Role of CHF1/Hey2 in Hypertrophy and Heart Failure

描述(由申请人提供)：心肌肥厚既是允许适应血流动力学负荷的生理过程，也是最终导致心腔扩张和发展为心力衰竭的病理过程。在西方社会，心力衰竭是发病率和死亡率的主要原因，发病率每年都在增加。尽管多条信号通路参与了肥厚的发生发展，但调控正常生理反应向非适应性病理反应转变的分子机制尚不清楚。此外，从肥厚到心力衰竭进展的分子机制仍有待阐明。最后，负性调节肥厚的因素特征更不明确，由于其潜在的治疗价值而引起人们极大的兴趣。我们之前已经克隆了毛发相关的基本螺旋-环-螺旋转录抑制因子CHF1/Hey2，并确定缺乏该转录因子的小鼠会患上扩张型心肌病。我们还发现，在心肌中过度表达CHF1/Hey2的转基因小鼠对苯肾上腺素诱导的肥大具有抵抗力。此外，我们还发现CHF1/Hey2与已知的肥大激活因子GATA4相互作用，并抑制GATA4依赖的转录。我们的发现提示CHF1/Hey2是肥厚和心力衰竭的重要调节因子。为了阐明CHF/Hey2调控肥厚发展和心力衰竭进展的机制，我们提出了以下具体目标：目的1：确定CHF1/Hey2对与肥厚相关的GATA4依赖的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如何影响肥大转录途径目标3：建立CHF1/Hey2条件基因敲除小鼠，并在体内测量其对肥厚的反应

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