mTOR signaling and regulation of alpha-cell mass and function

mTOR 信号传导以及 α 细胞质量和功能的调节

• 批准号: 9884855
• 负责人: Ernesto Bernal-Mizrachi
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884855
• 关键词: Acids; Affect; Alpha Cell; Amino Acids; Animal Experiments; B-Lymphocytes; Beta Cell; Cell Line; Cells; Chronic; Clinical Data; Complex; Data; Defect; Diabetes Mellitus; Disease; EIF4EBP1 gene; Equilibrium; Exhibits; Eye; FRAP1 gene; Functional disorder; Funding; Generations; Genetic; Genetic Models; Glucagon; Glucagon Receptor; Glucose; Goals; Health; Human; Hyperglycemia; Hypoglycemia; IGFBP2 gene; Individual; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Knowledge; Liver; Metformin; Modeling; Molecular; Molecular Genetics; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Overnutrition; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Predisposition; Publishing; Raptors; Receptor Signaling; Regulation; Research; Rodent Model; Role; Signal Pathway; Signal Transduction; Sirolimus; TSC1 gene; TSC2 gene; Testing; Time; Uncertainty; Veterans; anterior chamber; base; blood glucose regulation; design; diabetes control; diabetes management; diabetogenic; drug development; experimental study; glucose metabolism; human model; hyperglucagonemia; improved; in vivo; insight; insulin secretion; insulin sensitivity; islet; novel; novel strategies; novel therapeutics; physiologic model; prevent; reconstitution; response; therapy design

Diabetes mellitus is one of the most prevalent conditions affecting human health including veterans in the 21st century. Most of the focus of our efforts to understand the pathogenesis and therapy of the disease has focused on two major components: insulin sensitivity and insulin secretion. However, dysregulation in glucagon secretion is a major component in diabetes. Hyperglucagonemia plays key roles in the pathogenesis of hyperglycemia in type 2 diabetes and has a major impact in the glycemic volatility and susceptibility to hypoglycemia in type 1 diabetes. Our observations published during the current funding period suggest that downstream of insulin/Akt, the nutrient sensitive pathway (mTOR/Raptor or mTORC1) plays a major role in regulation of alpha cell mass and glucagon secretion. However, how mTORC1 acting on key downstream targets (4E-BPs and S6K) regulates the function and mass of alpha-cells in vivo and the potential contribution of these targets to the regulation of glucose metabolism remain unclear. The long-term goal of these studies is to uncover how the nutrient sensitive insulin/Akt/mTORC1 axis regulates α-cell mass and glucagon secretion in rodent models and humans. Our studies showed that loss of mTORC1 function in alpha-cells results in major abnormalities in alpha-cell mass and glucagon secretion. We also demonstrate that gain of mTORC1 results in chronic hyperglucagonemia and alpha cell mass expansion suggesting that this signaling pathway is critical for alpha cell mass and glucagon secretion. Based on these observations, we hypothesize that mTORC1 regulates alpha-cell mass mainly by a balance between S6K and 4E-BP signaling. The specific aims will assess the individual contribution of downstream targets of mTORC1 by establishing the role of mTORC1/4E-BP/eIF4E axis in regulation of alpha-cell mass, glucagon secretion and adaptation to diabetogenic conditions using novel alpha cell specific models. In addition, we will also identify the importance of mTORC1/S6K on the control of alpha-cell mass and glucagon secretion by generation of novel models with inducible gain of S6K function in alpha cells. Finally, how mTORC1 activation alters human alpha-cell responses will be determined using a model of human islet transplantation in the anterior chamber of the mouse eye. This proposal will provide important insights into the molecular mechanisms that govern alpha-cell mass expansion by mTORC1. This information can be used to uncover novel targets that can be used for treatment of diabetes and design interventions to rescue the defects in glucagon secretion in response to hypoglycemia in patients with diabetes.

糖尿病是21世纪影响人类健康（包括退伍军人）最普遍的疾病之一 世纪。我们努力了解该疾病的发病机制和治疗的大部分重点是 重点关注两个主要组成部分：胰岛素敏感性和胰岛素分泌。然而，胰高血糖素失调 分泌是糖尿病的主要成分。高胰高血糖素血症在糖尿病的发病机制中起关键作用 2 型糖尿病中的高血糖对血糖波动性和易感性有重大影响 1 型糖尿病中的低血糖。我们在当前资助期间发表的观察结果表明 在胰岛素/Akt 下游，营养敏感通路（mTOR/Raptor 或 mTORC1）在 调节α细胞质量和胰高血糖素分泌。然而，mTORC1如何作用于关键下游 靶标（4E-BP 和 S6K）调节体内 α 细胞的功能和质量及其潜在贡献 这些目标对葡萄糖代谢的调节仍不清楚。这些研究的长期目标是 揭示营养敏感的胰岛素/Akt/mTORC1轴如何调节α细胞质量和胰高血糖素分泌 在啮齿动物模型和人类中。我们的研究表明，α 细胞中 mTORC1 功能的丧失会导致 α细胞质量和胰高血糖素分泌的主要异常。我们还证明了 mTORC1 的增益 结果导致慢性高胰高血糖素血症和α细胞质量扩张，表明该信号通路是 对于α细胞质量和胰高血糖素分泌至关重要。根据这些观察，我们假设 mTORC1 主要通过 S6K 和 4E-BP 信号传导之间的平衡来调节 α 细胞质量。具体目标 将通过确定 mTORC1 下游靶标的作用来评估 mTORC1 下游靶标的个体贡献 mTORC1/4E-BP/eIF4E 轴调节 α 细胞质量、胰高血糖素分泌和适应 使用新型α细胞特定模型研究糖尿病发生条件。此外，我们还将确定重要性 mTORC1/S6K 通过生成新模型来控制 α 细胞质量和胰高血糖素分泌 α细胞中S6K功能的诱导增益。最后，mTORC1 激活如何改变人类 α 细胞 将使用前房中的人类胰岛移植模型来确定反应 老鼠的眼睛。该提案将为控制α细胞的分子机制提供重要的见解 mTORC1 的质量扩张。该信息可用于发现可用于 治疗糖尿病并设计干预措施来挽救胰高血糖素分泌缺陷 糖尿病患者的低血糖。