SCOR IN HEART FAILURE

心力衰竭的评分

• 批准号: 2638041
• 负责人: JOHN JR ROSS
• 金额: $ 122.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2638041
• 关键词: heart failure; myocardial ischemia /hypoxia

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.

这份来自加州大学圣地亚哥分校（UCSD）的申请， 一个关于“心力衰竭的分子生理学”的SCOR将与强大的 分析方法与相关的研究和管理经验， 研究计划，提供了一个新颖的，全面的和可转移的 研究心力衰竭的方法。 我们的总体目标是提高 了解分子、生理和超微结构基础 心力衰竭的适应性和适应不良信号机制。 的 研究策略包括：应用小鼠遗传学来识别 介导心功能不全的信号通路;鉴定 并利用基因工程技术克隆肥大和心力衰竭的候选基因 先进的分子方法靶向其表达在培养的 心肌细胞;新的基于基因的动物模型的发展， 利用启动子靶向 给定转基因在心室中的表达;体内 携带候选基因的转基因小鼠模型的表型表征 使用新开发的定量微血管造影方法， 应用这些血管造影方法来研究生长的影响， 心力衰竭的因素;家族性扩张性心力衰竭遗传基础的研究 使用连锁分析补充明确定义的心肌病 通过代表性差异分析的新分子技术， 生理、生物化学和分子技术的结合， 肾上腺素能刺激受体的适应不良效应的基础， 动物模型和人体组织中的受体后水平;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- 发现了肾上腺素能控制力-频率关系的关键作用;使用 新的电生理方法来研究钙离子转运系统， 包括肌浆网Ca ~（2+）ATP酶泵和Na ~+/Ca ~（2+） 在从衰竭的人心脏分离的细胞和实验中， 模型 心肌遗传和分子信号传导的主题 肥大和衰竭，临床心力衰竭中的遗传异常， 适应不良的β-肾上腺素能信号传导和Ca 2+转运的影响 蛋白质对心肌收缩的影响将在几个水平上进行研究 系统复杂性，包括分子，细胞，完整的动物， 伙计