IMAGING OF FAILED REGENERATION IN MUSCLES OF MUSCULAR DYSTROPHY PATIENTS

项目摘要 杜氏肌营养不良症(DMD)是一种神经肌肉疾病，由dystrophin和dstrophin基因突变引起 以进行性肌肉无力、早期失去行走能力、心肌病和呼吸系统疾病为特征 不够用。由于有限的自然病史数据和缺乏敏感性，DMD的临床试验一直受到阻碍 非侵入性结果测量。此外，这种单基因疾病表现出相当大的变异性 疾病的严重性。表型变异的产生，部分是由于遗传修饰物的存在，这些修饰物可以增强或 抑制疾病进程。 在此续订申请中，我们将检查报告的影响疾病的多态 进展，包括SPP1和LTBP4，相对于磁共振成像(MRI)生物标记物。LTBP4 编码潜伏的转化生长因子β结合蛋白(LTBP4)，在两种动物中都有高表达 并调节活性转化生长因子β的释放。DMD患者为纯合子 已有报道表明IAAM LTBP4单倍型表现为步行功能保留和转化生长因子β减少 与VTTT单倍型杂合子或纯合子患者的信号转导比较。基因分型 编码骨桥蛋白的spp1基因启动子区域的rs28357094多态性已被证明是 影响健康成年人的肌肉大小和偏心损伤，以及DMD的疾病严重程度。检视 这些遗传多态与核磁共振生物标记物之间的关联我们将利用 在大型DMD中采集的自然病史、下肢磁共振图像和生物样本 队列(ImagingDMD)。此外，我们将开发新的MRI策略来监控疾病的进展 心脏和呼吸肌。这将是第一个监测肋间肌肉病理的影像研究。 以及患有DMD的男孩的腹肌。我们假设具有保护性LTBP4的DMD患者 单倍型将显示心脏疾病进展较慢的速度和较轻的病理生理 呼吸肌。 这项研究的结果可能最终对同质患者的分层具有重要意义。 临床试验，帮助确定新的治疗靶点，并为临床试验靶向提供新的生物标志物 呼吸功能。

Project Summary Duchenne Muscular Dystrophy (DMD) is a neuromuscular disease caused by mutations in dystrophin and characterized by progressive muscle weakness, early loss of ambulation, cardiomyopathy and respiratory insufficiency. Clinical trials in DMD have been hampered by limited natural history data and a lack of sensitive noninvasive outcome measures. In addition, this single-gene disease displays considerable variability in disease severity. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. In this renewal application, we will examine the impact of polymorphisms reported to affect disease progression, including SPP1 and LTBP4, relative to magnetic resonance imaging (MRI) biomarkers. LTBP4 encodes the latent transforming growth factor (TGF) β binding protein (LTBP4), that is highly expressed in both cardiac and skeletal muscle, and regulates the release of active TGFβ. DMD patients homozygous for the IAAM LTBP4 haplotype have been reported to demonstrate preserved ambulatory function and reduced TGFβ signaling compared to patients heterozygous or homozygous for the VTTT haplotype. Genotype at polymorphism rs28357094 in the promoter region of the SPP1 gene, encoding osteopontin, has been shown to influence muscle size and eccentric injury in healthy adults, as well as disease severity in DMD. To examine the association between these genetic polymorphisms and MRI biomarkers we will take advantage of the natural history lower extremity Magnetic Resonance images and biological samples acquired in a large DMD cohort (ImagingDMD). In addition, we will develop novel MRI strategies to monitor disease progression in the heart and respiratory muscles. This will be the first imaging study to monitor muscle pathology in the intercostal and abdominal muscle in boys with DMD. We hypothesize that DMD patients with the protective LTBP4 haplotype will demonstrate slower rates of cardiac disease progression and less severe pathophysiology in the respiratory muscles. The results of this study may ultimately be important for the stratification of homogenous patients for clinical trials, help identify new therapeutic targets, and provide new biomarkers for clinical trials targeting respiratory function.