MANGANESE ENHANCED MRI: NON-INVASIVE MEASURE OF PATHOGENESIS OF DYSTROPHINOPATHY

描述（由申请人提供）：杜氏肌营养不良症（DMD）是最具破坏性的肌营养不良症类型，发病率为每3500名男性中有1例。DMD是一种X连锁的肌肉萎缩性疾病，由细胞骨架蛋白肌营养不良蛋白突变引起。年轻的DMD患者经历肌肉损伤，然后再生;然而，随着疾病的进展，再生受到阻碍，肌肉纤维逐渐被结缔组织和脂肪沉积物取代。严重的肌无力导致10至12岁的活动能力下降，最终在20至30岁时因呼吸和/或心力衰竭而死亡。虽然目前还没有治疗这种疾病的方法，但许多不同的DMD治疗方法正在进入临床试验。基于致病表型的轨迹，需要遵循儿童营养不良过程的时间进展的精确和可靠的非侵入性措施。本提案的目标是开发和验证一种新的MRI技术（锰增强MRI，MEMRI）作为一种非侵入性成像程序，以评估肌肉萎缩症的骨骼肌功能。拟议研究的具体目的是：1）确定静脉注射后骨骼肌内Mn 2+的生物分布，2）使用MEMRI建立一种评估营养不良骨骼肌结构/功能变化的稳健方法。如果成功，拟议的研究将提供一种目前尚未用于评估DMD骨骼肌结构和功能的强大非侵入性方法，这对于评估这些疗法的有益效果至关重要。

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is the most devastating type of muscular dystrophy, with an incidence of 1 in every 3500 males. DMD is an X-linked, muscle-wasting disease caused by mutations in the cytoskeletal protein dystrophin.. Young DMD patients experience muscle damage that is followed by regeneration; however, as the disease progresses regeneration is impeded and muscle fibers are progressively replaced by connective tissue and fatty deposits. Profound muscle weakness results in decreased mobility by 10 to 12 year of age and eventually death by the age of 20 to 30 due to respiratory and/or cardiac failure. While there is currently no treatment for the disease, many different therapeutic approaches for DMD are entering clinical trials. Based on the trajectory of the pathogenic phenotype precise and reliable non-invasive measures that follow the temporal progression of the dystrophic process in children are needed., The goal of this proposal is to develop and validate a novel MRI technique (manganese enhanced MRI, MEMRI) as a noninvasive imaging procedure to assess skeletal muscle function in muscular dystrophy. The Specific Aims of the proposed research are to: 1) establish the biodistribution of Mn2+ within skeletal muscle after intravenous injection, and 2) establish a robust method using MEMRI for assessment of structural/functional changes in dystrophic skeletal muscle. If successful, the proposed research will provide a robust non- invasive method currently not employed for assessing both structure and function of skeletal muscle in DMD, which will be critical in evaluating the beneficial effects of these therapies.