mTORC1 signaling and regulation of alpha-cell mass and function.

mTORC1 信号传导以及α细胞质量和功能的调节。

• 批准号: 9231264
• 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 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231264
• 关键词: Affect; Alpha Cell; Amino Acids; Animal Experiments; Animal Model; Beta Cell; Cell Line; Cell Proliferation; Cell physiology; Clinical Data; Complex; Diabetes Mellitus; Disease; Exhibits; FRAP1 gene; Genetic Models; Glucagon; Glucose; Goals; Growth Factor; Health; Human; Hyperglycemia; Hypoglycemia; IRS2 gene; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Knowledge; Liver; Maintenance; Mediating; Metabolic; Metabolism; Metformin; Molecular; Molecular Genetics; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Paracrine Communication; Pathogenesis; Pathogenicity; Pathway interactions; Physiological; Play; Predisposition; Process; Raptors; Receptor Signaling; Regulation; Research; Role; Sclerosis; Signal Transduction; Sirolimus; TSC1 gene; TSC1/2 gene; Testing; Tuberous sclerosis protein complex; blood glucose regulation; diabetes management; diabetes mellitus therapy; diabetogenic; drug development; experimental study; glucose metabolism; glucose output; hyperglucagonemia; in vivo; insight; insulin secretion; insulin sensitivity; insulin signaling; novel; novel therapeutics; physiologic model; public health relevance; targeted treatment

 DESCRIPTION (provided by applicant): Diabetes mellitus is one of the most prevalent conditions affecting human health 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, the current evidence suggests that hyperglucagonemia play major 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. The current evidence underscores the importance of the insulin/IRS2/Akt signaling on regulation of a-cell mass and glucagon secretion. However, how Akt signaling regulates the function and mass of a-cells in vivo and the potential contribution of this process to the regulation of glucose metabolism remain unclear. Downstream of Akt, TSC1/2 (Tuberous Sclerosis Complex) and mTOR/Raptor (mTORC1) emerge as prime candidates in this process, because they integrate signals from growth factors and nutrients. The long-term goal of these studies is to uncover how insulin/Akt signaling regulates a-cell mass and glucagon secretion. In preliminary experiments, we showed that loss of mTORC1 function in a-cells results in major abnormalities in a-cell mass and glucagon secretion. The objective of these studies is to build on these observations to understand how nutrient signaling regulates a-cell function and mass. We hypothesize that insulin signaling regulates a-cell mass and glucagon secretion mainly by modulation of mTORC1 signaling. The specific aims will determine how gain and loss of mTORC1 function modulates a-cell mass, glucagon secretion and adaptation to diabetogenic conditions. This proposal will provide important insights into the molecular mechanisms that govern a-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）： 糖尿病是影响21世纪人类健康的最普遍的疾病之一。我们努力理解该疾病的发病机理和治疗的大部分重点都集中在两个主要成分上：胰岛素敏感性和胰岛素分泌。然而，目前的证据表明，高谷藻血症在2型糖尿病中高血糖的发病机理中起着重要作用，并且对1型糖尿病的血糖波动性和对低血糖的易感性具有重大影响。当前的证据强调了胰岛素/IRS2/AKT信号传导对A细胞质量和胰高血糖素分泌的调节的重要性。但是，AKT信号如何调节体内A细胞的功能和质量以及该过程对调节葡萄糖代谢的潜在贡献尚不清楚。在此过程中，Akt，TSC1/2（结节硬化症复合物）和MTOR/RAPTOR（MTORC1）的下游是主要候选者，因为它们从生长因子和养分中整合了信号。这些研究的长期目标是揭示胰岛素/AKT信号如何调节A细胞质量和臀部分泌。在初步实验中，我们表明MTORC1功能在A细胞中的丧失会导致A细胞质量和谷歌分泌的主要异常。这些研究的目的是基于这些观察结果，以了解营养信号如何调节A细胞功能和质量。我们假设胰岛素信号传导主要通过调节MTORC1信号传导来调节A细胞质量和仰卧儿。具体的目的将决定MTORC1功能调制的增益和损失A细胞质量，谷歌分泌以及对糖尿病疾病的适应性。该提案将提供有关MTORC1 A细胞质量扩展的分子机制的重要见解。这些信息可用于扩大糖尿病的药物开发机会。