CONTRACTILE PROTEIN EXPRESSION IN FAILING HUMAN HEART

可收缩元件或肌节由多个薄的 和粗丝蛋白质，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 拥有或调节水解ATP的酶机制， 为收缩提供能量。 这种酶活性- 肌原纤维ATP酶-被肌动蛋白与肌球蛋白结合激活。 实际 肌球蛋白ATP酶，位于肌球蛋白重链（MyHC）头部 地区 几个关键的收缩因子的基因和功能表达 具有或调节ATP酶活性的蛋白质在细胞中被改变， 人类心脏衰竭 我们的科学家已经发现了 组和其他组在MyHC、肌球蛋白和肌球蛋白的mRNA和/或蛋白表达方面的差异 轻链和肌钙蛋白T同种型。 此外，潜在的 存在基因/蛋白质中尚未检测到的异常， 其它肌节成分的表达，其改变的表达可 在转基因动物中改变功能或产生心肌病表型 动物 尽管有明显的可能改变收缩蛋白 表达有助于发展和进步 心肌衰竭和心肌病，还没有一个 在失败与非失败中全面检查这个系统 人类的心脏 本申请建议进行这样的调查， 仅在人心室心肌中进行。 该提案 将1）进一步全面表征肌节基因， 衰竭和非衰竭人类心脏中的蛋白质表达，2） 确定α-/β-MyHC比率的正常化是否改善 人体心脏的内在收缩功能，以及3）研究 潜在的分子机制（刺激性甲状腺功能的下调 激素受体）的协调失调的MyHC亚型， 失败的人类心脏 这项调查将在 分离的心脏，分离的功能组织 心肌和完整的心脏。 在此生成的数据 这项提案应该确定收缩蛋白的表达是否改变， 是对衰竭的人类心脏收缩功能障碍的分子解释 心脏，如果这个系统可以治疗靶向。

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.