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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