The Relationship between Genomic Variants and MRI/MRS Markers in DMD

描述（由申请人提供）：这是母项目R01AR056973“肌营养不良的磁共振成像和生物标志物”的辅助申请。杜氏肌营养不良症（DMD）是最具破坏性的遗传相关神经肌肉疾病之一，每3500至6000名男孩中就有一人患有此病。营养不良的肌肉是脆弱的，在它们最终被肌内脂肪和纤维化所取代之前，会经历肌肉纤维变性和再生的反复循环。由于新的实验性治疗策略针对炎症和纤维化的抑制，本辅助研究建议检查磁共振（MR）标记物与纤维化和炎症的遗传修饰因子之间的联系，特别是Ltbp4和骨桥蛋白。磁共振成像的一个重大挑战是纤维化的量化，其特征是T2值短，而标准MRI可能无法显示。在这项辅助研究中，我们将增加对短T2敏感的新型MR采集，以监测在父母研究中登记的DMD男孩的大队列中的纤维化。这项辅助研究的中心假设是，肌肉纤维化和炎症的MR标记物与DMD的LTBP4和骨桥蛋白遗传变异和疾病进展有关。为了验证这一假设，我们提出以下三个目标。在Aim 1中，将在母体研究中增加额外的MR扫描，以捕获和量化具有极短T2值的MRI信号，以监测纤维化。扫描将在辅助研究第一年的基线进行横断面分析，并与来自患者成纤维细胞的潜在转化生长因子TGF¿结合蛋白-4 （LTBP4）多态性相关，这些成纤维细胞是作为母项目的一部分收集的。在目标2中，我们将对肌肉水分松弛和水分含量（水肿）进行额外的定量测量，并将其与血清炎症标志物和骨桥蛋白基因多态性的差异联系起来。最后，在Aim 3中，我们将利用母项目中的纵向功能和MR数据收集来研究纤维化、脂质沉积和功能性能丧失的MR标志物的1年变化与LTBP4/骨桥蛋白基因型之间的关系。这是一个对时间敏感的应用程序，可以利用基础设施投资，访问患有DMD的注册男孩，以及在父自然历史项目中广泛收集数据。拟议的辅助研究已通过

DESCRIPTION (provided by applicant): This is an ancillary application to the parent project R01AR056973, "Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy". Duchenne muscular dystrophy (DMD) is one of the most devastating genetically linked neuromuscular diseases and affects one in 3,500-6,000 boys. Dystrophic muscle is fragile and experiences repeated cycles of muscle fiber degeneration and regeneration, before they are ultimately replaced by intramuscular fat and fibrosis. Since new experimental therapeutic strategies are targeting the suppression of inflammation and fibrosis, this ancillary study proposes to examine the link between magnetic resonance (MR) markers and genetic modifiers of fibrosis and inflammation, specifically Ltbp4 and osteopontin. A significant challenge for MR has been the quantification of fibrosis, characterized by short T2 values, which may not be visualized by standard MRI. In this ancillary study, we will add novel MR acquisitions that are sensitive to short T2 to monitor fibrosis in the large cohort of boys with DMD enrolled in the parent study. The central hypothesis of this ancillary study is that MR markers of muscle fibrosis and inflammation are linked to LTBP4 and osteopontin genetic variants and disease progression in DMD. To test this hypothesis we propose the following three aims. In Aim 1 additional MR scans will be added to the parent study to capture and quantify MRI signals with extremely short T2 values to monitor fibrosis. Scans will be performed at baseline for cross-sectional analysis in year 1 of the ancillary study and correlated with latent transforming growth factor TGF¿ binding protein-4 (LTBP4) polymorphisms derived from patient fibroblast collected as part of the parent project. In Aim 2, we will perform additional quantitative measures of muscle water relaxation and water content (edema) and relate these to differences in serum profiles of inflammatory markers and polymorphisms in the osteopontin gene. Finally in Aim 3 we will take advantage of the longitudinal functional and MR data collection in the parent project to study the relationship between the 1-year change in MR markers of fibrosis, lipid deposition, and loss in functional performance and its association with LTBP4/Osteopontin genotype. This is a time-sensitive application to leverage the investment in infrastructure, access to enrolled boys with DMD, and extensive data collection in the parent natural history project. The proposed ancillary study is in response to RFA-AR-13-010 and is important for the development for future clinical trials in boys with DMD.