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

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年期间，美国新诊断的成年人数量几乎增加了两倍。2型糖尿病患者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，这导致肝脏葡萄糖产生不受抑制。我们已经证明，抗糖尿病药物二甲双胍和胰岛素都可以通过PKC / /磷酸化436丝氨酸的转录共激活物CBP。，导致肝脏葡萄糖生成受到抑制。一种相关的共激活因子p300缺乏这种磷酸化位点，也是调节葡萄糖产生的重要介质。我们在K99/R00奖中提出了3个目标，以进一步了解p300/CBP类共激活剂对肝脏糖异生的转录调控。在Aim 1中，我们将描述p300突变小鼠在禁食和进食状态下的胰岛素信号和糖异生酶基因表达谱，其中PKC?/?？磷酸化位点被重建。在Aim 2中，我们将鉴定介导胰高血糖素在CBP的Ser436位点去磷酸化的蛋白磷酸酶。在Aim 3中，我们将定义CREB-p300/CBP- torc2复合体中每种共激活剂在增强糖异生中的作用，以及CBP和p300间乙酰化在介导肝糖生成中的重要性。Aim 1的研究将在指导下的K99阶段完成，而Aims 2和3将在独立的R00阶段完成。本研究旨在探讨胰岛素和胰高血糖素在控制肝脏葡萄糖生成中的作用，这对于开发有效的糖尿病治疗新方法至关重要。

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.