The Distinct Role of CBP and p300 in Regulating Hepatic Glucose Production

CBP 和 p300 在调节肝葡萄糖生成中的独特作用

• 批准号: 8115793
• 负责人: Ling He
• 金额: $ 9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-20 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115793
• 关键词: Acetylation; Adult; Affect; Animals; Antidiabetic Drugs; Award; Binding; Blood; Blood Glucose; CREB1 gene; Cell Line; Cells; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diabetes Mellitus; Diet; Direct Costs; EP300 gene; Enzyme Gene; Enzymes; Exhibits; Facilities and Administrative Costs; Fasting; Fatty acid glycerol esters; Forskolin; Gene Expression; Gene Expression Profile; Genes; Glucagon; Gluconeogenesis; Glucose; Goals; Hepatic; Hepatocyte; Hyperglycemia; Individual; Insulin; Insulin Resistance; Knockout Mice; Liver; Mediating; Mediator of activation protein; Mentors; Metformin; Modality; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutation; Newly Diagnosed; Non-Insulin-Dependent Diabetes Mellitus; Okadaic Acid; Pancreas; Patients; Phase; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Prevalence; Protein Dephosphorylation; Protein phosphatase; Regulation; Relative (related person); Role; Serine; Signal Pathway; Site; Societies; Testing; Transcriptional Regulation; United States; Up-Regulation; calyculin A; feeding; glucose production; hepatic gluconeogenesis; hepatoma cell; insulin signaling; lipid biosynthesis; mortality; mutant mouse model; programs; public health relevance; reconstitution; small hairpin RNA

DESCRIPTION (provided by applicant): Diabetes mellitus is becoming more prevalent worldwide, with the number of newly diagnosed adults nearly tripling between 1980 and 2005 in the US. Fasting hyperglycemia in type 2 diabetes mellitus is caused by insulin resistance and elevated glucagon levels, which result in non-suppressible hepatic glucose production. We have shown that both the anti-diabetic agent metformin and insulin phosphorylate the transcriptional co-activator CBP at serine 436 via PKC?/?, leading to the suppression of hepatic glucose production. A related co-activator, p300, lacking this phosphorylation site, is also am important mediator in regulation glucose production. We propose 3 aims in this K99/R00 award to further understand transcriptional regulation of hepatic gluconeogenesis by the p300/CBP class of co-activators. In Aim 1, we will characterize the insulin signaling and gluconeogenic enzyme gene expression profile in the fasted and fed states in p300 mutant mice where the PKC?/??phosphorylation site has been reconstituted. In Aim 2, we will identify the protein phosphatase mediating glucagon dephosphorylation of CBP at Ser436. In Aim 3, we will define the role of each co-activator in the CREB-p300/CBP-TORC2 complex in augmenting gluconeogenesis and the importance of inter-acetylation of CBP and p300 in mediating hepatic glucose production. The studies in Aim 1 will be finished in mentored K99 phase, while Aims 2 and 3 will be finished in the independent R00 phase. The mechanistic studies in this proposal, which explore the actions of insulin and glucagon in controlling hepatic glucose production, will be critical for the development of effective new modalities in the treatment of diabetes mellitus. PUBLIC HEALTH RELEVANCE: in this proposal, we will attempt to define the roles of p300 in gluconeogenesis; identify the protein phosphatase mediated glucagon dephosphorylation of CBP; determine the acetylation of CBP and p300 in regulating glucose production in the liver. We hope to provide mechanistic understanding for the development of hyperglycemia found in patients with type 2 diabetes mellitus.

描述（由申请人提供）：糖尿病在世界范围内变得越来越普遍，在1980年至2005年之间，新诊断的成年人的数量几乎三倍。 2型糖尿病中的空腹高血糖是由胰岛素抵抗和胰高血糖素水平升高引起的，这导致不可抑制的肝葡萄糖产生。我们已经表明，抗糖尿病剂二甲双胍和胰岛素都通过PKC？/？/？/？/？磷酸化，从而抑制了肝葡萄糖产生的转录共激活器CBP。缺乏这种磷酸化位点的相关共激活因子P300也是调节葡萄糖产生的重要介体。我们提出了3个K99/R00奖的目标，以进一步了解p300/cbp的共激活剂对肝糖生成的转录调节。在AIM 1中，我们将表征胰岛素信号传导和糖原性酶基因表达在p300突变小鼠中的禁食和喂养状态中的PKC？/??磷酸化位点已重新构成的。在AIM 2中，我们将确定CBP在SER436处的蛋白质磷酸酶介导的胰高血糖酶去磷酸化。在AIM 3中，我们将定义每个共激活因子在CREB-P300/CBP-TORC2复合物在增强糖异生中的作用以及CBP和P300在介导肝葡萄糖产生中的乙酰化的重要性。 AIM 1的研究将以指导的K99阶段完成，而AIMS 2和3将在独立的R00阶段完成。该提案中的机械研究探讨了胰岛素和胰高血糖素在控制肝葡萄糖产生中的作用，对于开发有效的新方式在治疗糖尿病的治疗中至关重要。 公共卫生相关性：在此提案中，我们将尝试定义p300在糖异生中的作用；鉴定蛋白质磷酸酶介导的CBP的胰高血糖素去磷酸化；在调节肝脏中的葡萄糖产生中，确定CBP和P300的乙酰化。我们希望为在2型糖尿病患者中发现的高血糖的发展提供机械理解。