LOAD INDUCED CARDIAC HYPERTROPHY IN THE ADULT MAMMAL

描述（由申请人提供）： 本计划项目资助所依据的假设是心脏的血流动力学负荷是其结构和功能的主要调节器。虽然这一假设的预测同样适用于心脏生理学和病理生理学，但我们选择这些研究的主题是，如何增加负荷直接与心脏相互作用，以解释心脏肥大的原因和后果。在这方面，六个单独的项目构成了一套密切相关的研究。在第一个项目中，McDermott博士将从翻译机制如何控制心脏肥大期间的一般蛋白质合成的问题转向这些机制如何调节该生长过程所需的特定蛋白质的表达的问题。在第二个项目中，Spinale博士将专注于心肌梗死后发生的生长和重塑，具体的基质金属蛋白酶如何影响这一过程。在第三个项目中，Menick博士将把他在Na+-Ca 2+交换器上的工作扩展到研究一种调节机制，其中交换器活性的改变可能直接激活信号转导途径，导致交换器基因表达的变化。在第四个项目中，库珀博士将扩展他的工作，显示在肥大的心肌微管增加，直接测试是否一个密集的，稳定的微管网络是相关的收缩功能障碍的原因，然后寻找这种肥大的细胞骨架变化的基础上，增加磷酸化依赖的亲和力上调MAP 4的微管。在第五个项目中，Kuppuswamy博士将通过定义整合素激活过程中粘着斑复合物组装的机制，然后定义粘着斑复合物在肥大中的作用，询问整合素如何将心脏负荷转化为肥大细胞内信号的调节。在第六个项目中，Zile博士将把我们以前对肥厚相关收缩功能障碍的关注扩展到对肥厚相关舒张功能障碍的细胞机制的考虑，特别是在肥厚和衰老心脏中可能改变的心脏细胞粘弹性方面。因此，第一个和第五个项目涉及成人负荷诱导的心脏肥大的原因，第一个项目侧重于诱导蛋白质合成增加，第五个项目侧重于诱导的信号。其他四个项目涉及成年人负荷诱导心脏生长的后果，重点是细胞内或细胞外结构和调节因子的变化改变收缩功能及其在肥大中的调节的机制。

DESCRIPTION (provided by applicant): 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 predictions of this hypothesis are equally applicable to cardiac physiology and pathophysiology, 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 six individual projects form a closely interrelated set of studies. In the first Project, Dr. McDermott will turn from the question of how translational mechanisms control general protein synthesis during cardiac hypertrophy to the question of how these mechanisms regulate the expression of specific proteins that are required for this growth process. In the second Project, Dr. Spinale will focus on the growth and remodeling that occurs after myocardial infarction in terms of how specific matrix metalloproteinases affect this process. In the third Project, Dr. Menick will extend his work on the Na+-Ca2+ exchanger to the study of a regulatory mechanism wherein alterations of exchanger activity may directly activate signal transduction pathways, resulting in changes in exchanger gene expression. In the fourth Project, Dr. Cooper will extend his work showing augmented microtubules in hypertrophied myocardium to a direct test of whether a dense, stable microtubule network is the cause of the associated contractile dysfunction and then seek the basis for this hypertophic cytoskeletal change in terms of increased phosphorylation-dependent affinity of upregulated MAP4 for the microtubules. In the fifth Project, Dr. Kuppuswamy will ask how cardiac load is translated by integrins into modulation of intracellular signals for hypertrophy by defining the mechanisms of focal adhesion complex assembly during integrin activation and then defining the role of the focal adhesion complex in hypertrophy. In the sixth Project, Dr. Zile will extend our previous focus on hypertrophy-related systolic dysfunction to a consideration of cellular mechanisms responsible for hypertrophy-related diastolic dysfunction, especially in terms of cardiocyte viscoelastic properties that may be altered in the hypertrophied and aging heart. Thus, the first and fifth projects are concerned with causes of load-induced cardiac hypertrophy in the adult, with the first focused on induction of increased protein synthesis, and the fifth focused on signals for that induction. The other four projects are concerned with consequences of load-induced cardiac growth in the adult, being focused on mechanisms by which changes in structural and regulatory factors, both intracellular or extracellular, alter contractile function and its regulation in hypertrophy.