tuberous sclerosis protein complex; Uncertainty; cell growth regulation; cytokine; design; diabetes management; diabetogenic; drug development; experimental study; extracellular; improved; in vivo; insight; insulin secretion; islet; novel; novel therapeutic intervention; response

Project Summary/Abstract The capacity of β-cells to expand in response to insulin resistance is critical to develop type-2 diabetes and β- cell proliferation is a major component for these adaptive responses. The long-term goal of our previous and proposed studies under this award is to understand the molecular mechanisms that regulate β-cell mass and function. During the current funding period, we identified mTOR/raptor complex (mTORC1) as a major player in regulating β-cell mass and insulin secretion. We uncovered the individual contribution of the mTORC1 downstream targets 4E-BP, S6 kinases (S6K) and ULK on the regulation of -cell growth, proliferation, survival, insulin processing and secretion. We also discovered a novel mTORC1/4E-BP2/eIF4E/SH2B1 positive feedback loop that increases IRS2 signaling. However, uncertainty remains as to how mTORC1 acting on 4E-BP2, S6K and ULK controls -cell mass and insulin secretion. The objective of this application is to build on these observations and determine how mTORC1 regulates -cell mass and insulin secretion. We hypothesize that mTORC1 regulates (i) β-cell mass in a 4E-BP2/SH2B1 and JNK3-dependent manner and (ii) insulin secretion by regulating stages proximal to calcium influx and autophagy mediated process. The specific aims are (1) Establish how 4E-BP2/eIF4E acting on SH2B1 and JNK3 regulates β-cell mass expansion. (2) Determine how mTORC1 modulates insulin secretion and adaptation to diabetogenic conditions. This proposal will provide important insights into the molecular mechanisms that govern β-cell mass and insulin secretion by mTORC1. This information can be used to expand drug development opportunities for diabetes.

项目概要/摘要 β 细胞响应胰岛素抵抗而扩张的能力对于发展 2 型糖尿病和 β- 细胞增殖是这些适应性反应的主要组成部分。我们过去和现在的长期目标 该奖项提出的研究旨在了解调节 β 细胞质量的分子机制和 功能。在当前的资助期间，我们确定 mTOR/raptor 复合物 (mTORC1) 是 调节β细胞质量和胰岛素分泌。我们发现了 mTORC1 的个人贡献 下游靶标 4E-BP、S6 激酶 (S6K) 和 ULK 对  细胞生长、增殖、 生存、胰岛素加工和分泌。我们还发现了一个新的mTORC1/4E-BP2/eIF4E/SH2B1 增强 IRS2 信号传导的正反馈回路。然而，mTORC1 如何发挥作用仍存在不确定性 4E-BP2、S6K 和 ULK 控制  细胞质量和胰岛素分泌。该应用程序的目标是构建 根据这些观察结果并确定 mTORC1 如何调节  细胞质量和胰岛素分泌。我们 假设 mTORC1 以 4E-BP2/SH2B1 和 JNK3 依赖性方式调节 (i) β 细胞质量，以及 (ii) 通过调节钙流入和自噬介导过程的近端阶段来调节胰岛素分泌。具体的 目标是 (1) 确定 4E-BP2/eIF4E 如何作用于 SH2B1 和 JNK3 调节 β 细胞质量扩张。 (2) 确定 mTORC1 如何调节胰岛素分泌和适应糖尿病条件。这个提议 将为控制 β 细胞质量和胰岛素分泌的分子机制提供重要的见解 mTORC1。该信息可用于扩大糖尿病药物开发机会。