MR Assessment of Bioenergetics and Microvascular Function in Dystrophic Muscle

项目摘要 该项目的总体目标是评估新型磁共振成像(MRI)和 生物能量学的局部化31P-MRS测量 用于监测营养不良肌肉疾病进展和治疗的微血管功能。杜兴 肌营养不良症(DMD)的特征是进行性肌肉无力，功能退化 能力、丧失独立性和过早死亡。DMD儿童的肌肉中缺乏抗肌营养不良蛋白， 伴随着肌膜定位的神经元型一氧化氮合酶(NNOS)的缺乏。虽然 目前还没有治愈DMD的方法，一些有希望的治疗方法正在开发和评估中，年轻的 男孩主要是被攻击的对象。然而，疾病进展的可靠标志是 缺乏的，尤其是年轻男孩。最近的研究表明，在肌肉活力方面有相当大的希望。 用31P-MRS检测营养不良肌肉的状态作为早期病理标志。造成这些问题的原因是 能量干扰(例如，磷酸肌酸减少)以及对 疾病进展和治疗。营养不良肌肉中神经元型一氧化氮合酶的缺失 已被归因于在DMD骨骼肌收缩期间和之后导致血流量减少，以及 也可能导致报告的能量扰动和增加对损伤的敏感性 营养不良的肌肉。在目标1中，我们将使用小鼠模型(MDX)来深入了解 营养不良患者的能量状态和微血管功能的高分辨率磁共振成像在目标2中，我们将建立 含和不含nNOS结合的AAV-microdystrophin载体的治疗作用 域。最后，在目标3中，我们将这些方法应用于患有DMD和未受影响的男孩的下肢 使用横截面设计在一定年龄范围内进行控制。MR测量将评估1)的异质性 用31P二维化学位移成像检测肌肉的能量状态；2)用磁共振成像检测微血管功能 血氧水平依赖(BOLD)对比和动脉自旋标记(ASL)。此外，我们还将测试 这些指标在DMD和对照中的日常变异性。这个项目的总体假设是 生物能量学和微血管功能的局部磁共振测量将使早期发现疾病成为可能 年轻时的病理学，将对疾病的发展做出反应，并将在监测中有效 营养不良肌肉治疗的改进。我们预计，结果将导致可重复性 可用于评估针对DMD和其他神经肌肉疾病的潜在治疗的方法 疾病。

Project Summary The overall objective of this project is to evaluate the potential of novel magnetic resonance imaging (MRI) and localized 31phosphorus-magnetic resonance spectroscopy (31P-MRS) measures of bioenergetics and microvascular function to monitor disease progression and treatment in dystrophic muscle. Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness, deteriorating functional capabilities, loss of independence, and early death. Muscles in children with DMD are deficient in dystrophin, which is accompanied by a lack of sarcolemma-localized neuronal nitric oxide synthase (nNOS). Although there is no cure for DMD, a number of promising therapies are being developed and evaluated, and young boys are predominantly being targeted as subjects. However, reliable markers of disease progression are lacking, particularly in young boys. Recent studies have shown considerable promise in muscle energetic status measured with 31P-MRS as an early marker of pathology in dystrophic muscle. The cause of these energetic disturbances (e.g., reduced phosphocreatine) is poorly understood, as well as the response to disease progression and treatment. The lack of neuronal nitric oxide synthase (nNOS) in dystrophic muscle has been attributed to cause reduced blood flow during and following skeletal muscle contractions in DMD, and may also contribute to the reported energetic perturbations and increased susceptibility to damage in dystrophic muscle. In aim 1 we will use a murine model (mdx) to provide insight into the relationship between energetic status and microvascular function in dystrophy using high resolution MR. In aim 2, we will establish the effects of treatment with an established AAV-microdystrophin vector with and without the nNOS binding domain. Finally, in aim 3, we will apply these methods to the lower extremity of boys with DMD and unaffected controls in a range of ages using a cross sectional design. MR measures will evaluate 1) heterogeneity of energetic status among muscles using 31P 2D chemical shift imaging and 2) microvascular function using MRI blood oxygenation-level dependent (BOLD) contrast and arterial spin labeling (ASL). Furthermore, we will test the day-to-day variability of these measures in DMD and controls. The overall hypothesis of this project is that localized MR measures of bioenergetics and microvascular function will enable early detection of disease pathology at a young age, will be responsive to disease progression, and will be effective in monitoring improvements with treatment in dystrophic muscle. We anticipate that the results will lead to reproducible methods that can be implemented to evaluate potential treatments targeted at DMD and other neuromuscular diseases.