SWITCHING OF METABOLIC GENES IN UNLOADED HEART

一些患者手术治疗的意外后果 心力衰竭患者的心脏功能改善， 机械卸载 扩张型心绞痛患者的早期临床证据 心肌病表明，这种改善甚至可能持续 左心室辅助装置（LVAD）移除后。 的 这种现象的机制尚不清楚。 因为一个小 在放置LVAD期间取出一块心肌，并且 因为可以在移植时研究同一心脏， 我们已经能够获得初步证据表明左心室 卸载导致基因的重新编程，用于代谢途径， 心脏产生的能量符合胎儿的特征 的基因表达。 我们认为，这种现象可能成为一种新的 评估和治疗晚期心力衰竭的范例。 具体目标1是鉴定和定量蛋白质的转录本 并比较它们的表达水平 在正常的、衰竭的和机械卸载的人类心脏中。 我们还将 定量心脏特异性开关的转录物， 同种型转换与心室功能变化相关。 具体目标2是测量转录、表达和转录水平的变化。 代用品中能量底物代谢酶的活性 左室去负荷模型。底物代谢的变化将 在工作的心中衡量。 全面了解基因 开关将提供深入了解机制的功能 心脏的恢复。 此外，预期其产生分子量为100000的化合物。 预测泵装置安全移除的标记。 如果 假设是正确的，通过卸载激活胎儿基因也可能 成为心脏病基因治疗的替代方法 失败

An unexpected consequence of the surgical management of some patients with heart failure is an improvement in cardiac function following mechanical unloading. Early clinical evidence in patients with dilated cardiomyopathy suggests that this improvement may even be sustained after the removal of the left ventricular assist device (LVAD). The mechanisms for this phenomenon are not understood. Because a small piece of myocardium is taken out during placement of the LVAD, and because the same heart can be studied at the time of transplantation, we have been able to obtain preliminary evidence that left ventricular unloading leads to a reprogramming of genes for metabolic pathways of energy production in the heart which is consistent with a fetal pattern of gene expression. We suggest that this phenomenon may become a new paradigm in the assessment and treatment of advanced heart failure. Specific Aim 1 is to identify and quantitate transcripts for proteins of energy substrate metabolism and to compare their levels of expression in normal, failing, and mechanically unloaded human heart. We will also quantitate transcripts of cardiac specific switches and test whether isoform switches correlate with changes in ventricular function. Specific Aim 2 is to measure changes in transcription, expression and activities of enzymes of energy substrate metabolism in a surrogate model of left ventricular unloading. Shifts in substrate metabolism will be measured in the working heart. A full understanding of gene switching will provide insight into mechanisms underlying functional recovery of the heart. Furthermore, it is expected to yield a molecular marker predicting the safe removal of the pump device. If the hypothesis is correct, activation of fetal genes by unloading may also become an alternative approach to gene therapy in the treatment of heart failure.