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

描述(申请人提供)：Duchenne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名。DMD是一种X连锁的肌肉萎缩疾病，由细胞骨架蛋白dystrophin突变引起。年轻的DMD患者经历肌肉损伤，随后是再生；然而，随着疾病的进展，再生受阻，肌肉纤维逐渐被结缔组织和脂肪沉积取代。严重的肌肉无力会导致10到12岁的儿童行动不便，最终会因为呼吸和/或心脏衰竭而在20到30岁时死亡。虽然目前还没有治疗这种疾病的方法，但许多不同的治疗DMD的方法正在进入临床试验。基于疾病表型的轨迹，需要精确和可靠的非侵入性测量来跟踪儿童营养不良过程的时间进程。本建议的目的是开发和验证一种新的MRI技术(锰增强磁共振成像，MEMRI)作为一种非侵入性成像方法来评估肌营养不良症的骨骼肌功能。这项研究的具体目的是：1)建立静脉注射后Mn2+在骨骼肌中的生物分布；2)建立一种稳健的MEMRI方法来评估营养不良骨骼肌的结构/功能变化。如果成功，这项拟议的研究将提供一种强大的非侵入性方法，目前还没有用于评估DMD的骨骼肌结构和功能，这将是评估这些疗法的有益效果的关键。

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.