Role of CHF1/Hey2 in Hypertrophy and Heart Failure

描述（由申请人提供）：心脏肥厚是一个允许适应血流动力学负荷的生理过程，也是一个最终导致心室扩张和心力衰竭的病理过程。心力衰竭是西方社会发病率和死亡率的主要原因，发病率每年都在增加。尽管多种信号通路与肥大的发生有关，但调控从正常生理反应到不适应病理反应转变的分子机制尚不清楚。此外，从肥厚到心力衰竭的分子机制仍有待阐明。最后，负向调节肥厚的因素甚至没有很好地表征，并且由于其潜在的治疗价值而引起了极大的兴趣。我们之前已经克隆了基本的螺旋-环-螺旋，毛发相关的转录抑制因子CHF1/Hey2，并确定缺乏这种转录因子的小鼠会发展为扩张型心肌病。我们还发现，在心肌中过表达CHF1/Hey2的转基因小鼠对苯肾上腺素诱导的心肌肥大具有抗性。此外，我们发现CHF1/Hey2与已知的肥大激活因子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调控肥厚发展和心衰进展的机制，我们提出以下具体目标：目的1：确定CHF1/Hey2对与肥厚相关的gata4依赖性转录机制的影响；目的2：通过基因表达的时间序列分析确定CHF1/Hey2如何影响肥厚转录途径；在体内培养心肌中缺乏CHF1/Hey2的CHF1/Hey2条件敲除小鼠，测定其对心肌肥厚的反应

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