CONTRACTILE PROTEIN EXPRESSION IN FAILING HUMAN HEART

收缩元素或肌节由多个薄片组成 和粗丝蛋白，它们是 心脏的结构和功能。收缩蛋白是一种 调节收缩功能的主要手段，因为它们 拥有或调节将三磷酸腺苷水解为 为收缩提供能量。这种酶活性- 肌原纤维ATPase-通过肌动蛋白与肌球蛋白结合而激活。实际的 肌球蛋白ATPase，位于肌球蛋白重链(MyHC)头部 区域。几种关键收缩蛋白的基因及其功能表达 具有或调节ATPase活性的蛋白质在 人类的心脏衰竭。我们发现了严重的异常情况 MyHC、肌球蛋白的mRNA和/或蛋白表达 轻链和肌钙蛋白T亚型。此外，潜在的 基因/蛋白质中存在尚未检测到的异常 其他肌节成分的表达改变可以 转基因改变功能或产生心肌病表型 动物。尽管明显存在改变收缩蛋白的可能性 表达有助于…的发展和进步 心肌衰竭和心肌病，还没有一个 在失败与不失败中对这一制度的全面审查 人类的心脏。本申请书建议进行这样的调查，以 仅在人的心室心肌中进行。这项建议 将1)进一步全面表征肉瘤基因和 衰竭与不衰竭心脏中蛋白质的表达 确定α/β-MyHC比率的正常化是否有所改善 人类心脏的内在收缩功能，以及3)调查 潜在的分子机制(刺激性甲状腺功能下调 激素受体)与心肌细胞MyHC异构体的协调失调 衰竭的人类心脏。这项调查将在 移植心脏，功能的隔离组织制剂 心肌和完好无损的心脏。在此中生成的数据 建议应确定收缩蛋白的表达是否发生变化 是衰竭人类心脏收缩功能障碍的分子解释 心脏，以及这个系统是否能在治疗上有针对性。

The contractile elements or sarcomeres are comprised of multiple thin and thick filament proteins that are important determinants of the structure and function of the heart. Contractile proteins are one of the primary means of regulating contractile function, because they possess or regulate the enzymatic machinery that hydrolyzes ATP to provide the energy for contraction. This enzymatic activity- myofibrillar ATPase-is activated by actin binding to myosin. The actual enzyme myosin ATPase, resides in the myosin heavy chain (MyHC) head region. The genes and functional expression of several key contractile proteins that possess or regulate ATPase activity are altered in the failing human heart. Major abnormalities have been detected by our group and others in the mRNA and/or protein expression of MyHC, myosin light chains, and troponin T isoforms. Additionally, the potential exists for as yet undetected abnormalities in the gene/protein expression of other sarcomere components whose altered expression can change function or produce a cardiomyopathy phenotype in transgenic animals. Despite the obvious potential for altered contractile protein expression to contribute to the development and progression of myocardial failure and cardiomyopathies, there has not been a comprehensive examination of this system in the failing vs. nonfailing human heart. This application proposes such an investigation, to be conducted exclusively in human ventricular myocardium. The proposal will 1) further and comprehensively characterize sarcomeric gene and protein expression in the failing and nonfailing human heart, 2) determine if normalization of the alpha-/beta-MyHC ratio improves intrinsic systolic function in the human heart, and 3) investigate a potential molecular mechanism (down-regulation of stimulatory thyroid hormone receptors) for the coordinate dysregulation of MyHC isoforms in the failing human heart. This investigation will be conducted in explanted hearts, isolated tissue preparations of functioning myocardium, and in the intact heart. The data generated in this proposal should determine if altered expression of contractile proteins is a molecular explanation for systolic dysfunction in the failing human heart, and if this system can be targeted therapeutically.