LOAD INDUCED CARDIAC HYPERTROPHY IN THE ADULT MAMMAL

本计划项目补助金所依据的假设是， 心脏的血流动力学负荷是其结构的主要调节器 和功能虽然这一假设的预测同样 适用于心脏生理学，我们选择的问题， 这些研究的主题是增加的负荷如何直接相互作用 用心脏来解释心脏病的原因和后果 肥厚在此背景下，五个独立项目形成了一个紧密的 一系列相互关联的研究。在项目#1中，麦克德莫特博士，他使用了 体外加载的心肌细胞和组织，以及体内加载的心肌， 定义肥大中的翻译控制，将把这项工作扩展到 问题是，增加的预防活性的eIF-4 E，他 与肥大有因果关系。在项目#2中，Carabello博士将 在此基础上，研究显示二尖瓣返流的肥大程度较低 比主动脉瓣狭窄，前者有心室重构，而后者没有。 后者，通过询问未能重新正常化壁应力如何引起 这个过程在项目#3中，梅尼克博士将扩展他的发现， 钠钙交换基因的心脏表达所必需的元件，如 以及一种对心脏表达和肥大细胞的重要的新元件， 上调，以研究基因编码的转录调控 一种在肥大中对钙稳态至关重要的蛋白质。在项目#4中， 博士库珀将扩展他的工作，显示扩增微管， 肥大心肌和微管稳定和上调 微管蛋白，试图建立一个因果关系， 这些基因表达的变化与收缩 功能障碍，强调亚型特异性变化的作用， 微管蛋白表达。此外，在一项新的倡议中，我们将探讨我们最近的 这一发现表明，肥大微管的改变可能具有 在β-肾上腺素能受体功能改变中的作用， 肥大微管的改变可能在β- 肾上腺素能受体功能特征性心脏肥大。在 新的项目#5，博士Zile将利用他的发展，一个独特的， 表型稳定的分离成人心肌细胞模型，以研究 信号通路通过其负载耦合到成人的生长 心肌细胞因此，第一个和第五个项目涉及的是原因 负荷诱导的心脏肥大在成人中，第一个重点 第五个集中在诱导增加蛋白质合成， 这一感应的信号。其他三个项目涉及 成年人负荷诱导的心脏肥大的后果， 重点关注结构和监管变化的机制， 细胞内或细胞外的成分， 在心肌肥厚中的作用及其调节。

The hypothesis upon which this Program Project Grant is based is that hemodynamic loading of the heart is the primary regulator of its structure and function. While the prediction of this hypothesis are equally applicable to cardiac physiology, the question which we have chosen as the subject of these studies is that of how increased load interacts directly with the heart to explain the causes and consequences of cardiac hypertrophy. In this context, the five individual projects form a closely interrelated set of studies. In Project #1, Dr. McDermott, who has used cardiocytes and tissue loaded in vitro, and myocardium loaded in vivo, to define translational control in hypertrophy, will extend this work to the question of whether the increased translationally active eIF-4E that he finds is causally linked to hypertrophy. In Project #2, Dr. Carabello will build on this studies showing less hypertrophy in mitral regurgitation than aortic stenosis, with ventricular remodeling in the former but not in the latter, by asking how failure to re-normalize wall stress induces this process. In Project #3, Dr. Menick will extend his discovery of elements requisite for cardiac expression of the Na-Ca exchanges gene, as well as a novel element important for cardiac expression and hypertrophic upregulation, to studies of transcriptional regulation of a gene encoding a protein critical to calcium homeostasis in hypertrophy. In Project #4, Dr. Cooper will extend his work showing augmented microtubules in hypertrophied myocardium and microtubule stabilization and upregulation of microtubule proteins, to an attempt to establish a cause-and-effect relationship between these changes in gene expression and contractile dysfunction, with an emphasis on the role of isoform-specific changes in tubulin expression. Also, in a new initiative, we will explore our recent discovery suggesting that hypertrophic microtubule alterations may have a role in the altered beta-adrenergic receptor function suggesting that hypertrophic microtubule alterations may have a role in the altered beta- adrenergic receptor function characteristic of cardiac hypertrophy. In the new Project #5, Dr. Zile will exploit his development of a unique, phenotypically stable isolated adult cardiocyte model to study the signalling pathways by which load is coupled to growth in the adult cardiocyte. Thus, the first and fifth projects are concerned with causes of load-induced cardiac hypertrophy in the adult, with the first focused on inducting of increased protein synthesis, and the fifth focused on signals for that induction. The other three projects are concerned with consequences of load-induced cardiac hypertrophy in the adult, being focused on mechanisms by which changes in structural and regulatory elements, whether intracellular or extracellular, alter contractile function and its regulation in cardiac hypertrophy.