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

项目摘要/摘要 β细胞对胰岛素抵抗的反应能力是患2型糖尿病和β的关键 细胞增殖是这些适应性反应的主要组成部分。我们以前和现在的长期目标 根据该奖项提议的研究是为了了解调节β-细胞质量和 功能。在目前的资助期间，我们确定mTOR/Raptor Complex(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 下游靶向4E-BP、S6激酶(S6K)和ULK调控-细胞的生长、增殖、 生存、胰岛素的加工和分泌。我们还发现了一个新的mTORC1/4E-BP2/eIF4E/SH2B1 增加IRS2信令的正反馈环路。然而，mTORC1如何发挥作用仍不确定 在4E-BP2上，S6K和ULK控制细胞质量和胰岛素的分泌。此应用程序的目标是构建 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依赖的方式调节(I)β细胞质量和(Ii) 通过调节钙离子内流和自噬调节过程中的胰岛素分泌。具体的 目的：(1)研究4E-BP2/eIF4E对SH2B1和JNK3细胞增殖的调节作用；(2) 确定mTORC1如何调节胰岛素分泌和对糖尿病发生条件的适应。这项建议 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.这些信息可以用来扩大糖尿病的药物开发机会。

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.