Imaging of failed Regeneration in muscles of muscular dystrophy patients

该项目的重点是开发和验证非侵入性生物标志物来表征疾病 Duchenne肌营养不良（DMD）、胶原VI相关肌病的进展（Ullrich和Bethlem） 和Dysferinopathies（LGMD 2B/MM）。尽管肌营养不良的预后差，但治疗 缺乏干预措施，临床试验的结果指标仅限于 肌肉功能和生活质量、肌肉分解的血清生物标志物和侵入性肌肉活检。 额外的定量结果测量是无创的，对肌肉结构的变化敏感 和组合物，以促进有前途的新干预措施从临床前 临床试验的研究。因此，项目3将侧重于磁共振成像（MRI）， MRS（磁共振波谱）策略来监测营养不良的病理生理学特征。在目标1中， 将实施MR自然史研究以评估下肢的进展性受累 三个不同的肌营养不良人群的肌肉。此外，该目标还将评估 MR参数改变与肌肉力量和功能丧失之间的关系。目标2是一个探索性目标 其重点是开发新的MR策略来量化营养不良骨骼肌中的纤维化。 最先进的序列，如超短回波和光谱成像，将得到优化和测试 在目的2a中的肌营养不良的鼠模型中。目标2b将依赖于开发一种新设计的 线圈和优化脉冲序列，以定量映射受试者的肌肉纤维化和肌内脂肪 用临床3 T系统检测肌肉萎缩症。最后，将结合心脏MR技术， 实施以评估DMD男孩的心脏功能和进行性心肌受累。 我们预计，在本研究中优化和验证的MR技术将适用于临床 在广泛的肌营养不良症中进行试验。

This project is focused on the development and validation of noninvasive biomarkers to characterize disease progression in Duchenne Muscular Dystrophy (DMD), Collagen VI related myopathies (Ullrich and Bethlem) and the Dysferiinopathies (LGMD2B/MM). Despite the poor prognosis of muscular dystrophy, therapeufic interventions have been lacking and outcome measures for clinical trials have been limited to measures of muscle funcfion and quality of life, serum biomarkers of muscle breakdown, and invasive muscle biopsies. Additional quantitative outcome measures that are noninvasive and sensitive to changes in muscle structure and composition are needed to facilitate the rapid translation of promising new interventions from preclinical studies to clinical trials. Therefore, Project 3 will focus on magnetic resonance imaging (MRI) and spectroscopy (MRS) strategies to monitor pathophysiological features of dystrophy. In Aim 1 a longitudinal MR natural history study will be implemented to evaluate the progressive involvement of the lower extremity muscles in three disfinct muscular dystrophy populations. In addifion, this aim will assess the relationship between alterafions in MR parameters and loss of muscle strength and funcfion. Aim 2 is an exploratory aim that focuses on the development of novel MR strategies to quantify fibrosis in dystrophic skeletal muscle. State-of-the art sequences, such as ultra short echo and spectroscopic imaging, will be opfimized and tested in murine models of muscular dystrophy in Aim 2a. Aim 2b will rely on the development of a newly designed coil and opfimized pulse sequences to quantitafively map muscle fibrosis and intramuscular fat in subjects with muscular dystrophy using a clinical 3T system. Finally, a combinafion of cardiac MR techniques will be implemented to evaluate cardiac funcfion and progressive myocardial involvement in boys with DMD. We anticipate that the MR techniques opfimized and validated in this study will be appropriate for clinical trials in a wide range of muscular dystrophies.