SCOR IN HEART FAILURE

心力衰竭的评分

• 批准号: 2229639
• 负责人: THOMAS W SMITH
• 金额: $ 171.7万
• 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/2229639
• 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.

在美国，心力衰竭是导致残疾和死亡的主要原因， 影响到至少250万人，估计新增40万人 每年的病例数。心力衰竭的防治进展 在很大程度上是由于不完整的 对基本的生物现象和机制的理解 临床综合征。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 心力衰竭作为一个连续体的基本现象和机制 事件的进展是由煽动原因引起的，例如， 个人或亲属DNA序列中的碱基替换 家族性扩张型或肥厚型心肌病 构成临床综合征的细胞和器官功能与调节 心力衰竭的可能性，而不考虑最初的煽动原因。这个 参与项目的负责人有丰富的以前的工作记录 协作，并将努力集中在六个互动项目上 有很大面积的界面。项目I试图测试 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性 不适当或过量的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研究了一氧化氮在人类正常心肌和心肌细胞中的作用。 血管调节，并验证了NO紊乱的假说 调节参与了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)工具测试通过以下途径减少能源储备的假设 肌酸激酶系统在衰竭时损害收缩储备 心肌。项目4还广泛使用转基因技术来 明确单个GTP结合蛋白在正常和 心肌细胞的病理功能，试图阐明G的作用 已知存在的受干扰的跨膜信号传递过程中的蛋白质 在心力衰竭方面。我们认为，一个前瞻性的计划应该解决 导致心力衰竭的主要遗传因素，特别是在 这些研究的设计灵感来自于来自患者的新发现 遗传性心力衰竭。因此，Project 5攻击 家族性扩张型心肌病的遗传基础寻求首诊 染色体(S)和因果基因(S)和形成基础的突变 这是心力衰竭的原因。项目6建议研究心力衰竭 心脏MHC基因错义突变，利用同源重组 制作已知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将广泛使用核心B用于隔离 心肌细胞的制备和功能表征，同时项目 2和5将在稍后的这些研究过程中使用核心B。在所有的 这些互动项目，合作的调查人员将保持 时刻保持警惕，抓住机遇，增进对 基本的生物和病理生物学现象和机制 关于改进对高危患者的预防和治疗。集合体 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和 调查人员和项目之间的技术交流。