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：
9913511
负责人：
Ernesto Bernal-Mizrachi
金额：
$ 45.55万
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/9913511
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 therapeutics 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.

项目摘要/摘要 β细胞响应胰岛素耐药性扩展的能力对于发展2型糖尿病和β-至关重要细胞增殖是这些自适应反应的主要组成部分。我们以前和以前的长期目标根据该奖项提出的研究是了解调节β细胞质量和的分子机制功能。在当前的资金期间，我们确定MTOR/RAPTOR综合体（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为4E-BP，S6激酶（S6K）和ULK靶向细胞生长，增殖，增殖，生存，胰岛素加工和分泌。我们还发现了一种新颖的MTORC1/4E-BP2/EIF4E/SH2B1 正反馈循环增加IRS2信号传导。但是，关于MTORC1如何表现仍然存在不确定性在4E-BP2上，S6K和ULK控制细胞质量和胰岛素分泌。该应用程序的目的是构建在这些观察结果上，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，并且（II）通过调节钙影响和自噬介导过程的阶段来调节胰岛素分泌。具体目的是（1）确定4E-BP2/EIF4E在SH2B1上的作用如何调节β细胞质量膨胀。（2）确定MTORC1如何调节胰岛素的分泌并适应糖尿病疾病。这个建议将提供有关控制β细胞质量和胰岛素分泌的分子机制的重要见解 mtorc1。这些信息可用于扩大糖尿病的药物开发机会。