Genetic modifiers of Duchenne Muscular Dystrophy

杜氏肌营养不良症的遗传修饰

基本信息

批准号：
10522759
负责人：
KEVIN M FLANIGAN
金额：
$ 94.62万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522759
关键词：
20 year old Affect Age Award Becker Muscular Dystrophy Birth C-terminal Candidate Disease Gene Cardiac Cardiomyopathies Cessation of life Clinical Clinical Trials DNA Data Databases Deoxyribonucleases Diagnosis Disease Disease Progression Duchenne muscular dystrophy Dystrophin Engineering Enrollment Europe Exons Family Fatty acid glycerol esters Fibrosis First Independent Research Support and Transition Awards Funding Future Gene Mutation Gene-Modified Genes Genetic Genetic Polymorphism Genomic Segment Genotype Goals Grant Hi-C Hypersensitivity Link Magnetic Resonance Imaging Maps Measures Medical Care Costs Methods Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Fibers Muscular Dystrophies Mutation Myopathy Natural History Necrosis Open Reading Frames Outcome Parents Pathway interactions Patients Phenotype Principal Investigator Proteins Quantitative Trait Loci Recontacts Records Research Research Personnel Resources SNP array SNP genotyping Sampling Severities Severity of illness Siblings Signal Transduction Single Nucleotide Polymorphism Site Skeletal Muscle THBS1 gene Testing Therapeutic Intervention Thrombospondin 1 United States National Institutes of Health Update Validation Variant Walking Work career cohort coronary fibrosis data archive density disability dystrophinopathy exon skipping gene therapy genome-wide genomic data heart function in silico male micro-dystrophin novel novel strategies novel therapeutics opportunity cost patient stratification phenotypic data preservation programs promoter psychologic pulmonary function socioeconomics therapy outcome trait validation studies

项目摘要

Project Summary Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder that affects approximately 1:3500 to 1:5200 live male births caused by mutations in the X-linked DMD gene. DMD gene mutations result in absence of the dystrophin protein in muscle fibers, leading to myofiber necrosis, endomysial fibrosis, and fat replacement. It is a devastating disorder, leading to loss of ambulation by age 12, and historically to death by age 20. The psychological and socioeconomic effects on families are enormous; these include but are not limited to the costs of medical care, opportunity costs for career and work, and the psychological toll taken on parents and siblings. Our long-term goal is to understand which genes modify disease progression and severity of DMD. Confirming a hypothesis derived from a genetic modifier of muscular dystrophies in mice, we have recently used data from patients enrolled in the United Dystrophinopathy Project (UDP) to demonstrate that polymorphisms in the LTBP4 gene influence age at loss of ambulation. Our objective in this project is to identify additional genetic modifiers of skeletal muscle, cardiac, and ventilatory function, and our central hypothesis is that such modifiers can be identified by use of the UDP database, a unique resource that contains detailed phenotypic data and archived DNA samples from over 900 DMD patients. Our specific aims are to 1) update and analyze phenotypic data within the UDP cohort, 2) map modifier traits by high- density single nucleotide polymorphism arrays, and 3) validate newly identified putative genetic modifiers. Validation will engage collaborating networks of investigators in the US and Europe, who have additional natural history cohorts of DMD patients. At the conclusion of these Aims, we will have gained new information about modifier genes associated with the severity and progression of DMD.

项目概要杜氏肌营养不良症 (DMD) 是一种退行性肌肉疾病，影响大约 1:3500 至 1:5200 的男性活产是由 X 连锁 DMD 突变引起的基因。 DMD 基因突变导致肌纤维中肌营养不良蛋白的缺失，导致肌纤维坏死、肌内膜纤维化和脂肪替代。这是一种毁灭性的疾病，导致 12 岁时丧失行走能力，并在历史上导致 20 岁时死亡。对家庭的心理和社会经济影响是巨大的；这些包括但都是不限于医疗费用、职业和工作的机会成本以及对父母和兄弟姐妹造成的心理伤害。我们的长期目标是了解哪些基因改变 DMD 的疾病进展和严重程度。证实所得出的假设来自小鼠肌营养不良症的基因修饰剂，我们最近使用了来自参加联合肌营养不良项目 (UDP) 的患者证明 LTBP4 基因的多态性影响丧失行走能力的年龄。我们的目标是该项目旨在确定骨骼肌、心脏和骨骼肌的其他基因修饰剂通气功能，我们的中心假设是可以识别这些调节剂通过使用 UDP 数据库，这是一种包含详细表型数据的独特资源并存档了 900 多名 DMD 患者的 DNA 样本。我们的具体目标是 1) 更新和分析 UDP 队列中的表型数据，2）通过高-映射修饰性状密度单核苷酸多态性阵列，以及 3) 验证新鉴定的推定值基因修饰剂。验证将涉及美国调查人员的合作网络欧洲有更多的 DMD 患者自然史队列。在完成这些目标后，我们将获得有关修饰基因的新信息与 DMD 的严重程度和进展有关。