Akt/mTOR signaling and regulation of cell cycle in beta-cells

描述（由申请人提供）：β细胞响应胰岛素抵抗而扩增的能力对发展2型糖尿病至关重要，β细胞增殖是这些适应性反应的主要组成部分。我们以前和拟议中的研究的长期目标是了解调节β细胞质量的分子机制，重点是增殖。在目前的资助期间，我们专注于Akt和结节性硬化症复合体2（TSC 2）调节β细胞质量和细胞周期进程的机制。这些研究确定了TSC 2和mTOR/raptor复合物（mTORC 1）是调节β细胞质量和增殖的重要分子。mTORC 1通过激活4 E-BP和S6激酶（S6 K）控制生长和增殖。此外，mTORC 1还介导负反馈回路以减弱Akt信号传导。然而，关于mTORC 1控制β细胞扩增的潜在机制和关键下游效应物仍然存在不确定性。本申请的目的是了解mTORC 1靶点如何调节β细胞质量和增殖。我们假设mTORC 1信号传导引起的β细胞质量扩增是由两个过程之间的平衡介导的：下游靶点的激活和IRS/Akt信号传导的负反馈抑制。具体目标是（1）确定mTORC 1靶点如何调节β-细胞质量扩增。这些研究将评估S6 K1和4 E-BP对细胞生长和增殖调节的各自贡献。(2)确定mTORC 1介导的负反馈如何降低Akt信号传导调节β细胞质量扩增。这些实验将评估GSK 3 β和FoxO在mTORC 1-S6 K介导的IRS/Akt信号反馈抑制中的作用。这一提议将为mTORC 1控制β细胞质量扩增的分子机制提供重要的见解。这些信息可用于扩大糖尿病药物开发机会。

DESCRIPTION (provided by applicant): The capacity of �-cells to expand in response to insulin resistance is critical to develop type-2 diabetes and �-cell proliferation is a major component for these adaptive responses. The long-term goal of our previous and proposed studies under this award is the understanding of the molecular mechanisms that regulate �-cell mass with emphasis in proliferation. During the current funding period, we focused on the mechanisms by which Akt and the tuberous sclerosis complex 2 (TSC2) regulate �-cell mass and cell cycle progression. These studies identified the TSC2 and the mTOR/raptor complex (mTORC1) as important molecules regulating �-cell mass and proliferation. mTORC1 controls growth and proliferation by activation of 4E-BP and S6 kinases (S6K). Moreover, mTORC1 also mediates a negative feedback loop to attenuate Akt signaling. However, uncertainty remains as to the underlying mechanism and key downstream effectors responsible for controlled �-cell expansion by mTORC1. The objective of this application is to understand how mTORC1 targets regulate �-cell mass and proliferation. We hypothesize that �-cell mass expansion by mTORC1 signaling is mediated by a balance between two processes: activation of downstream targets and negative feedback inhibition of IRS/Akt signaling. The specific aims are (1) to establish how mTORC1 targets regulate �-cell mass expansion. These studies will evaluate the individual contributions of S6K1 and 4E-BP on regulation of cell growth and proliferation. (2) Determine how decreased Akt signaling by mTORC1-mediated negative feedback modulates �-cell mass expansion. These experiments will evaluate the role of GSK3� and FoxO on mTORC1-S6K mediated feedback inhibition on IRS/Akt signaling. This proposal will provide important insights into the molecular mechanisms that govern �-cell mass expansion by mTORC1. This information can be used to expand drug development opportunities for diabetes.