SCOR IN HEART FAILURE

心力衰竭是美国残疾和死亡的主要原因， 影响到至少250万人，估计有40万新的 案件每年。 心力衰竭的防治进展 在很大程度上，由于不完整的 了解基本的生物现象和机制，其基础是 临床综合征 这个心力衰竭SCOR提案解决了这个问题， 从基础研究到临床研究。 我们统一的主题观点 心力衰竭是一系列基本现象和机制， 从一个刺激的原因，例如，单个 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 细胞和器官的功能和调节，包括临床综合征 无论最初的诱因如何。 的 参与项目的领导者有丰富的生产记录， 合作，并集中精力在六个互动项目 有大量的接口区域。 项目一旨在测试 假设心肌中产生的一氧化氮（NO）调节 心肌对自主神经影响的收缩反应，以及 不适当的或过量的NO产生有助于收缩 功能障碍和心力衰竭。 该项目广泛地与 项目2研究了NO在人类正常心肌和心肌细胞中的作用， 血管调节，并测试的假设，干扰NO 调节有助于临床心力衰竭的发病机制。 项目3结合了生物物理学、生物化学和分子生物学 （转基因）工具来测试的假设，减少能源储备，通过 肌酸激酶系统在衰竭时损害收缩储备 心肌 项目4还广泛利用转基因技术， 确定单个GTP结合蛋白在正常和 心脏细胞的病理功能，寻求阐明G 已知存在于受干扰的跨膜信号传导过程中的蛋白质 心脏衰竭 我们认为，一个前瞻性的计划应该解决 遗传因素是导致心力衰竭的主要因素，特别是如果 这些研究的设计是由来自患者的新发现所告知的， 遗传性心力衰竭 因此，Project 5攻击了 家族性扩张型心肌病的遗传基础首先寻求确定 染色体和致病基因以及构成疾病基础的突变 心脏衰竭的原因 项目6建议研究心力衰竭， β心脏MHC基因错义突变，使用同源重组， 产生明确定义的特定碱基置换的小鼠模型， 引起家族性肥厚型心肌病的临床表现。 项目1、3、4和6将广泛使用核心B， 心肌细胞制备和功能表征，而项目 2和5将在这些研究的后期使用核心B。 在所有 这些互动项目，合作研究人员将保持 不断提高警惕，抓住机会， 基本的生物学和病理学现象和机制 改善对高危患者的预防和治疗。 总额 协调的SCOR项目工作的生产率预计将超过 由于促进了思想的流动， 研究人员和项目之间的技术。

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.