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。

基本信息

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
项目类别：
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

项目摘要

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21世纪影响人类健康的最普遍的疾病之一，我们了解该疾病的发病机制和治疗的大部分努力集中在两个主要组成部分：胰岛素敏感性和胰岛素分泌。有证据表明，高胰高血糖素血症在 2 型糖尿病高血糖的发病机制中发挥着重要作用，并对 1 型糖尿病的血糖波动和低血糖易感性产生重大影响。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调节的重要性，然而，Akt 信号传导如何调节体内 a 细胞的功能和质量以及该过程对葡萄糖调节的潜在贡献。 Akt 下游的 TSC1/2（结节性硬化症复合物）和 mTOR/Raptor (mTORC1) 成为这一过程中的主要候选者，因为它们整合了来自生长因子和营养物质的信号。这些研究的长期目标是揭示胰岛素/Akt 信号传导如何调节 a 细胞质量和胰高血糖素分泌。在初步实验中，我们表明 a 细胞中 mTORC1 功能的丧失会导致 a 细胞质量和胰高血糖素的严重异常。这些研究的目的是在这些观察的基础上了解营养信号如何调节 a 细胞功能和质量，我们发现胰岛素信号主要通过调节 mTORC1 来调节 a 细胞质量和胰高血糖素分泌。具体目标将确定 mTORC1 功能的获得和丧失如何调节 a 细胞质量、胰高血糖素分泌和对糖尿病条件的适应。该提案将为 mTORC1 控制 a 细胞质量扩张的分子机制提供重要见解。可用于扩大糖尿病药物开发机会。