ADMINISTRATIVE CORE

行政核心

• 批准号: 6808272
• 负责人: GEORGE COOPER
• 金额: $ 9.95万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6808272
• 关键词: ADMINISTRATIVE; CORE

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.

该计划项目拨款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，但我们选择作为这些研究主题的问题是增加的负荷如何与心脏直接相互作用，以解释心脏肥大的原因和后果。在此背景下，这六个单独的项目形成了一组密切相关的研究。在项目#1中，麦克德莫特博士将从翻译机制如何在心脏肥大期间控制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。在项目 #2 中，Spinale 博士将重点研究心肌梗塞后发生的生长和重塑，以及特定基质金属蛋白酶如何影响这一过程。在项目#3中，Menick博士将把他在Na+-Ca2+交换器方面的工作扩展到调节机制的研究，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。在项目#4中，库珀博士将扩展他的工作，显示肥厚心肌中微管的增强，以直接测试是否存在致密、稳定的微管。 微管网络是相关收缩功能障碍的原因，然后通过上调的 MAP4 对微管的磷酸化依赖性亲和力增加来寻找这种肥大细胞骨架变化的基础。在新的项目 #5 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，探讨整合素如何将心脏负荷转化为细胞内肥厚信号的调节。 。在新的项目#6中，Zile博士将把我们之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，特别是在肥厚和舒张功能障碍中可能改变的心肌细胞粘弹性特性方面。衰老的心脏。因此，第一个和第五个项目涉及成人负荷引起的心脏肥大的原因，第一个项目侧重于诱导蛋白质合成增加，第五个项目侧重于该诱导的信号。其他四个项目 关注负荷引起的成人心脏生长的后果，重点关注细胞内或细胞外结构和调节因素的变化改变收缩功能及其肥厚调节的机制。