Molecular Epidemiology of Dilated Cardiomyopath

扩张型心肌病的分子流行病学

• 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
• 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

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.

该提案通过确定疾病基因突变的频率、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型心肌病的分子流行病学问题。特发性扩张型心肌病（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，但该疾病通常是遗传的和遗传异质性的。 连锁研究已经确定了17个FDC疾病基因座，包括P.I.的实验室在9号染色体上的一个大的常染色体显性FDC的亲属。到目前为止，已经确定了8个疾病基因：P.I.的实验室对发现导致X连锁FDC的肌营养不良蛋白基因突变做出了贡献，最近，在FDC和可变骨骼肌受累患者中发现了核纤层蛋白A/C基因突变。 其他研究者报道了导致FDC的心肌肌动蛋白、δ-肌聚糖、结蛋白、tafazzin、β-肌球蛋白重链和肌钙蛋白T的突变。然而，FDC和总体DCM人群中细胞骨架基因突变的患病率、类型和临床相关性尚不清楚。本申请提出了一系列旨在检验以下假设的实验：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、不同的预后价值和不同的临床相关性，3）几种FDC基因仍未鉴定，它们可能编码细胞骨架蛋白。本提案的具体目的是：1）研究FDC患者队列并评价其亲属，以确定遗传模式、表型、自然史，并招募分子遗传学研究; 2）使用候选基因方法和位置候选克隆方法鉴定和表征引起FDC的新基因; 3）通过研究具有或不具有家族性特征的大型患者群体中FDC基因突变的患病率、类型和基因型/表型相关性，分析已知和新型疾病基因的分子流行病学。已经从478名受试者中收集了临床数据、DNA和（在FDC的情况下）淋巴母细胞系，我们预计每年将招募20至30个新家庭。 实验方法包括已知和新的候选基因的突变筛选，定位克隆的FDC基因的9号染色体上的连锁和关联研究，分析的频率和基因型/表型的相关性，使用一个大型数据库设计这些研究。对导致DCM的基因和突变的鉴定将大大增加对这种疾病的分子基础的理解，并将允许开发新的基于分子的诊断和治疗策略。

项目成果

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
• 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]

• 发表时间: 2004
• 期刊: Italian heart journal. Supplement : official journal of the Italian Federation of Cardiology.
• 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。

• 发表时间: 2004
• 期刊: Italian heart journal. Supplement : official journal of the Italian Federation of Cardiology
• 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.

• DOI: 10.1186/1750-1172-1-27
• 发表时间: 2006-07-13
• 期刊: Orphanet journal of rare diseases
• 影响因子: 3.7
• 作者: Taylor MR;Carniel E;Mestroni L
• 通讯作者: Mestroni L