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，影响了至少470万人，每年估计有40万新病例。在预防和治疗心力衰竭方面的进展在程度上是有限的，这在一定程度上是由于对基本的生物学现象和临床综合征背后的机制的不完全理解。这项心力衰竭SCOR提案从基础研究到临床研究的各个方面来解决这个问题。这些研究的统一主题是心力衰竭是一个分子现象和细胞机制的连续体。这些指导从一个潜在的原因，如一个家族性扩张型心肌病个体DNA中的单个核苷酸替换，到细胞和器官功能和调节的多重干扰，包括心力衰竭的临床综合征，而不管最初的诱发原因是什么。参与的项目负责人有着广泛的产品协作记录，并将他们的努力集中在五个交互项目上，并付出了大量的接口努力。C. Seidman博士的项目旨在确定遗传性扩张型心肌病的遗传原因，并期望在下一个资助期内出现一个共同的主题，解释这种疾病的显著遗传异质性。Dr. (Michel) Project旨在确定在心力衰竭的发展和进展过程中，小囊泡和心肌细胞信号蛋白之间相互作用的作用。项目3 （Ingwall）结合生物物理、生化和分子生物学工具，验证了通过肌酸激酶系统减少能量储备损害可收缩突变的G/a0亚基，从而发展为扩张性心肌病伴代偿性肥厚的假设。这些人在两个月内死于心力衰竭。在这些小鼠中，将转基因表达与心力衰竭联系起来的途径将被确定。塞德曼博士的项目开发了两种基因工程小鼠系，它们是家族性肥厚性心肌病的模型；研究人员将对这些小鼠进行研究，以确定哪些因素会加重心脏肥厚，在某些情况下，还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）密切合作，Core B拥有制备和表征单个肌细胞收缩功能的技术，以及获得小鼠和人类心脏的无创成像以评估心脏功能的技术。心脏组织学、免疫组织化学和原位杂交将由CORE c （Schoen）提供，以评估基因在心肌中的表达。在所有这些互动项目中，合作的基本生物现象和机制对改善高危患者的预防和治疗起着重要作用。协调项目努力的总生产力已经超过了单个组成部分的预期，我们预计这些好处将在下一个拨款期间进一步扩大。

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.