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

基本信息

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
项目类别：
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

项目摘要

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，这是我们之前和未来的长期目标。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在当前的资助期间，我们确定 mTOR/raptor 复合物 (mTORC1) 是其中的主要参与者。我们发现了 mTORC1 的个体贡献。下游靶标 4E-BP、S6 激酶 (S6K) 和 ULK 对  细胞生长、增殖、我们还发现了一种新的 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的目的是构建。我们根据这些观察结果确定 mTORC1 如何调节  细胞质量和胰岛素分泌。培养 mTORC1 以 4E-BP2/SH2B1 和 JNK3 依赖性方式调节 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。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。确定 mTORC1 如何调节胰岛素分泌和适应糖尿病条件。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。