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

项目总结/摘要 这是母项目R 01 AR 056973“磁共振成像和 肌营养不良症的生物标志物”。 杜氏肌营养不良症（DMD）是一种最具破坏性的遗传连锁神经肌肉萎缩症， 每3，500至6，000名男孩中就有一人患有这种疾病。营养不良的肌肉很脆弱， 肌肉纤维变性和再生，然后最终被肌内脂肪取代， 纤维化由于新的实验性治疗策略靶向抑制炎症和 纤维化，这项辅助研究提出检查磁共振（MR）标记物和 纤维化和炎症的遗传修饰剂，特别是Ltbp 4和osetopontin。面临的一个重大挑战 MR是纤维化的量化，其特征在于短T2值，其可能无法通过 标准MRI。在本辅助研究中，我们将增加对短T2敏感的新型MR采集，以进行监测 在参加母研究的DMD男孩的大队列中， 这项辅助研究的中心假设是，肌肉纤维化和炎症的MR标记物是相关的， LTBP 4和骨桥蛋白基因变异与DMD疾病进展的关系。为了验证这一假设， 提出以下三个目标。在Aim 1中，将在母研究中添加额外的MR扫描，以捕获 并以极短的T2值量化MRI信号以监测纤维化。扫描将在 辅助研究第1年横断面分析的基线，与潜在转化相关 来源于患者成纤维细胞的生长因子TGF β结合蛋白4（LTBP 4）多态性， 的父项目。在目标2中，我们将进行肌肉水松弛的额外定量测量， 水含量（水肿），并将这些与炎症标志物的血清谱差异相关， 骨桥蛋白基因多态性。最后，在目标3中，我们将利用纵向泛函 在父项目中收集MR数据，以研究1年MR变化之间的关系 纤维化、脂质沉积和功能丧失的标志物及其与 LTBP 4/骨桥蛋白基因型。 这是一个时间敏感的应用程序，以利用基础设施投资，获得入学的男孩与 DMD，以及在母自然历史项目中的广泛数据收集。拟议的辅助研究载于 对RFA-AR-13-010的反应，对DMD男孩未来临床试验的发展很重要。

Project Summary/Abstract 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 osetopontin. 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.