SCOR IN HEART FAILURE

心力衰竭的评分

• 批准号: 2857834
• 负责人: CHRISTINE E SEIDMAN
• 金额: $ 203.41万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-15 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2857834
• 关键词: heart failure; molecular pathology

Heart failure is a leading cause of disability and death in the U.S., affecting at least 2.5 million individuals, with an estimated 400,000 new cases per year. Progress in the prevention and treatment of heart failure has been limited in magnitude, due in large part to an incomplete understanding of basic biologic phenomena and mechanisms that underlie the clinical syndrome. This Heart Failure SCOR proposal attacks the problem across a spectrum from basic to clinical studies. Our unifying theme views heart failure as a continuum of basic phenomena and mechanisms that underlie the progression of events from an inciting cause e.g., a single base substitution in the DNA sequence of an individual or kindred with familial dilated or hypertrophic cardiomyopathy -- to the disturbances of cell and organ function and regulation that comprise the clinical syndrome of heart failure irrespective of the initial inciting cause. The participating Project Leaders have an extensive record of prior productive collaboration, and have focused their efforts on six interactive projects with substantial areas of interface. Project I seeks to test the hypothesis that nitric oxide (NO) produced in the myocardium regulates the contractile responsiveness of cardiac muscle to autonomic influences, and that inappropriate or excessive NO production contributes to contractile dysfunction and heart failure. This project interacts extensively with Project 2 which examines in humans the role of NO in normal myocardial and vascular regulation, and tests the hypothesis that disturbances of NO regulation contribute to the pathogenesis of clinical heart failure. Project 3 combines biophysical, biochemical, and molecular biological (transgenic) tools to test the hypothesis that decreased energy reserve via the creatine kinase system impairs contractile reserve in the failure myocardium. Project 4 also makes extensive use of transgenic technology to define the role of individual GTP-binding proteins in the normal and pathological function of cardiac cells, seeking to elucidate the role of G proteins in the disturbed transmembrane signalling processes known to exist in heart failure. We believe that a forward-looking program should address genetic factors that are primary in leading to heart failure, especially if the design of these studies is informed by new findings from patients with genetically-based forms of heart failure. Thus, Project 5 attacks the genetic basis of familial dilated cardiomyopathy seeking first to identify the chromosome(s) and causal gene(s) and mutations that form the basis of this cause of heart failure. Project 6 proposes to study heart failure in beta cardiac MHC gene missense mutations, using homologous recombination to produce well-defined mouse models of specific base substitutions known to cause the clinical manifestations of familial hypertrophic cardiomyopathy. Projects 1, 3, 4 and 6 will make extensive use of Core B for isolated cardiac myocyte preparation and functional characterization, while Projects 2 and 5 will use Core B later in the course of these studies. In all of these interactive projects, the collaborating investigators will maintain constant vigilance for opportunities to bring an enhanced understanding of fundamental biological and pathobiological phenomena and mechanisms to bear on improved prevention and treatment of patients at risk. The aggregate productivity of coordinated SCOR project efforts is expected to exceed that of the individual parts due to facilitation of the flow of ideas and technologies among investigators and projects.

心力衰竭是美国残疾和死亡的主要原因， 影响至少 250 万人，估计有 40 万人受到影响 每年的案例。 心力衰竭的预防和治疗进展 其规模有限，很大程度上是由于不完整 了解基本的生物现象和机制 临床综合征。 这个心力衰竭 SCOR 提案解决了这个问题 涵盖从基础研究到临床研究的各个领域。 我们统一的主题观点 心力衰竭作为基本现象和机制的连续体 事件的进展是由一个煽动原因引起的，例如，一个单一的事件 个体或亲属的 DNA 序列中的碱基替换 家族性扩张型或肥厚型心肌病——对以下疾病的干扰 构成临床综合征的细胞和器官功能和调节 心力衰竭的发生与最初的诱发原因无关。 这 参与的项目负责人拥有丰富的先前生产记录 合作，并集中精力开展六个互动项目 具有大量的接口区域。 项目 I 试图测试 假设心肌产生的一氧化氮（NO）调节 心肌对自主神经影响的收缩反应，以及 不适当或过多的 NO 产生会导致收缩 功能障碍和心力衰竭。 该项目与以下机构广泛互动 项目 2 检查人体中 NO 在正常心肌和 血管调节，并检验 NO 紊乱的假设 调节有助于临床心力衰竭的发病机制。 项目3结合了生物物理、生物化学和分子生物学 （转基因）工具来检验通过减少能量储备的假设 肌酸激酶系统会损害衰竭时的收缩储备 心肌。 项目4还广泛利用转基因技术 定义单个 GTP 结合蛋白在正常和 心肌细胞的病理功能，寻求阐明 G 的作用 已知存在的受干扰的跨膜信号传导过程中的蛋白质 在心力衰竭中。 我们认为，前瞻性计划应该解决 遗传因素是导致心力衰竭的主要原因，特别是如果 这些研究的设计是基于患者的新发现 基于遗传的心力衰竭。 因此，项目 5 攻击的是 家族性扩张型心肌病的遗传基础首先寻求识别 构成基础的染色体和因果基因以及突变 这是心力衰竭的原因。 项目 6 提议研究心力衰竭 β心脏MHC基因错义突变，利用同源重组 产生已知的特定碱基替换的明确定义的小鼠模型 引起家族性肥厚型心肌病的临床表现。 项目 1、3、4 和 6 将广泛使用 Core B 来实现隔离 心肌细胞的制备和功能表征，同时项目 2 和 5 稍后将在这些研究过程中使用核心 B。 在所有的 这些互动项目，合作研究人员将维护 不断警惕机会，以加深对 基本的生物学和病理生物学现象和机制 改善高危患者的预防和治疗。 总计 协调 SCOR 项目工作的生产力预计将超过 由于促进思想的流动和 研究人员和项目之间的技术。