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.

该计划项目授予的假设是心脏的血液动力学负荷是其结构和功能的主要调节剂。尽管该假设的预测同样适用于心脏生理和病理生理学，但我们选择的作为这些研究主题的问题是，增加负荷如何直接与心脏相互作用以解释心脏肥大的原因和后果。在这种情况下，六个单独的项目形成了一组紧密相互关联的研究。在项目＃1中，麦克德莫特（McDermott）博士将从一个问题转化为转化机制如何控制心脏肥大过程中的一般蛋白质合成的问题，以至于这些机制如何调节这种生长过程所需的特定蛋白质的表达。在项目＃2中，Spinale博士将关注心肌梗塞后在特定基质金属蛋白酶影响该过程的生长和重塑上。在项目＃3中，Menick博士将将其在NA+ -CA2+交换器上的工作扩展到对调节机制的研究，其中交换器活性的改变可能直接激活信号转导途径，从而导致交换器基因表达的变化。在项目＃4中，库珀博士将扩展其工作，显示肥大心肌中的增强微管，直接测试是否稠密，稳定 微管网络是相关的收缩功能障碍的原因，然后就微型管上上调的MAP4对磷酸化依赖性亲和力的增加而寻求这种催产性细胞骨架变化的基础。在新的项目5中，Kuppuswamy博士将询问通过整合素将心脏负荷转化为肥大的细胞内信号的调节，通过定义整合素激活过程中焦点粘附复合物组装的机制，然后定义局灶性粘附在肥大中的作用。在新项目6中，Zile博士将把我们先前对与肥大相关的收缩功能障碍的关注扩展到考虑导致肥大相关舒张期功能障碍的细胞机制，尤其是在心细胞粘弹性特性方面，这些特性可能会改变肥大和衰老的心脏。因此，第一个和第五个项目涉及成年人负荷诱导心脏肥大的原因，首先是诱导蛋白质合成增加的诱导，而第五个集中于该诱导的信号。其他四个项目 关注成年人负荷引起的心脏增长的后果，集中在结构和调节因子的机制上，包括细胞内或细胞外，收缩功能及其在肥大中的调节。