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.

糖尿病是影响人类健康的最普遍的疾病之一，包括21世纪的退伍军人。 世纪。我们努力了解这种疾病的发病机制和治疗方法的大部分重点是 集中在两个主要组成部分：胰岛素敏感性和胰岛素分泌。然而，胰高血糖素的失调 分泌物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型糖尿病的高血糖症，并对血糖波动性和对糖尿病的易感性有重大影响。 1型糖尿病的治疗我们在本资助期内发表的观察结果表明， 在胰岛素/Akt的下游，营养敏感途径（mTOR/Raptor或mTORC 1）在以下方面起主要作用： 调节α细胞质量和胰高血糖素分泌。然而，mTORC 1如何作用于关键下游 靶点（4 E-BP和S6 K）调节体内α细胞的功能和质量， 这些目标的葡萄糖代谢的调节仍不清楚。这些研究的长期目标是 揭示营养敏感性胰岛素/Akt/mTORC 1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mTORC 1功能的丧失导致 α细胞质量和胰高血糖素分泌的主要异常。我们还证明了mTORC 1的增加 导致慢性高胰高血糖素血症和α细胞团扩张，表明该信号通路是 对α细胞质量和胰高血糖素分泌至关重要。基于这些观察，我们假设， mTORC 1主要通过S6 K和4 E-BP信号之间的平衡来调节α细胞质量。具体目标 将通过建立以下作用来评估mTORC 1下游靶点的个体贡献： mTORC 1/4 E-BP/eIF 4 E轴在调节α细胞质量、胰高血糖素分泌和适应 使用新的α细胞特异性模型的糖尿病发生条件。此外，我们还将确定 mTORC 1/S6 K对α-细胞质量和胰高血糖素分泌的控制 α细胞中S6 K功能的可诱导增益。最后，mTORC 1激活如何改变人类α细胞 将使用人胰岛移植在前房中的模型来确定反应。 老鼠眼这一建议将提供重要的见解的分子机制，管理α细胞 通过mTORC 1进行质量膨胀。这些信息可用于发现新的靶点， 治疗糖尿病和设计干预措施，以挽救胰高血糖素分泌缺陷， 糖尿病患者的低血糖。