Novel genes for dilated cardiomyopathy: molecular basis of the disease

扩张型心肌病的新基因：该疾病的分子基础

• 批准号: 6569679
• 负责人: Robert E Roberts
• 金额: $ 18.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6569679
• 关键词: artificial chromosomes; autosomal dominant trait; clinical research; family genetics; fibrous protein; gene mutation; genetic mapping; genetically modified animals; growth factor; human subject; idiopathic dilated cardiomyopathy; laboratory mouse; microfilaments; molecular assembly /self assembly; molecular pathology; morphometry; tissue /cell culture; transfection /expression vector; artificial chromosomes; autosomal dominant trait; clinical research; family genetics; fibrous protein; gene mutation; genetic mapping; genetically modified animals; growth factor; human subject; idiopathic dilated cardiomyopathy; laboratory mouse; microfilaments; molecular assembly /self assembly; molecular pathology; morphometry; tissue /cell culture; transfection /expression vector

The overall objective of the current SCOR and the PROPOSED RENEWAL is to elucidate the molecular basis for the long-term adaptive response of the heart to injury, both inherited and acquired, whether manifested by hypertrophy or dilatation. In this project we focus on the paradigm of dilated cardiomyopathy affecting primarily the left ventricle. Although six genetic loci are associated with the disease, none of the causative genes have been identified. We propose to identify two of these genes, mapped to1q32 and 10q23 in our families, using either a positional candidate or positional cloning approach. We will use physical mapping information available on the World Wide Web to identify YAC clones and ESTs which map to the critical regions. We will use this cloned material to identify new genetic markers to further delineate the region as well as new candidate genes to be sequenced in our families. We further propose to map a novel locus in a family we have identified that is no linked to any known FDCM locus and ultimately to identify that gene as well. Having identified a missense mutation (Il3451/Met) in the desmin gene which is responsible for DCM in a family, we will conduct in vitro studies to investigate the effect of this mutation on filament assembly and through expression in myocytes attempt to determine the reason for the cardiac restricted phenotype. In vivo studies will be conducted following expression in the transgenic mouse to ascertain the morphological changes and their temporal evolution in relationship to evolving ventricular dysfunction. Utilizing cell morphometry it will be determined whether there is a hypertrophic as well as a dilatory response as determined by the extent of myocyte thickening versus myocyte elongation. Should the phenotype be primarily ventricular dilation as expected from the phenotype in patients with FDCM, it will be of great interest despite a dilatory response to determine whether the usual growth factors (FAS, IGF-1, TGFbeta) or cytoskeletal pathways (integrin kinase, Rho-A, FAK) involved in hypertrophy are also up-regulated. These objectives address the hypothesis that identifying genetic defects and unraveling the molecular basis for familial DCM will provide insight fundamental to the understanding of ventricular dilatation and failure observed in response to a variety of other familial and acquired diseases.

当前的SCOR的总体目标和提出的续签是阐明心脏对损伤的长期自适应反应的分子基础，无论是由肥大还是扩张表现出来。在这个项目中，我们着重于主要影响左心室的扩张心肌病的范式。尽管六个遗传基因座与该疾病有关，但尚未鉴定出任何病因基因。我们建议使用位置候选者或位置克隆方法鉴定其中两个基因，并将其映射到我们家庭中的1q32和10q23。我们将使用万维网上可用的物理映射信息来识别映射到关键区域的YAC克隆和EST。我们将使用这种克隆的材料来识别新的遗传标记，以进一步描述该地区以及在我们家庭中测序的新候选基因。我们进一步建议在一个家庭中绘制一个新颖的基因座，我们发现，该基因座与任何已知的FDCM基因座无关，并最终也确定该基因。在识别出负责家族中DCM的Desmin基因中的错义突变（IL3451/MET）之后，我们将进行体外研究，以研究该突变对细丝组装的影响以及通过肌细胞中的表达来试图确定心脏限制表型的原因。在转基因小鼠中表达后，将进行体内研究，以确定形态变化及其与不断发展的心室功能障碍关系的时间演变。利用细胞形态计量学，将确定是否有肥厚性和扩张反应，这取决于心肌细胞增厚与肌细胞伸长的程度。如果表型主要是FDCM患者表型所预期的心室扩张，那么尽管对确定通常的生长因子（FAS，IGF-1，TGFBETA）还是细胞骨架途径（Integin kinase，Rho-A，FAK，fak）是否涉及的超骨架也涉及的超肌素质途径是否也涉及涉及的超肌肉，但它仍会引起人们的关注。这些目标解决了以下假设：鉴定遗传缺陷并揭示家族性DCM的分子基础，将为理解心室扩张和因响应其他各种家族性和获得性疾病而观察到的失败提供洞察力。