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

Akt/mTOR 信号传导和 β 细胞细胞周期的调节

• 批准号: 8244194
• 负责人: Ernesto Bernal-Mizrachi
• 金额: $ 34.17万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244194
• 关键词: Amino Acids; Apoptosis; Attenuated; Award; Beta Cell; Cell Count; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cell Size; Cell physiology; Cells; Complex; Data; Diabetes Mellitus; Equilibrium; Eukaryotic Initiation Factor-4E; Exhibits; Failure; Feedback; Funding; Genetic Models; Glucose; Goals; Growth; Growth Factor; IRS1 gene; IRS2 gene; Individual; Insulin; Insulin Resistance; Knowledge; Link; Mediating; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; PDPK1 gene; Pathway interactions; Physiological; Play; Process; Raptors; Regulation; Ribosomal Protein S6 Kinase; Role; Signal Pathway; Signal Transduction; TSC1/2 gene; Testing; Tuberous sclerosis protein complex; Uncertainty; Work; attenuation; cell growth regulation; design; diabetes management; drug development; extracellular; human FRAP1 protein; improved; insight; novel therapeutics; research study; response

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.

描述（由申请人提供）：细胞对胰岛素抵抗的扩张能力对2型糖尿病的发展至关重要，而细胞增殖是这些适应性反应的主要组成部分。我们之前和提议的研究的长期目标是了解调节细胞质量的分子机制，重点是增殖。在目前的资助期内，我们专注于Akt和结节硬化复合体2 （TSC2）调节细胞质量和细胞周期进程的机制。这些研究确定了TSC2和mTOR/raptor复合物（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还介导一个负反馈回路来减弱Akt信号。然而，mTORC1控制细胞扩增的潜在机制和关键下游效应物仍然不确定。本应用程序的目的是了解mTORC1靶点如何调节细胞质量和增殖。我们假设mTORC1信号传导介导的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。具体目的是：(1)确定mTORC1靶点如何调节细胞质量扩增。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)确定mtorc1介导的负反馈介导的Akt信号减少如何调节细胞团扩增。这些实验将评估GSK3¿和FoxO在mTORC1-S6K介导的IRS/Akt信号反馈抑制中的作用。这一建议将为mTORC1控制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的开发机会。