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

描述（由申请人提供）：<$-细胞响应胰岛素抵抗而扩增的能力对于发展2型糖尿病至关重要，<$-细胞增殖是这些适应性反应的主要组成部分。我们以前的长期目标和拟议的研究根据这个奖项是调节的分子机制的理解细胞质量与增殖的重点。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）作为调节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，关于负责mTORC 1控制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靶点如何调节细胞质量和增殖。我们假设，- mTORC 1信号传导引起的细胞质量扩增由两个过程之间的平衡介导：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信号传导调节细胞质量扩增。这些实验将评估GSK 3和FoxO对mTORC 1-S6 K介导的IRS/Akt信号传导反馈抑制的作用。该提议将为mTORC 1控制细胞质量扩增的分子机制提供重要见解。这些信息可用于扩大糖尿病药物开发机会。 公共卫生相关性：2型糖尿病患者的胰岛细胞不能扩增或适应胰岛素抵抗。目前的证据支持这样的概念，即mTORC 1在胰岛素需求增加的状态下是有活性的，并且在胰岛细胞适应胰岛素抵抗中起主要作用。本申请的目标是揭示mTORC 1如何调节胰岛细胞质量，以努力开发鉴定药理学靶点的策略，从而改善胰岛细胞质量和功能，用于治疗糖尿病。

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. PUBLIC HEALTH RELEVANCE: Failure of ¿-cells to expand or adapt to insulin resistance results in type 2 diabetes. The current evidence support the concept that mTORC1 is active in states of increased insulin demand and plays a major role in ¿- cell adaptation to insulin resistance The goal of this application is to unravel how mTORC1 regulates ¿-cell mass in an effort to develop strategies to identify pharmacological targets to improve ¿-cell mass and function for the treatment of diabetes.