SWITCHING OF METABOLIC GENES IN UNLOADED HEART

一些病人手术治疗的意外后果 心力衰竭是心功能的改善 机械卸货。扩张型糖尿病患者的早期临床证据 心肌病表明，这种改善甚至可能持续下去。 取下左心室辅助装置(LVAD)后。这个 这一现象的机制尚不清楚。因为一个小的 在放置LVAD时取出一块心肌，并 因为同一颗心脏可以在移植时进行研究， 我们已经获得了初步证据表明左心室 卸载导致新陈代谢途径的基因重新编程 心脏中的能量产生与胎儿的模式一致 关于基因表达的。我们认为，这种现象可能会成为一种新的 晚期心力衰竭评估和治疗的范例。 具体目标1是鉴定和定量蛋白质的转录本。 能量底物代谢并比较它们的表达水平 在正常的、衰竭的和机械卸载的人的心脏中。我们还将 量化心脏特异开关的转录本，并测试 异构体开关与心功能的变化相关。 具体目标2是测量转录、表达和 代谢物中能量底物代谢酶的活性 左心室卸载模型。底物代谢的转变将 在工作的心脏中被测量。对基因的全面了解 交换将提供对潜在功能的机制的见解 心脏的恢复。此外，它有望产生一种分子 预测泵设备安全拆卸的标记。如果 假设是正确的，通过卸载激活胎儿基因也可能 成为心脏基因治疗的替代方法 失败了。

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.