cAMP/CREB Signaling and Cardiac Function

cAMP/CREB 信号传导和心脏功能

基本信息

批准号：
7482978
负责人：
MARC R MONTMINY
金额：
$ 38.38万
依托单位：
VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7482978
关键词：
Address Adenoviruses Adenylate Cyclase Adrenergic Receptor Agonist Animal Model Binding Binding Proteins CREB-binding protein CREB1 gene Cardiac Cardiac Myocytes Cells Congestive Congestive Heart Failure Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Responsive DNA-Binding Protein Dilated Cardiomyopathy Dominant-Negative Mutation Elevation Exhibits Gene Expression Gene Targeting Genes Goals Heart Heart failure Image Knock-out Knockout Mice Luciferases Maintenance Measures Mediating Modeling Modification Mus Nuclear Pathway interactions Patients Performance Phosphorylation Process Protein Binding Protein Dephosphorylation Protein Overexpression RNAi vector Relative (related person)Reporter Role Second Messenger Systems Signal Transduction Testing Transcriptional Regulation Transducers Transgenic Mice Transgenic Organisms Wild Type Mouse beta-adrenergic receptor chromatin immunoprecipitation gain of function human CREBBP protein improved in vivo mortality mutant polypeptide promoter protective effect second messenger transcription factor

项目摘要

The second messenger cAMP appears critical for maintenance of cardiac function; intracellular cAMP accumulation is typically reduced in congestive heart failure (CHF). Increasing cellular cAMP levels in heart by cardiac-directed expression of adenyl cyclase type VI (ACvi) improves cardiac performance and survival in animal models of CHF. In contrast, treatment with beta-adrenergic receptor (PAR) agonists increases mortality in CHF patients. Mechanisms explaining the salutary effects of ACVI are now being addressed, but little is known about how ACvi expression may influence transcriptional regulation in cardiac myocytes and other cells in the heart. Cyclic AMP has been shown to stimulate cellular gene expression via the PKA-mediated phosphorylation of the transcription factor cAMP Response Element Binding protein (CREB) at Ser133, a modification that promotes recruitment of the coactivator CREB Binding Protein (CBP) to the promoter. Additionally, cAMP triggers nuclear entry of the latent cytoplasmic CREB coactivator, Transducer of Regulated CREB 2 (TORC2), which enhances target gene expression via a direct interaction with CREB on relevant promoters. Supporting a role for CREB in mediating the effects of cAMP on cardiac function, transgenic mice expressing a phosphorylation defective Ser133Ala CREB polypeptide in heart exhibit dilated cardiomyopathy. Whether and by what mechanism CREB, CBP, and TORC2 mediate the protective effects of ACvi on cardiac function, however, is unclear. The overall goals of this Proposal are: 1. To test whether CREB mediates the salutary effects of ACVI on cardiac function and cardiac myocyte gene expression. 2. To test the role of the CREB:TORC2 pathway in this process.

第二信使训练营对维持心脏功能至关重要。细胞内营地充血性心力衰竭（CHF）通常会减少积累。心脏中的细胞营地水平增加通过心脏定向的腺基环酶VI型（ACVI）的表达可改善心脏性能和生存在CHF的动物模型中。相反，β-肾上腺素能受体（PAR）激动剂的治疗增加 CHF患者的死亡率。现在已经解决了解释ACVI的有益影响的机制，但是关于ACVI表达如何影响心肌细胞中的转录调节，几乎了解心脏中的其他细胞。循环AMP已显示可通过PKA介导的细胞基因表达转录因子cAMP反应元件结合蛋白（CREB）的磷酸化在 SER133，一种促进共激活因子CREB结合蛋白（CBP）募集的修饰发起人。此外，营地触发潜在细胞质CREB共激活因子的核进入传感器调节的CREB 2（TORC2），通过与CREB直接相互作用增强了靶基因表达相关促进者。支持CREB在介导CAMP对心脏功能的影响中的作用，表达磷酸化缺陷Ser133ala creb多肽的转基因小鼠表现出扩张心肌病。无论是什么机构，CREB，CBP和TORC2都会介导保护效果但是，ACVI在心脏功能上尚不清楚。该提案的总体目标是： 1。测试CREB是否介导ACVI对心脏功能和心肌细胞的有益影响基因表达。 2。测试CREB：TORC2途径在此过程中的作用。