Improved Diagnostic of the Muscular Dystrophies

改进肌营养不良症的诊断

• 批准号: 7574443
• 负责人: ERIC P. HOFFMAN
• 金额: $ 52.86万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 2011-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7574443
• 关键词: Address; Adhalin; Affinity; Affinity Chromatography; Algorithms; Animal Model; Antibody Formation; Applications Grants; Area; Arts; Award; Biochemical; Biochemical Pathway; Bioinformatics; Biological; Biological Models; Biopsy; Book Chapters; Calpain; Candidate Disease Gene; Categories; Classification; Collaborations; Computers; Confounding Factors (Epidemiology); DYSF gene; Data; Data Analyses; Data Set; Databases; Defect; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Duchenne muscular dystrophy; Dystrophin; Electrical Engineering; Emery-Dreifuss Muscular Dystrophy; Etiology; Fingerprint; Functional disorder; Funding; Future; Gene Proteins; Generations; Genes; Genetic; Genome; Genomics; Genotype; Goals; Grant; Heterogeneity; Individual; Inherited; Internet; Investigation; Knowledge; Laboratories; Lamin Type A; Learning; Left; Limb-Girdle Muscular Dystrophies; Manuscripts; Membrane; Merosin; Messenger RNA; Methods; Modeling; Molecular; Molecular Diagnostic Techniques; Molecular Probes; Molecular Profiling; Muscle; Muscle Weakness; Muscular Dystrophies; Mutation; Myopathy; National Heart, Lung, and Blood Institute; Noise; Nuclear Envelope; Online Systems; Pathway interactions; Patients; Peer Review; Performance; Phenotype; Pilot Projects; Post-Translational Protein Processing; Principal Investigator; Procedures; Production; Progress Reports; Proteins; Publications; Publishing; Quality Control; RNA; Relative (related person); Research; Research Personnel; Rest; Reverse Transcriptase Polymerase Chain Reaction; Sarcoglycans; Scientist; Screening procedure; Sensitivity and Specificity; Sequence Analysis; Series; Signal Transduction; Source; Spinal cord injury; Statistical Models; System; Testing; Time; Tissues; Transcript; United States National Institutes of Health; Validation; Visual; Weight; Work; base; data modeling; disorder control; emerin; experience; genome-wide; heuristics; improved; in vivo; innovation; insight; loss of function; loss of function mutation; member; muscle regeneration; novel; novel diagnostics; programs; spastin; therapeutic target; tool; wasting

DESCRIPTION (provided by applicant): The proposed research is for the fourth competitive renewal of a long-term project to define the molecular basis of the muscular dystrophies. Previous awards have been used to define novel causes of muscular dystrophy, conduct genotype/phenotype correlations, probe molecular mechanisms of the different types, and to develop sensitive and specific molecular tests. During the previous award period, the applicant turned to genome-wide expression profiling of patient muscle biopsy RNA to interrogate both molecular pathophysiology of Duchenne muscular dystrophy, as well as continuing work on new genetic causes of muscular dystrophy. The new preliminary data on a 128 muscle biopsy whole-genome (U133A/B) profiling study demonstrates proof of principle that novel biochemical pathways can be defined using large scale data modeling and statistical analyses. Specifically, the investigators define a temporal pathway of Lamin A/C-Rb-MyoD in muscle regeneration that is specifically perturbed in Emery-Dreifuss muscular dystrophy. The proposed aims are to extend this data analysis into the poorly defined and heterogeneous Limb-girdle muscular dystrophy group of disorders. This new application is very heavily oriented towards large-scale data generation, data modeling and statistical analyses. The specific aims are: 1. to develop mRNA fingerprints diagnostic of the most common known causes of limb-girdle muscular dystrophy (LGMD); 2. to define biochemical pathways for Limb-girdle muscular dystrophy from the profiling data, as has been done for Emery-Dreifuss dystrophy; 3. extend data modeling into the definition of novel diagnostic categories of LGMD. The proposed research will be conducted by a collaborative team of molecular geneticists (Drs. Hoffman, Bakay, Zhao), and data modeling and statistical computer scientists and electrical engineers (Drs. Wang, Xuan, Miller). Importantly, all data will be released to the public via a highly evolved web database portal developed by the PI's lab (PEPR), including web-based dynamic data analysis tools.

描述（由申请人提供）：拟议的研究是长期项目的第四次竞争性更新，旨在定义肌营养不良症的分子基础。先前的奖项已用于定义肌营养不良症的新病因、进行基因型/表型相关性、探索不同类型的分子机制以及开发敏感和特异的分子测试。在上一个奖项期间，申请人转向对患者肌肉活检 RNA 进行全基因组表达谱分析，以探究杜氏肌营养不良症的分子病理生理学，并继续研究肌营养不良症的新遗传原因。 128 例肌肉活检全基因组 (U133A/B) 分析研究的新初步数据证明了可以使用大规模数据建模和统计分析来定义新的生化途径的原理证明。具体来说，研究人员定义了 Lamin A/C-Rb-MyoD 在肌肉再生中的时间通路，该通路在 Emery-Dreifuss 肌营养不良症中受到特别干扰。拟议的目标是将这种数据分析扩展到定义不明确且异质性的肢带型肌营养不良症组。这个新应用程序非常面向大规模数据生成、数据建模和统计分析。具体目标是： 1. 开发 mRNA 指纹图谱，诊断肢带型肌营养不良症 (LGMD) 最常见的已知病因； 2. 根据分析数据定义肢带型肌营养不良症的生化途径，就像对 Emery-Dreifuss 营养不良症所做的那样； 3.将数据建模扩展到LGMD新诊断类别的定义中。拟议的研究将由分子遗传学家（Hoffman、Bakay、Zhao 博士）以及数据建模和统计计算机科学家和电气工程师（Wang、Xuan、Miller 博士）组成的协作团队进行。重要的是，所有数据都将通过 PI 实验室 (PEPR) 开发的高度发展的网络数据库门户向公众发布，包括基于网络的动态数据分析工具。