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：
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
项目类别：
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

项目摘要

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，1980 年至 2005 年间，美国新诊断的成年人数量几乎增加了两倍。 2 型糖尿病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，这会导致肝脏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均通过 PKC?/? 磷酸化丝氨酸 436 处的转录共激活剂 CBP，从而抑制肝葡萄糖的产生。相关的辅激活因子 p300 缺乏该磷酸化位点，也是调节葡萄糖产生的重要介质。我们在此 K99/R00 奖项中提出了 3 个目标，即进一步了解 p300/CBP 类共激活剂对肝脏糖异生的转录调节。在目标 1 中，我们将表征 p300 突变小鼠在禁食和进食状态下的胰岛素信号传导和糖异生酶基因表达谱，其中 PKC？/？磷酸化位点已被重建。在目标 2 中，我们将鉴定介导 CBP Ser436 胰高血糖素去磷酸化的蛋白磷酸酶。在目标 3 中，我们将定义 CREB-p300/CBP-TORC2 复合物中每种共激活剂在增强糖异生中的作用，以及 CBP 和 p300 乙酰化在介导肝葡萄糖生成中的重要性。目标 1 的研究将在指导的 K99 阶段完成，而目标 2 和 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葡萄糖产生中的作用，对于开发治疗糖尿病的有效新方法至关重要。公共健康相关性：在本提案中，我们将尝试定义 p300 在糖异生中的作用；鉴定蛋白磷酸酶介导的 CBP 胰高血糖素去磷酸化；确定 CBP 和 p300 的乙酰化在调节肝脏葡萄糖产生中的作用。我们希望为 2 型糖尿病患者发生高血糖提供机制理解。