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: 9171979
• 负责人: Ernesto Bernal-Mizrachi
• 金额: $ 23.97万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 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 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171979
• 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.

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，而�细胞的增殖是这些适应性反应的主要组成部分。该奖项下我们先前和提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，我们重点研究了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程的机制。这些研究确定TSC2和mTOR/Raptor复合体(MTORC_1)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mTORC1c控制的�细胞扩增的潜在机制和关键下游效应器的不确定性仍然存在。这项应用的目的是了解mTORC1靶如何调控�细胞的质量和增殖。我们假设mTORC 1信号转导的�细胞质量扩张是由两个过程之间的平衡调节的：激活下游靶标和负反馈抑制IRS/AKT信号。具体目的是(1)确定mTORC1靶基因如何调控�细胞的大量扩增。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)研究mTORC_1介导的负反馈抑制Akt信号对�细胞增殖的调节作用。这些实验将评估GSK3、�和FoxO在mTORC1S6K介导的反馈抑制IRSAkt信号通路中的作用。这一提议将为控制mTORC1mTORC1a-�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。