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: 6302291
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-02-07 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302291
• 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.

扩张的心肌病是心肌的一种原发性疾病，可导致心脏肿大，收缩功能受损，并且经常心力衰竭。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方法来定义在染色体1、2和6上在三个不同基因座编码的家族性扩张的心肌病基因。将采用位置克隆方法和候选分析来定义这些疾病基因座的突变基因。我们的方法将受益于SCOR中与其他研究人员的密切相互作用，他们的努力确定心力衰竭扰动的途径应提供有关候选基因性质的重要线索。项目1还将广泛使用核心B和C中提供的专业知识，以充分阐明人类这种病理的临床范围。这些研究可能会导致其他疾病基因座的定义和其他疾病基因的鉴定。遗传病因的完整曲目遗传性心力衰竭及其相关表型具有很大的潜力，可以发现有关这种知名综合征的新范式。鉴定疾病基因将改善患心力衰竭风险的个体的诊断，这将使纵向研究并实现预防性干预。更广泛地与Drs合作。 Michel，Neer，Ingwall和J. Seidman，引起人心力衰竭的基因缺陷的鉴定将有助于阐明肌细胞对突变蛋白的细胞和分子反应。了解基因突变触发的复杂信号最终应为收缩功能障碍的分子机制提供重要的见解，这些障碍会导致许多其他启动事件引起的心力衰竭。