ADMINISTRATIVE CORE

本计划项目资助所基于的假设是，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，但我们选择作为这些研究主题的问题是，增加的负荷如何直接与心脏相互作用，以解释心脏肥厚的原因和后果。在这方面，这六个单独的项目构成了一套密切相关的研究。在项目#1中，McDermott博士将从翻译机制如何控制心脏肥厚过程中一般蛋白质合成的问题转向这些机制如何调节生长过程所需的特定蛋白质的表达。在项目#2中，Spinale博士将专注于心肌梗死后发生的生长和重塑，即特定基质金属蛋白酶如何影响这一过程。在项目#3中，Menick博士将扩展他对Na+-Ca2+交换剂的研究，以研究交换剂活性的改变可能直接激活信号转导途径，从而导致交换剂基因表达的变化。在项目4中，库珀博士将扩展他的工作，展示增厚心肌中的微管增强，以直接测试是否致密，稳定

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 Project #1, 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 Project #2, 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 Project #3, 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 Project #4, 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 new Project #5, 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 new Project #6, 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.