SCOR IN HEART FAILURE

这份来自加州大学圣地亚哥分校(UCSD)的申请 关于《心力衰竭的分子生理学》的SCOR将是强有力的 具有相关研究和管理经验的分析方法 研究计划提供了一个新颖、全面和可转让的 探讨心力衰竭的研究。我们的总体目标是改进 对分子、生理和超微结构基础的理解 用于心力衰竭中的适应性和非适应性信号机制。这个 研究策略包括：应用小鼠遗传学识别 介导心功能不全的信号通路；鉴定 并克隆肥厚和心力衰竭的候选基因 靶向其在培养细胞中表达的先进分子方法 心肌细胞；新的基于遗传的动物模型的发展 利用可靶向的启动子进行心肌肥厚和衰竭 特定转基因在体内的室壁表达 携带候选基因的转基因小鼠模型的表型特征 使用新开发的定量微血管造影术方法； 应用这些血管造影方法研究生长发育的影响 心力衰竭的因素；家族性扩张症的遗传基础研究 补充连锁分析的明确家系中的心肌病 通过代表性差异分析的新的分子技术； 结合生理、生化和分子技术来研究 肾上腺素能刺激对受体的不良适应效应的基础 动物模型和人体组织中受体后水平；生理学研究 力频关系异常对心脏的影响 实验模型和心力衰竭患者以及最近- 发现肾上腺素能控制力-频率关系的关键作用；使用 研究钙转运系统的新的电生理学方法， 包括肌浆网钙ATPase泵和钠/钙 衰竭人心脏和实验性心脏分离细胞中的交换剂 模特们。心肌中的遗传和分子信号主题 肥大和衰竭，临床心力衰竭的遗传异常， 非适应性β-肾上腺素能信号转导及其对钙离子转运的影响 有关心肌收缩的蛋白质将在多个水平上进行研究 系统的复杂性，包括分子、细胞、完整的动物，以及 天哪。

This application from the University of California at San Diego (UCSD) for a SCOR on "The Molecular Physiology of Heart Failure" will align powerful analytic methods with relevant research and administrative experience in a research plan which offers a novel, comprehensive and transferrable approach tot he study of heart failure. Our overall goal is to improve understanding of the molecular, physiological, and ultrastructural bases for adaptive and maladaptive signaling mechanisms in heart failure. The research strategies include: the application of mouse genetics to identify the signaling pathways which mediate cardiac dysfunction; identification and cloning of candidate genes for hypertrophy and heart failure using advanced molecular approaches for targeting their expression in cultured myocardial cells; the development of novel genetic-based animal models of ventricular hypertrophy and failure utilizing promoters that can target expression of a given transgene in to the cardiac ventricles; in vivo phenotypic characterization of transgenic murine models harboring candidate genes using newly developed quantitative microangiographic methods; the application of these angiographic methods to study the effects of growth factors in heart failure; studies on the genetic bases for familial dilated cardiomyopathy in well-defined kindreds using linkage analysis supplemented by the new molecular technique of representational difference analysis; the alignment of physiologic, biochemical and molecular techniques to study the bases for maladaptive effects of adrenergic stimulation at the receptor and post-receptor levels in animal models and human tissue; physiologic studies on the cardiac effects of abnormal force-frequency relations in experimental models and in patients with heart failure and of the recently- discovered key role of adrenergic control of force-frequency relations; use of novel electrophysiologic methods to study the Ca2+ transport system, including the sarcoplasmic reticular Ca2+ ATPase pump and the Na+/Ca2+ exchanger in isolated cells from failing human hearts and in experimental models. The themes of genetic and molecular signaling in myocardial hypertrophy and failure, genetic abnormalities in clinical heart failure, maladaptive beta-adrenergic signaling and the influence of Ca2+ transport proteins on myocardial contraction will be investigated at several levels of system complexity, including the molecular, cellular, intact animal, and man.