Role of CHF1/Hey2 in Hypertrophy and Heart Failure

描述（由申请人提供）：心脏肥大既是一种生理过程，允许适应血流动力学负荷，也是一种病理过程，最终导致腔室扩张并进展为心力衰竭。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。虽然多个信号通路已被牵连在肥大的发展，调节从正常的，生理反应过渡到适应不良，病理反应的分子机制知之甚少。此外，负责从肥大到心力衰竭的进展的分子机制仍有待阐明。最后，负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人们的极大兴趣。我们以前克隆了基本螺旋-环-螺旋，毛相关的转录抑制因子，CHF 1/Hey 2，并确定缺乏这种转录因子的小鼠发展扩张型心肌病。我们还发现，在心肌中过表达CHF 1/Hey 2的转基因小鼠对苯肾上腺素诱导的肥大有抵抗力。此外，我们发现CHF 1/Hey 2与GATA 4（一种已知的肥大激活剂）相互作用，并抑制GATA 4依赖性转录。我们的研究结果表明，CHF 1/Hey 2是一个重要的调节肥大和心力衰竭。为了阐明CHF/Hey 2调节肥大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CHF 1/Hey 2对与肥大相关的GATA 4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CHF 1/Hey 2如何影响肥大转录途径目的3：制备心肌中缺乏CHF 1/Hey 2的CHF 1/Hey 2条件性敲除小鼠，并测量其对体内肥大的反应

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