Role of CHF1/Hey2 in Hypertrophy and Heart Failure

CHF1/Hey2 在肥厚和心力衰竭中的作用

基本信息

批准号：
7408024
负责人：
MICHAEL T CHIN
金额：
$ 40.3万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7408024
关键词：
Affect Binding Biological Assay Cardiac Myocytes Cessation of life Complex Congenital Abnormality Data Development Dilatation - action Dilated Cardiomyopathy EP300 gene Electrophoretic Mobility Shift Assay Gene Expression Gene Targeting Genes Genetic Transcription Heart Hypertrophy Heart failure Helix-Turn-Helix Motifs Hypertrophy In Vitro Incidence Knock-out Knockout Mice Measures Mediating Mitogen-Activated Protein Kinases Molecular Morbidity - disease rate Mus Muscle Cells Myocardium Pathologic Processes Pathological Dilatation Pathway interactions Perinatal Phenylephrine Physiological Physiological Processes Protein Overexpression Regulation Reporter Resistance Role Serum Signal Pathway Societies Stimulus Stress Therapeutic Time Series Analysis Transcription Repressor/Corepressor Transcriptional Activation Transgenic Mice chromatin immunoprecipitation hemodynamics in vivo interest loss of function mortality programs response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Cardiac hypertrophy is 'both a physiologic process allowing for adaptation to hemodynamic load and a pathologic process ultimately resulting in chamber dilatation and progression to heart failure. Heart failure is a leading cause of morbidity and mortality in Western Society, with the incidence increasing every year. Although multiple signaling pathways have been implicated in the development of hypertrophy, the molecular mechanisms that regulate the transition from a normal, physiologic response to a maladaptive, pathological response are poorly understood. In addition, the molecular mechanisms responsible for the progression from hypertrophy to heart failure remain to be elucidated. Finally, factors that negatively regulate hypertrophy are even less well characterized, and are of tremendous interest due to their potential therapeutic value. We have previously cloned the basic helix-loop-helix, hairy-related transcriptional repressor, CHF1/Hey2, and determined that mice lacking this transcription factor develop a dilated cardiomyopathy. We have also found that transgenic mice overexpressing CHF1/Hey2 in the myocardium are resistant to phenylephrine-induced hypertrophy. Furthermore, we have found that CHF1/Hey2 interacts with GATA4, a known activator of hypertrophy, and suppresses GATA4-dependent transcription. Our findings suggest that CHF1/Hey2 is an important regulator of hypertrophy and heart failure. To elucidate the mechanisms by which CHF/Hey2 regulates the development of hypertrophy and the progression to heart failure, we propose the following specific aims: Aim 1: Determine the effects of CHF1/Hey2 on GATA4-dependent transcriptional mechanisms associated with hypertrophy Aim 2: Determine how CHF1/Hey2 affects hypertrophic transcriptional pathways through time series analysis of gene expression Aim 3: Generate CHF1/Hey2 conditional knockout mice lacking CHF1/Hey2 in the myocardium and measure their response to hypertrophy in vivo

描述（由申请人提供）：心脏肥大“既是适应血流动力学负荷的生理过程，也是最终导致心室扩张和进展为心力衰竭的病理过程”。心力衰竭是西方社会发病和死亡的主要原因，发病率逐年增加。尽管多种信号通路与肥大的发展有关，但调节从正常生理反应向适应不良病理反应转变的分子机制仍知之甚少。此外，从肥厚进展到心力衰竭的分子机制仍有待阐明。最后，负面调节肥大的因素甚至还没有得到很好的表征，但由于其潜在的治疗价值而引起了极大的兴趣。我们之前克隆了基本的螺旋-环-螺旋、毛相关转录抑制因子CHF1/Hey2，并确定缺乏这种转录因子的小鼠会患上扩张型心肌病。我们还发现，心肌中过度表达 CHF1/Hey2 的转基因小鼠能够抵抗去氧肾上腺素诱导的肥大。此外，我们发现 CHF1/Hey2 与已知的肥大激活剂 GATA4 相互作用，并抑制 GATA4 依赖性转录。我们的研究结果表明 CHF1/Hey2 是肥厚和心力衰竭的重要调节因子。为了阐明 CHF/Hey2 调节肥厚发展和心力衰竭进展的机制，我们提出以下具体目标：目标 1：确定 CHF1/Hey2 对与肥厚相关的 GATA4 依赖性转录机制的影响目标 2：通过基因表达的时间序列分析确定 CHF1/Hey2 如何影响肥大转录途径目标 3：生成缺乏 CHF1/Hey2 的条件敲除小鼠心肌中的 CHF1/Hey2 并测量它们对体内肥大的反应