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

基本信息

批准号：
8515392
负责人：
Ling He
金额：
$ 23.21万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515392
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 Health 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 reconstitution small hairpin RNA

项目摘要

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 wil identify the protein phosphatase mediating glucagon dephosphorylation of CBP at Ser436. In Aim 3, we wil 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.

糖尿病在世界范围内变得越来越普遍，新诊断的成年人数量接近 1980 年至 2005 年间，美国 2 型糖尿病患者的空腹高血糖增加了两倍。胰岛素抵抗和胰高血糖素水平升高，导致肝葡萄糖产生不可抑制。我们已经证明，抗糖尿病药物二甲双胍和胰岛素都会磷酸化转录共- 通过 PKC 在丝氨酸 436 处激活 CBP¿ /¿ ，导致肝葡萄糖产生受到抑制。辅激活剂 p300 缺乏该磷酸化位点，也是调节葡萄糖的重要介质我们在此 K99/R00 奖项中提出了 3 个目标，以进一步了解转录调控。 p300/CBP 类共激活剂促进肝脏糖异生在目标 1 中，我们将表征胰岛素。 p300 突变小鼠禁食和进食状态下的信号传导和糖异生酶基因表达谱 PKC 在哪里？ /¿在目标 2 中，我们将鉴定蛋白质的磷酸化位点。磷酸酶介导 CBP Ser436 去磷酸化在目标 3 中，我们将定义以下作用： CREB-p300/CBP-TORC2 复合物中的每个共激活剂增强糖异生作用和 CBP 和 p300 间乙酰化在介导肝脏葡萄糖生成中的重要性目标 1 中的研究。目标 2 和目标 3 将在独立的 R00 阶段完成。该提案中的机制研究探讨了胰岛素和胰高血糖素在控制肝功能方面的作用葡萄糖的产生对于开发治疗糖尿病的有效新方法至关重要梅利图斯。