Molecular Epidemiology of Dilated Cardiomyopath

扩张型心肌病的分子流行病学

基本信息

批准号：
6849697
负责人：
Luisa Mestroni
金额：
$ 55.51万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-01-01 至 2005-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6849697
关键词：
cardiovascular disorder epidemiology clinical research disease /disorder etiology family genetics functional /structural genomics gene frequency gene mutation genetic mapping genetic screening genetic susceptibility genotype high performance liquid chromatography human genetic material tag human subject idiopathic dilated cardiomyopathy molecular cloning molecular genetics phenotype

项目摘要

This proposal addresses the molecular epidemiology of dilated cardiomyopathy by determining the frequency of disease gene mutations, and the genotype/phenotype correlations in the patient population, and their clinical relevance. Idiopathic dilated cardiomyopathy (DCM) is a disease affecting the cardiac muscle and is a primary cause of heart failure leading to heart transplant. The etiology of DCM is mainly unknown, but the disease is frequently inherited and genetically heterogeneous. Linkage studies have identified 17 FDC disease loci including a locus mapped by the P.I.'s laboratory on chromosome 9 in a large kindred with autosomal dominant FDC. Thus far, 8 disease genes have been identified: the P.I.'s laboratory has contributed to the discovery of mutations in dystrophin gene leading to X-linked FDC, and more recently, has discovered lamin A/C gene mutations in patients with FDC and variable skeletal muscle involvement. Other investigators have reported mutations in cardiac actin, delta-sarcoglycan, desmin, tafazzin, beta-myosin heavy chain and troponin T leading to FDC. However, the prevalence, type and clinical relevance of cytoskeletal gene mutations in FDC, and in the overall DCM population are unknown. This application proposes a series of experiments designed to test the following hypotheses: 1) gene mutations are a frequent cause of FDC, 2) different gene mutations may have different frequency, different prognostic value, and different clinical relevance, 3) several FDC genes are still unidentified, and they are likely to encode cytoskeletal proteins. The Specific Aims of this proposal are: 1) to investigate of a cohort of patients with FDC and to evaluate their relatives to determine the inheritance pattern, the phenotype, the natural history, and recruit for molecular genetics studies; 2) to identify and characterize novel genes causing FDC using a candidate gene approach and a positional candidate cloning approach; 3) to analyze the molecular epidemiology of known and novel disease genes by studying the prevalence, type, and genotype/phenotype correlation of the FDC gene mutations in a large patient population with or without a familial trait. Clinical data, DNA and, in the case of FDC, lymphoblastoid cell lines have already been collected from 478 subjects, and we anticipate the enrollment of 20 to 30 new families/year. The experimental methods include mutation screening of known and novel candidate genes, positional cloning of the FDC gene on chromosome 9 by linkage and association studies, analysis of the frequency and genotype/phenotype correlations using a large database designed for these studies. The identification of the genes and mutations responsible for DCM will greatly increase the understanding of the molecular basis of this disease and will allow for the development of new molecular- based diagnostic and therapeutic strategies.

该建议通过确定疾病基因突变的频率以及患者人群中的基因型/表型相关性及其临床相关性来解决扩张心肌病的分子流行病学。特发性扩张性心肌病（DCM）是一种影响心肌的疾病，是导致心脏移植的心力衰竭的主要原因。 DCM的病因主要是未知的，但是该疾病经常是遗传的，并且在遗传上是异质的。连锁研究已经确定了17个FDC疾病基因座，其中包括由P.I.的实验室在9号染色体上绘制的基因座，该基因座在具有常染色体显性率的大型FDC中。到目前为止，已经鉴定出8种疾病基因：P.I.的实验室有助于发现肌营养不良蛋白基因突变，导致X连锁FDC，最近发现FDC患者的层lamin A/C基因突变和可变的骨骼肌受累。其他研究人员报告了心肌动蛋白，Delta-Sarcoglycan，Desmin，Tafazzin，β-肌球蛋白重链和肌钙蛋白T的突变，导致FDC。但是，FDC中细胞骨架基因突变以及DCM总体中的流行率，类型和临床相关性尚不清楚。该应用提出了一系列旨在测试以下假设的实验：1）基因突变是FDC的常见原因，2）不同的基因突变可能具有不同的频率，不同的预后值和不同的临床相关性，3）几个FDC基因仍然未识别，并且可能会结构cytoskeletal蛋白质。该提案的具体目的是：1）调查FDC患者队列的研究，并评估其亲戚以确定遗传模式，表型，自然史和分子遗传学研究的招募； 2）使用候选基因方法和位置候选克隆方法来识别和表征引起FDC的新基因； 3）通过研究具有或没有家族性状的大患者人群中FDC基因突变的患病率，类型和基因型/表型相关性来分析已知和新型疾病基因的分子流行病学。临床数据，DNA和在FDC的情况下，已经从478名受试者中收集了淋巴细胞细胞系，我们预计每年有20至30个新家庭入学。实验方法包括对已知和新型候选基因的突变筛选，通过链接和关联研究在9号染色体上对FDC基因的位置克隆，使用为这些研究设计的大型数据库对频率和基因型/表型相关性的分析。对DCM负责的基因和突变的鉴定将大大增加对该疾病分子基础的理解，并允许发展新的基于分子的诊断和治疗策略。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Injectable Hydrogels for Cardiac Tissue Engineering.

DOI：
10.1002/mabi.201800079
发表时间：
2018-06
期刊：
Macromolecular bioscience
影响因子：
4.6
作者：
Peña B;Laughter M;Jett S;Rowland TJ;Taylor MRG;Mestroni L;Park D
通讯作者：
Park D

Utility of Left and Right Ventricular Strain in Arrhythmogenic Right Ventricular Cardiomyopathy: A Prospective Multicenter Registry.

左心室应变和右心室应变在致心律失常性右心室心肌病中的效用：前瞻性多中心登记。

DOI：
10.1161/circimaging.123.015671
发表时间：
2023
期刊：
Circulation. Cardiovascular imaging
影响因子：
0
作者：
Namasivayam,Mayooran;Bertrand,PhilippeB;Bernard,Samuel;Churchill,TimothyW;Khurshid,Shaan;Marcus,FrankI;Mestroni,Luisa;Saffitz,JeffreyE;Towbin,JeffreyA;Zareba,Wojciech;Picard,MichaelH;Sanborn,DanitaYoerger;NorthAmericanARVC
通讯作者：
NorthAmericanARVC

[The natural history of dilated cardiomyopathy: a review of the Heart Muscle Disease Registry of Trieste]

[扩张型心肌病的自然史：的里雅斯特心肌疾病登记处回顾]

DOI：
发表时间：
2004
期刊：
Italian heart journal. Supplement : official journal of the Italian Federation of Cardiology.
影响因子：
0
作者：
DiLenarda,Andrea;Pinamonti,Bruno;Mestroni,Luisa;Salvi,Alessandro;Sabbadini,Gastone;Gregori,Dario;Perkan,Andrea;Zecchin,Massimo;Carniel,Elisa;Bussani,Rossana;Silvestri,Furio;Morgera,Tullio;Camerini,Fulvio;Sinagra,Gianfranco;Gru
通讯作者：
Gru

[How the natural history of dilated cardiomyopathy has changed. Review of the Registry of Myocardial Diseases of Trieste]

[扩张型心肌病的自然史如何改变。

DOI：
发表时间：
2004
期刊：
Italian heart journal. Supplement : official journal of the Italian Federation of Cardiology
影响因子：
0
作者：
DiLenarda,Andrea;Pinamonti,Bruno;Mestroni,Luisa;Salvi,Alessandro;Sabbadini,Gastone;Gregori,Dario;Perkan,Andrea;Zecchin,Massimo;Carniel,Elisa;Bussani,Rossana;Silvestri,Furio;Morgera,Tullio;Camerini,Fulvio;Sinagra,Gianfranco
通讯作者：
Sinagra,Gianfranco

Cardiomyopathy, familial dilated.