Facioscapulohumeral Dystrophy Clinical Trial Foundations

项目2--摘要 以前，我们已经建立了肌肉功能、组织病理学、核磁共振成像之间的关系 特征和候选分子生物标记物。这项建议将把原来的研究扩展到进一步 完善MRI异常、组织病理学、RNA生物标志物和疾病之间的时间关系 进展；在独立的FSHD队列中验证这些相关性，并将这些研究扩展到包括 DNA甲基化；并确定免疫细胞分子表型是否识别寡克隆T细胞 FSHD肌肉扩张。这将通过三个目标来实现。目标1将延长我们之前的 FSHD的纵向生物标记物临床研究以确定与疾病进展的相关性。个人 患有FSHD的患者有缓慢进行性的虚弱，至少需要12个月才能表现出明显的 整体肌肉力量下降。在这个目标中，我们将扩展我们最初的研究，以确定预测价值 疾病活跃度的不同衡量标准。AIM 2将包括第三个临床研究站点，以验证和扩展 分子和影像的相关性，并确定与疾病进展的关系。一组 验证数据集对于了解MRI之间关联的真实预测能力至关重要 从我们先前的研究中发现，肌肉病理和RNA生物标志物。此外，还包括 将检测DUX4基因座的DNA甲基化，以检查其与疾病外显率的关系 和进步。AIM 3将对FSHD肌肉的炎症反应进行分子分析。我们的 先前对FSHD的MRI和肌肉活检的研究表明，STIR+信号与炎性细胞相关 渗入FSHD。这一目标将决定浸润性细胞的分子表型，它们的克隆性 复杂性，以及任何主导T细胞受体序列的序列。这项研究的意义在于 它将识别和验证预测FSHD肌肉疾病活动和进展的测量方法 这将为未来的治疗试验提供严格的试验设计。

PROJECT 2 - ABSTRACT Previously, we have established a correlation between muscle function, histopathology, MRI imaging characteristics, and candidate molecular biomarkers. This proposal will extend the original study to further refine the temporal relationship of MRI abnormalities, tissue pathology, RNA biomarkers, and disease progression; validate these correlations in an independent FSHD cohort and extend these studies to include DNA methylation; and determine whether immune cell molecular phenotyping identifies an oligoclonal T-cell expansion in FSHD muscle. This will be accomplished by three aims. Aim 1 will extend our previous longitudinal biomarker clinical study of FSHD to determine correlations with disease progression. Individuals with FSHD have slowly progressive weakness that requires at least 12 months to demonstrate significant decline in overall muscle strength. In this aim we will extend our original study to determine the predictive value of different measures of disease activity. Aim 2 will include a third clinical study site to validate and expand molecular and imaging correlations and determine the relationship to disease progression. Collection of a validation data set is essential to understand the true predictive power of associations between the MRI findings, muscle pathology, and RNA biomarkers suggested from our prior study. Additionally, the degree of DNA methylation at the DUX4 locus will be determined to examine its relation to the rate of disease penetrance and progression. Aim 3 will perform a molecular analysis of the inflammatory response in FSHD muscle. Our prior study of MRI and muscle biopsy in FSHD shows a correlation of STIR+ signal with an inflammatory cell infiltrate in FSHD. This aim will determine the molecular phenotype of the infiltrating cells, their clonal complexity, and the sequence of any dominate T-cell receptor sequences. The significance of this study is that it will identify and validate measurements that predict disease activity and progression in FSHD muscles that will inform rigorous trial design for future therapeutic trials.