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，由肌营养不良蛋白突变引起， 其特征在于进行性肌无力、早期丧失肌张力、心肌病和呼吸系统疾病。 不足DMD的临床试验受到有限的自然病史数据和缺乏敏感的 非侵入性结果测量。此外，这种单基因疾病显示出相当大的变异性， 疾病严重程度。表型变异的出现，部分是由于存在遗传修饰剂， 抑制疾病进程。 在这次更新申请中，我们将研究报告的影响疾病的多态性的影响。 进展，包括SPP 1和LTBP 4，相对于磁共振成像（MRI）生物标志物。LTBP4 编码潜伏性转化生长因子（TGF）β结合蛋白（LTBP 4），该蛋白在两种组织中均高度表达。 心脏和骨骼肌，并调节活性TGFβ的释放。DMD患者中， IAAM LTBP4单倍型已被报道显示保留了行走功能和降低了TGFβ 与VTTT单倍型杂合或纯合的患者相比，基因型 编码骨桥蛋白的SPP 1基因启动子区的多态性rs 28357094已被证明 影响健康成年人的肌肉大小和偏心性损伤，以及DMD的疾病严重程度。审查 这些遗传多态性和MRI生物标志物之间的关联，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策略来监测疾病进展， 心脏和呼吸肌这将是第一次成像研究，以监测肌肉病理在肋间 和腹部肌肉的变化。我们假设具有保护性LTBP 4的DMD患者 单倍型将显示心脏疾病进展的较慢速率和较不严重的病理生理学， 呼吸肌 这项研究的结果最终可能对同质性患者的分层很重要， 临床试验，帮助确定新的治疗靶点，并为临床试验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.