CLINICAL AND GENETIC DIVERSITY OF FAMILIAL DILATED CARDIOMYOPATHY

家族性扩张型心肌病的临床和遗传多样性

• 批准号: 6421863
• 负责人: CHRISTINE E SEIDMAN
• 金额: $ 21.47万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6421863
• 关键词: clinical research; cytogenetics; family genetics; genetic disorder; genetic mapping; genetic polymorphism; human subject; idiopathic dilated cardiomyopathy; laboratory mouse; myocardium disorder

Dilated cardiomyopathy is a primary disorder of the myocardium that produces cardiac enlargement with impaired systolic function, and frequently heart failure. Of the multiple causes for this pathology, increasing evidence indicates 20-35% of dilated cardiomyopathies are familial and have a genetic etiology. This project will use molecular genetic approaches to define familial dilated cardiomyopathy genes encoded at three distinct loci on chromosomes 1, 2, and 6. Positional cloning approaches and candidate analysis will be employed to define mutated genes at these disease loci. Our approaches will benefit from the close interactions with other investigators in the SCOR, whose efforts to identify pathways perturbed in heart failure should provide important clues regarding the nature of candidate genes. Project 1 will also make extensive use of the expertise and technologies provide in Cores B and C to fully elucidate the clinical spectrum of this pathology in humans. These studies will likely result in the definition of additional disease loci and the identification of other disease genes. Compilation of a full repertoire of genetic etiologies for inherited forms of heart failure and their associated phenotypes has great potential for discovering new paradigms about this poorly understood syndrome. Identification of disease genes will improve diagnosis of individuals at risk for developing heart failure which will enable longitudinal study and enable preventive interventions. More broadly, and in collaboration with Drs. Michel, Neer, Ingwall and J. Seidman, identification of gene defects that cause human heart failure will help to elucidate the cell and molecular responses of the myocyte to mutated proteins. Understanding the complex signals triggered by gene mutations should ultimately provide important insight into the molecular mechanisms for contractile dysfunction that cause heart failure incited by many other initiating events.

扩张性心肌病是一种原发性心肌疾病，会导致心脏增大、收缩功能受损，并经常导致心力衰竭。在这种病理学的多种原因中，越来越多的证据表明20-35%的扩张型心肌病是家族性的，并且具有遗传病因。该项目将使用分子遗传学方法来确定家族性扩张型心肌病基因编码在染色体1，2和6上的三个不同的位点。将采用定位克隆方法和候选分析来确定这些疾病位点的突变基因。我们的方法将受益于与SCOR中其他研究人员的密切互动，他们在心力衰竭中识别干扰途径的努力应该为候选基因的性质提供重要线索。项目1还将广泛利用核心B和C中提供的专业知识和技术，以充分阐明这种病理学在人类中的临床谱。这些研究将可能导致更多疾病位点的定义和其他疾病基因的鉴定。编制一个完整的遗传性心力衰竭及其相关表型的遗传病因库，对于发现这种知之甚少的综合征的新范式具有很大的潜力。疾病基因的鉴定将改善对有发生心力衰竭风险的个体的诊断，这将使纵向研究和预防干预成为可能。更广泛地说，与Michel，Neer，Ingwall和J. Seidman博士合作，鉴定导致人类心力衰竭的基因缺陷将有助于阐明肌细胞对突变蛋白质的细胞和分子反应。了解基因突变引发的复杂信号最终应该提供重要的洞察收缩功能障碍的分子机制，导致心力衰竭由许多其他引发事件。