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
基本信息
- 批准号:6423879
- 负责人:
- 金额:$ 18.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 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
项目摘要
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.
目前SCOR和拟议更新的总体目标是阐明心脏对损伤的长期适应性反应的分子基础,无论是表现为肥大还是扩张,无论是遗传的还是后天的。在这个项目中,我们主要关注主要影响左心室的扩张型心肌病的范例。虽然有六个基因座与这种疾病相关,但没有一个致病基因被确定。我们建议使用位置候选或位置克隆的方法来鉴定这些基因中的两个,分别定位于我们家族中的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。我们将使用这一克隆材料来识别新的遗传标记,以进一步描绘该区域,以及将在我们的家庭中进行测序的新的候选基因。我们进一步建议定位一个我们已经确定的与任何已知的FDCM基因座没有关联的家族中的一个新的基因座,并最终确定该基因。在确定了一个家族中导致DCM的结蛋白基因错义突变(Il3451/Met)后,我们将进行体外研究,以探讨该突变对心肌微丝组装的影响,并试图通过在心肌细胞中的表达来确定心脏限制性表型的原因。体内研究将在转基因小鼠表达后进行,以确定与演变中的心功能障碍相关的形态变化及其时间演变。利用细胞形态计量学,将根据心肌细胞增厚与延长的程度来确定是否存在肥大和扩张反应。如果FDCM患者的表型主要是脑室扩张,尽管有扩张性反应,但确定与肥厚有关的常见生长因子(Fas、IGF-1、TGFbeta)或细胞骨架途径(整合素激酶、Rho-A、FAK)是否也上调将是非常有意义的。这些目标解决的假设是,识别遗传缺陷和解开家族性DCM的分子基础将为理解在应对各种其他家族性和获得性疾病时观察到的脑室扩张和衰竭提供基本的洞察力。
项目成果
期刊论文数量(0)
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Robert E Roberts其他文献
Robert E Roberts的其他文献
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{{ truncateString('Robert E Roberts', 18)}}的其他基金
Genetic basis of arrhythmogenic right ventricular dysplasia (ARVD)
致心律失常性右心室发育不良(ARVD)的遗传基础
- 批准号:
6569685 - 财政年份:2002
- 资助金额:
$ 18.5万 - 项目类别:
Genetic basis of arrhythmogenic right ventricular dysplasia (ARVD)
致心律失常性右心室发育不良(ARVD)的遗传基础
- 批准号:
6564979 - 财政年份:2002
- 资助金额:
$ 18.5万 - 项目类别:
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:
6564973 - 财政年份:2002
- 资助金额:
$ 18.5万 - 项目类别:
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 - 财政年份:2002
- 资助金额:
$ 18.5万 - 项目类别:
Genetic basis of arrhythmogenic right ventricular dysplasia (ARVD)
致心律失常性右心室发育不良(ARVD)的遗传基础
- 批准号:
6423885 - 财政年份:2001
- 资助金额:
$ 18.5万 - 项目类别:
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:
6302321 - 财政年份:2000
- 资助金额:
$ 18.5万 - 项目类别:
NOVEL CHROMOSOME LOCI RESPONSIBLE FOR HYPERTROPHIC CARDIOMYOPATHY AND MUTATIONS
导致肥厚型心肌病和突变的新染色体位点
- 批准号:
6110445 - 财政年份:1999
- 资助金额:
$ 18.5万 - 项目类别:
DNA LINKAGE--A GENE(S) RESPONSIBLE FOR FAMILIAL DILATED CARDIOMYOPATHY
DNA连锁——导致家族性扩张型心肌病的基因
- 批准号:
6110444 - 财政年份:1999
- 资助金额:
$ 18.5万 - 项目类别:
NOVEL CHROMOSOME LOCI RESPONSIBLE FOR HYPERTROPHIC CARDIOMYOPATHY AND MUTATIONS
导致肥厚型心肌病和突变的新染色体位点
- 批准号:
6273029 - 财政年份:1998
- 资助金额:
$ 18.5万 - 项目类别:
DNA LINKAGE--A GENE(S) RESPONSIBLE FOR FAMILIAL DILATED CARDIOMYOPATHY
DNA连锁——导致家族性扩张型心肌病的基因
- 批准号:
6273028 - 财政年份:1998
- 资助金额:
$ 18.5万 - 项目类别:
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