cAMP/CREB Signaling and Cardiac Function

cAMP/CREB ​​信号传导和心脏功能

• 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
• 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

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cAMP似乎对维持心脏功能至关重要; 在充血性心力衰竭（CHF）中，蓄积通常减少。增加心脏中的细胞cAMP水平 通过心脏定向表达腺苷酸环化酶VI型（ACvi）改善心脏性能和存活率 在CHF动物模型中。相比之下，β-肾上腺素能受体（PAR）激动剂治疗增加了 CHF患者的死亡率。目前正在研究解释儿童营养不良有益影响的机制，但 关于ACvi表达如何影响心肌细胞中的转录调节知之甚少， 心脏中的其他细胞。环腺苷酸已被证明通过PKA介导的细胞内基因表达刺激细胞基因表达。 磷酸化的转录因子cAMP反应元件结合蛋白（CREB）， Ser 133，一种促进共激活因子CREB结合蛋白（CBP）募集到 启动子此外，cAMP触发潜伏的细胞质CREB辅激活因子，转导子， 调节CREB 2（TORC 2），通过与CREB的直接相互作用增强靶基因的表达。 相关推动者。支持CREB在介导cAMP对心脏功能的作用中的作用， 在心脏中表达磷酸化缺陷型Ser 133 Ala CREB多肽的转基因小鼠表现出扩张的 心肌病CREB、CBP和TORC 2是否以及通过何种机制介导保护作用 然而，ACvi对心脏功能的影响尚不清楚。 本提案的总体目标是： 1.研究CREB是否介导ACVI对心功能和心肌细胞的有益作用 基因表达。 2.为了测试CREB：TORC 2通路在这个过程中的作用。