LOAD-INDUCED CARDIAC HYPERTROPHY

这项计划项目赠款所依据的假设是 心脏的血流动力学负荷是心脏的主要动态调节因素。 成人心肌的结构和功能特性。而当 这一假说的预测同样适用于心脏 生理学和病理生理学，我选择的中心问题 因为本应用程序的主题是增加的负载如何相互作用 直接以心肌为中心因素解释病因和 心肌肥厚的后果。在这一背景下，五个 各个项目形成了一套密切相关的研究。在项目中 #1，麦克德莫特博士将使用心肌细胞和组织 体外和体内负荷的心肌，以定义翻译控制 在传递增加的负荷时必须具有重要作用的机构 转化为蛋白质合成的加速速度导致净 细胞蛋白质的积累是肥大的标志。在 配套项目，项目2，Carabello博士将在他的研究的基础上 显示二尖瓣关闭不全时心肌肥厚程度比 通过询问负荷的哪个方面呈现给主动脉狭窄 心肌可能导致不能有效地传递负荷信号 转化为蛋白质合成。他和麦克德莫特博士将在研究方面合作 蛋白质合成和翻译控制的问题，这是常见的问题 这两个项目。在项目3中，梅尼克博士将把 离开肯特博士的两个关键观察：初始Na+进入 拉伸依赖的阳离子通道似乎是一种强制性事件 诱导肥大，Na-Ca交换器的基因表达 在心脏压力超负荷后很早就被诱发。由于钠钙 交易所感应很可能是关键下游事件的标志 负荷转化为肥厚，梅尼克博士将尝试 明确调控Na-Ca表达的分子机制 肥大诱导过程中的交换器基因。在项目4中，库珀博士 将使用体外负载的心肌细胞和组织和心肌 体内负荷研究负荷诱导细胞骨架的作用 压力超负荷引起的收缩功能障碍可能有改变 心肌肥厚。由于微管在脑组织中的重要作用 压力超负荷肥厚所见的收缩功能障碍 已经确定，该项目的一个关键组件将是 微管蛋白表观变化的控制机制研究 稳定性和/或合成。在伙伴项目，项目5中，Zile博士 将寻求确定非正常遵守的机制 肥厚心肌在心脏间质水平的改变 肌肉细胞中的组织和细胞骨架的变化。这最后两个 项目将检查增加的负荷和任何 相关的神经体液改变。因此，前三个项目是 大鼠负荷性心肌肥厚的原因探讨 成体，前两个集中在诱导增加的 蛋白质合成，第三个集中在信号上 归纳法。最后两个项目关注的是 成人负荷诱导的心肌肥厚，两者都受到关注 结构元素的变化方式，无论它们是细胞外的还是 在细胞内，改变肥厚心脏的收缩功能。

The hypothesis upon which this Program Project Grant is based is that hemodynamic loading of the heart is the primary dynamic regulator of the structural and functional properties of adult myocardium. While the predictions of this hypothesis are equally applicable to cardiac physiology and pathophysiology, the central question which I have chosen as the subject of this application is that of how increased load interacts directly with the myocardium as a central factor explaining the causes and consequences of cardiac hypertrophy. Within this context, the five individual projects form a closely interrelated set of studies. In Project #1, Dr. McDermott will use cardiac muscle cells and tissue loaded in vitro, and myocardium loaded in vivo, to define translational control mechanisms which must be of major importance in transducing increased load into the accelerated rate of protein synthesis resulting in net accumulation of cellular protein, the hallmark of hypertrophy. In the companion project, Project #2, Dr. Carabello will build on his studies showing that cardiac hypertrophy is much less in mitral regurgitation than in aortic stenosis by asking what aspect of load presentation to the myocardium may cause a failure to effectively transduce the load signal into protein synthesis. He and Dr. McDermott will work together on studies of protein synthesis and translational control, concerns that are common to both projects. In Project #3, Dr. Menick will take as a point of departure two critical observations of Dr. Kent: initial Na+ entry through stretch-dependent cation channels appears to be an obligatory event in hypertrophy induction, and gene expression for the Na-Ca exchanger is induced very early after cardiac pressure overloading. Since Na-Ca exchanger induction may well be a marker for critical downstream events in the transduction of load into hypertrophy, Dr. Menick will attempt to define molecular mechanisms that regulate the expression of the Na--Ca exchanger gene during hypertrophy induction. In Project #4, Dr. Cooper will use cardiac muscle cells and tissue loaded in vitro and myocardium loaded in vivo to investigate the role that load-induced cytoskeletal alterations may have in the contractile dysfunction of pressure overload cardiac hypertrophy. Since an important role for the microtubules in the contractile dysfunction seen with pressure overload hypertrophy has already been identified, a critical component of this project will be a study of the mechanisms controlling the apparent changes in tubulin stability and/or synthesis. In the companion project, Project #5, Dr. Zile will seek to determine the mechanisms for the abnormal compliance of hypertrophied myocardium at the levels of interstitial changes in cardiac tissue and cytoskeletal changes in the muscle cell. These last two projects will examine the effects of both increased load and any associated neurohumoral changes. Thus the first three projects are concerned with the causes of load-induced cardiac hypertrophy in the adult, with the first two being focused on the induction of increased protein synthesis, and the third being focused on signals for that induction. The last two projects are concerned with the consequences of load-induced cardiac hypertrophy in the adult, with both being focused on ways that changes in structural elements, whether they be extracellular or intracellular, alter the contractile function of the hypertrophied heart.