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.

该提案通过确定疾病基因突变的频率、患者群体中的基因型/表型相关性及其临床相关性来研究扩张型心肌病的分子流行病学。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 的病因主要未知，但该疾病通常是遗传性的且具有遗传异质性。连锁研究已经确定了 17 个 FDC 疾病基因座，其中包括由 P.I. 实验室在一个常染色体显性 FDC 家族的 9 号染色体上绘制的基因座。迄今为止，已鉴定出 8 个疾病基因：P.I. 实验室已发现导致 X 连锁 FDC 的抗肌营养不良蛋白基因突变，最近又发现了 FDC 患者的核纤层蛋白 A/C 基因突变以及变异骨骼肌参与。其他研究人员报告了导致 FDC 的心脏肌动蛋白、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实验，旨在检验以下假设：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) 几个 FDC 基因仍未被识别，它们很可能编码细胞骨架蛋白。该提案的具体目标是：1）调查一组 FDC 患者并评估其亲属以确定遗传模式、表型、自然史，并招募进行分子遗传学研究； 2) 使用候选基因方法和位置候选克隆方法来鉴定和表征引起FDC的新基因； 3) 通过研究具有或不具有家族特征的大量患者群体中 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 和淋巴母细胞系（就 FDC 而言），我们预计每年将有 20 至 30 个新家庭入组。实验方法包括已知和新候选基因的突变筛选、通过连锁和关联研究在9号染色体上定位克隆FDC基因、使用为这些研究设计的大型数据库分析频率和基因型/表型相关性。对导致 DCM 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，并将允许开发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.

用于心脏组织工程的可注射水凝胶。

DOI：
发表时间：
2018-06
期刊：
影响因子：
4.6
作者：
Peña, Brisa;Laughter, Melissa;Jett, Susan;Rowland, Teisha J;Taylor, Matthew R G;Mestroni, Luisa;Park, Daewon
通讯作者：
Park, Daewon

Prevalence of desmin mutations in dilated cardiomyopathy.

扩张型心肌病中结蛋白突变的患病率。

DOI：
发表时间：
2007-03-13
期刊：
影响因子：
37.8
作者：
Taylor, Matthew R G;Slavov, Dobromir;Ku, Lisa;Di Lenarda, Andrea;Sinagra, Gianfranco;Carniel, Elisa;Haubold, Kurt;Boucek, Mark M;Ferguson, Debra;Graw, Sharon L;Zhu, Xiao;Cavanaugh, Jean;Sucharov, Carmen C;Long, Carlin S;Bristow, Michael R;L
通讯作者：
L

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：
发表时间：
2023-12
期刊：
影响因子：
0
作者：
Namasivayam, Mayooran;Bertrand, Philippe B;Bernard, Samuel;Churchill, Timothy W;Khurshid, Shaan;Marcus, Frank I;Mestroni, Luisa;Saffitz, Jeffrey E;Towbin, Jeffrey A;Zareba, Wojciech;Picard, Michael H;Sanborn, Danita Yoerger;North American ARVC
通讯作者：
North American ARVC

Transcriptome analysis of human heart failure reveals dysregulated cell adhesion in dilated cardiomyopathy and activated immune pathways in ischemic heart failure.

人类心力衰竭的转录组分析揭示了扩张型心肌病中细胞粘附失调和缺血性心力衰竭中激活的免疫途径。

DOI：
发表时间：
2018-11-12
期刊：
影响因子：
4.4
作者：
Sweet, Mary E;Cocciolo, Andrea;Slavov, Dobromir;Jones, Kenneth L;Sweet, Joseph R;Graw, Sharon L;Reece, T Brett;Ambardekar, Amrut V;Bristow, Michael R;Mestroni, Luisa;Taylor, Matthew R G
通讯作者：
Taylor, Matthew R G

[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：
2004-04
期刊：
影响因子：
0
作者：
Di Lenarda, 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