AKT/mTOR signaling and regulation of cell cycle in B-cells

项目总结/摘要 β-细胞响应胰岛素抵抗而扩增的能力对于发展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。我们的长期目标， 该奖项下的拟议研究是了解调节β细胞质量的分子机制， 功能在目前的资助期间，我们确定mTOR/raptor复合体（mTORC 1）是一个主要的参与者， 调节β细胞质量和胰岛素分泌。我们发现了mTORC 1的个体贡献 下游靶向4 E-BP、S6激酶（S6 K）和ULK对肿瘤细胞生长、增殖 存活、胰岛素加工和分泌。我们还发现了一个新的mTORC 1/4 E-BP 2/eIF 4 E/SH 2B 1 增加IRS 2信号传导的正反馈回路。然而，关于mTORC 1如何发挥作用仍然存在不确定性。 对4 E-BP 2、S6 K和ULK的作用控制胰岛β细胞质量和胰岛素分泌。该应用程序的目标是建立 并确定mTORC 1如何调节胰岛细胞质量和胰岛素分泌。我们 假设mTORC 1（i）以4 E-BP 2/SH 2B 1和JNK 3依赖性方式调节β细胞群，以及（ii） 胰岛素分泌通过调节邻近钙内流和自噬介导的过程的阶段。具体 目的是（1）确定4 E-BP 2/eIF 4 E如何作用于SH 2B 1和JNK 3调节β细胞团扩增。（二） 确定mTORC 1如何调节胰岛素分泌和适应致糖尿病条件。这项建议 将提供重要的见解的分子机制，管理β细胞质量和胰岛素分泌， mTORC 1。这些信息可用于扩大糖尿病药物开发机会。

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.