The Role of c-Myc in Glucose Homeostasis

c-Myc 在血糖稳态中的作用

• 批准号: 7428795
• 负责人: DONALD K. SCOTT
• 金额: $ 23.61万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7428795
• 关键词: Binding; Data; Diabetes Mellitus; Diet; Enzyme Gene; Fasting; Fatty acid glycerol esters; Gene Expression; Genes; Genetic Transcription; Glucokinase; Glucose; Goals; Hepatic; Hepatocyte; Insulin; Intervention; Laboratories; Liver; Measures; Mediating; Metabolic; Obesity; Patients; Pattern; Plasma; Play; Principal Investigator; Process; Protein Overexpression; Publishing; Range; Regulation; Role; Signal Transduction; Streptozocin; Structure of beta Cell of islet; Testing; Transgenic Mice; Work; blood glucose regulation; c-myc Genes; cell growth regulation; diabetic; extracellular; feeding; glucose metabolism; glucose output; glucose production; glycemic control; improved; insight; insulin signaling; novel strategies; prevent; programs; promoter; response; transcription factor

DESCRIPTION (provided by applicant): Insulin is permissive for powerful glucose-generated signaling metabolites that initiate a program of gene expression that increases hepatic utilization and decreases glucose production. Diabetes mellitus interrupts the relationship between insulin and glucose signaling, and leads to disregulated hepatic metabolic gene expression; the liver essentially becomes trapped in the fasted state, unable to process abundant extracellular metabolic fuel. Despite the predominant role of glucose signaling in the coordinated regulation of metabolic genes, very few laboratories are working to unravel the mechanisms of glucose action. My laboratory is one of these, and here we take a new approach to dissect the mechanisms of glucose signaling and the phenotypic switch of the liver as it transits from the fasted to the fed state. The transcription factor c-Myc has potent control over the regulation of cellular glucose metabolism and is a candidate for coordinating changes in gene expression that occur at the end of a fast. Our recently published and preliminary data demonstrate that endogenous levels of c-Myc are required for glucose-regulated gene expression in hepatocytes, and that c-Myc binds to the promoters of glucose-responsive genes in a glucose-dependent manner. Together, these data provide evidence that c-Myc plays an active and direct role in the coordinated expression of metabolic genes by glucose metabolism. We hypothesize that c-Myc is necessary for glucose mediated gene transcription and normal glucose metabolism in hepatocytes, and that glucose modifies c-Myc activity. Specific Aim 1 will determine the alterations in gene expression patterns and the metabolic consequences of acutely reducing or increasing expression of c-Myc in hepatocytes. Specific Aim 2 will determine the mechanisms by which c-Myc regulates metabolic gene expression. The studies outlined in the present proposal will provide new insights into the mechanisms by which c-Myc coordinates glucose regulated gene expression and promotes the fasted-to-fed transition in the liver. The long-range goal of these studies is to understand the coordinating mechanisms of glucose-regulated gene expression so that interventions may be developed to circumvent impaired insulin signaling and improve glycemic control in diabetic patients.

描述（由申请人提供）：胰岛素允许产生强大的葡萄糖产生的信号代谢物，这些代谢物启动基因表达程序，从而增加肝脏利用并减少葡萄糖产生。糖尿病会中断胰岛素和葡萄糖信号传导之间的关系，并导致肝脏代谢基因表达失调；肝脏基本上陷入禁食状态，无法处理丰富的细胞外代谢燃料。尽管葡萄糖信号传导在代谢基因的协调调节中发挥着主导作用，但很少有实验室致力于揭示葡萄糖作用机制。我的实验室就是其中之一，在这里我们采用一种新方法来剖析葡萄糖信号传导机制和肝脏从禁食状态过渡到进食状态时的表型转换。转录因子 c-Myc 对细胞葡萄糖代谢的调节具有有效的控制作用，并且是协调禁食结束时发生的基因表达变化的候选因子。我们最近发表的初步数据表明，内源水平的 c-Myc 是肝细胞中葡萄糖调节基因表达所必需的，并且 c-Myc 以葡萄糖依赖性方式与葡萄糖反应基因的启动子结合。总之，这些数据提供了证据，表明 c-Myc 在葡萄糖代谢的代谢基因协调表达中发挥着积极而直接的作用。我们假设 c-Myc 对于肝细胞中葡萄糖介导的基因转录和正常葡萄糖代谢是必需的，并且葡萄糖会改变 c-Myc 活性。具体目标 1 将确定基因表达模式的改变以及肝细胞中 c-Myc 表达急剧减少或增加的代谢后果。具体目标 2 将确定 c-Myc 调节代谢基因表达的机制。本提案中概述的研究将为 c-Myc 协调葡萄糖调节基因表达并促进肝脏从禁食到进食的转变的机制提供新的见解。这些研究的长期目标是了解葡萄糖调节基因表达的协调机制，以便开发干预措施来规避胰岛素信号传导受损并改善糖尿病患者的血糖控制。