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

描述(由申请人提供)：细胞对胰岛素抵抗的反应能力是发展2型糖尿病的关键，细胞增殖是这些适应性反应的主要组成部分。我们之前和该奖项下拟议的研究的长期目标是了解调控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(TSC2)调节细胞质量和细胞周期进展的机制。这些研究确定TSC2和mTOR/Raptor复合体(MTORC1)是调节细胞质量和增殖的重要分子。MTORC1通过激活4E-BP和S6激酶(S6K)来控制生长和增殖。此外，mTORC1还介导了一个负反馈环来减弱Akt信号。然而，对于mTORC1控制的细胞扩张的潜在机制和关键下游效应器仍然存在不确定性。这个应用的目的是了解mTORC1靶标如何调节细胞质量和增殖。我们假设，mTORC1信号通过激活下游靶点和负反馈抑制IRS/Akt信号之间的平衡来调节细胞质量的扩张。具体目标是(1)确定mTORC1靶标如何调节细胞质量扩张。这些研究将评估S6K1和4E-BP在调节细胞生长和增殖方面的单独贡献。(2)通过mTORC1介导的负反馈，确定Akt信号的减少如何调节细胞团的扩张。这些实验将评估GSK3和FoxO在mTORC1-S6K介导的反馈抑制IRS/Akt信号转导中的作用。这一提议将为mTORC1控制细胞质量扩张的分子机制提供重要的见解。这些信息可以用来扩大糖尿病的药物开发机会。 公共卫生相关性：细胞不能扩增或适应胰岛素抵抗会导致2型糖尿病。目前的证据支持这一概念，即mTORC1在胰岛素需求增加的状态下是活跃的，并在细胞对胰岛素抵抗的适应中发挥主要作用。这项应用的目标是揭示mTORC1如何调节细胞质量，以努力开发策略，以确定药物靶点，以改善糖尿病治疗的细胞质量和功能。

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.