Improved Diagnostic of the Muscular Dystrophies

描述（由申请人提供）：拟议的研究是一个长期项目的第四次竞争性更新，以确定肌营养不良症的分子基础。以前的奖项已被用于定义肌营养不良症的新原因，进行基因型/表型相关性，探测不同类型的分子机制，并开发敏感和特异性的分子测试。在上一个奖项期间，申请人转向患者肌肉活检RNA的全基因组表达谱，以询问杜氏肌营养不良症的分子病理生理学，以及继续研究肌营养不良症的新遗传原因。关于128个肌肉活检全基因组（U133 A/B）分析研究的新的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物化学途径的原则证据。具体来说，研究人员定义了核纤层蛋白A/C-Rb-MyoD在肌肉再生中的时间通路，该通路在Emery-Dreifuss肌营养不良症中特别受到干扰。建议的目的是将此数据分析扩展到定义不明确和异质性肢带型肌营养不良症组的疾病。这个新的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.开发诊断肢带型肌营养不良症（LGMD）的最常见已知原因的mRNA指纹; 2.从分析数据中定义肢带型肌营养不良症的生化途径，如对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（霍夫曼博士，Bakay，Zhao），数据建模和统计计算机科学家和电气工程师（Wang，Xuan，米勒博士）的合作团队进行。重要的是，所有数据将通过PI实验室（PEPR）开发的高度发展的网络数据库门户网站向公众发布，包括基于网络的动态数据分析工具。

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.