SPECIALIZED CENTER OF RESEARCH IN HEART FAILURE

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470万人，估计每年有40万新病例。心力衰竭的预防和治疗进展在一定程度上受到限制，这在一定程度上是由于对作为临床综合征基础的基本生物学现象和机制的不完全了解。这项心力衰竭SCOR提案解决了从基础到临床研究的一系列问题。统一这些研究的主题是，心力衰竭是分子现象和细胞机制的连续体。无论最初的诱因是什么，这些都直接导致了从一个潜在的原因，如患有家族性扩张型心肌病的个体DNA中的单核苷酸替换，发展到构成心力衰竭临床综合征的细胞和器官功能和调节的多重紊乱。参与项目的负责人有丰富的生产协作记录，并将精力集中在五个互动项目上，并付出了大量的接口努力。塞德曼博士的项目试图确定遗传性扩张型心肌病的遗传原因，期望在下一次授予期间将出现一个共同的主题，解释这种疾病的显着遗传异质性。米歇尔博士项目致力于确定在心力衰竭的发展和进展过程中，小凹和心肌细胞信号蛋白之间的相互作用所起的作用。项目3(Ingwall)结合了生物物理、生化和分子生物学工具来测试这一假说，即通过肌酸激酶系统减少能量储备会损害收缩突变的G/a0亚单位，从而发展为扩张型心肌病并代偿性肥厚。这些人在两个月内死于心力衰竭。将确定转基因表达与这些小鼠心力衰竭之间的联系。塞德曼博士的项目已经开发了两个基因工程系小鼠，它们是家族性肥厚型心肌病的模型；将对这些小鼠进行研究，以确定哪些因素会加剧心肌肥厚，在某些情况下会导致扩张型心肌病和心力衰竭。所有项目都将与Core B(Mende和Lee)密切互动，后者拥有制备和表征单个心肌细胞收缩功能的技术，以及获得小鼠和人类心脏的非侵入性成像以评估心脏功能。心脏组织学、免疫组织化学和原位杂交将由core c(Schoen)提供，以评估心肌中的基因表达。在所有这些互动项目中，合作的基本生物现象和机制关系到改善对处于危险中的患者的预防和治疗。协调项目努力的总生产力已经超出了各个组成部分的预期，我们预计这些惠益在下一个授权期将进一步扩大。

Heart failure is a leading cause of disability and death in the U.S. affecting at least 4.7 million individuals, with an estimated 400,000 new cases each year. Progress in the prevention and treatment of heart failure has been limited in magnitude due in some 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 of basic to clinical studies. The theme unifying these studies is that heart failure is a continuum of molecular phenomena and cellular mechanisms. These direct the progression from an underlying cause, such as a single nucleotide substitution in the DNA of an individual with familial dilated cardiomyopathy-to the multiple 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 produce collaboration and have focused their efforts on five interactive projects with substantial efforts of interface. Dr. C. Seidman's project seeks to identify genetic causes of inherited dilated cardiomyopathy with the expectation that during the next granting period a common theme will emerge that explains the significant genetic heterogeneity of this condition. Dr. (Michel) Project seeks to define the role of the interactions between caveolae and myocyte signaling proteins that evolve during the development and progression of heart failure. Project 3 (Ingwall) combines biophysical, biochemical and molecular biologic tools to test the hypothesis that decreased energy reserve via the creatine kinase system impairs contractile mutated G/a0 subunits that develop dilated cardiomyopathy with compensatory hypertrophy. These die of heart failure within two months. Pathways that link transgene expression to heart failure in these mice will be defined. Dr. Seidman's project has developed two genetically engineered lines of mice that are models of familial hypertrophic cardiomyopathy; these mice will be studied to determine those factors that worsen cardiac hypertrophy and in some, cause dilated cardiomyopathy and heart failure. All projects will interact closely with Core B (Mende and Lee), which has the technology to prepare and characterize contractile function of individual myocytes as well as to obtain non-invasive imaging of murine and human hearts to evaluate cardiac function. Cardiac histology, immunohistochemistry and in situ hybridization will be provided by CORE c (Schoen) to evaluate gene expression in the myocardium. In all of these interactive projects, the collaborating fundamental biological phenomena and mechanisms that bear on improved prevention and treatment of patients at risk. The aggregate productivity of coordinated project efforts has already exceeded the expectations of the individual components and we anticipate that these benefits will expand even further during the next granting period.