DP ARF Ultrasound for Monitoring Muscle Degeneration in Duchenne Muscular Dystrop

描述(申请人提供)：Duchenne肌营养不良症(DMD)是一种X连锁隐性遗传病，影响大约3500名男性新生儿中的1名，骨骼肌和心肌逐渐退化，被纤维组织和脂肪取代。随之而来的肌肉无力通常在5岁时出现在患病的男孩身上，他们通常在10岁时不能走路，并在十几岁或二十出头时死亡。12-15目前没有任何治疗方法阻止或逆转DMD的进展，但许多重要的分子发现导致了广泛的治疗前景。16-22然而，将这些前景转化为临床试验被推迟了，因为不充分的结果衡量标准缺乏对个别肌肉的敏感性，没有与改变生活的事件(例如，失去行走能力)相关，和/或直到疾病发展到后期才提供有意义的措施。2常规测试未能作为临床上有意义的结果的早期和具体指标，这是在实现儿童和成人的DMD和其他30多种肌营养不良的新疗法方面的一个重大差距。目前还需要一种有效的、非侵入性的方法来测量肌营养不良蛋白缺乏对个体肌肉的组成和功能的影响，这种需求尚未得到满足。为了满足这一需求，我们的实验室正在开发一种新的双推(DP)声辐射力(ARF)超声成像方法，该方法非侵入性地和集中地区分肌肉的力学特性以描绘与DMD相关的成分和结构变化。30我们在金毛猎犬肌肉营养不良(GRMD)(人类DMD的相关模型)上的初步数据31-36支持DP ARF区分受影响狗的股直肌(RF)中的纤维沉积和颅缝匠肌(CS)中的真正肥大，37这与先前对这些肌肉的病理学研究一致。31，33，34在具有Myostatin抑制的杂交GRMD犬中获得了可比较的DP ARF结果38-40表明这种纤维沉积(RF)和真正肥大(CS)的趋势如预期的那样在促进肌肉生长的背景下得到保留。进一步发展DP ARF超声作为非侵入性监测营养不良肌肉退行性机械和成分变化的有效工具是本研究计划的长期目标。作为实现我们长期目标的关键的第一步，这项拟议研究的目标是证明DP ARF用于描述营养不良肌肉的机械特性和组成。我们的研究将遵循两个平行的方向：1)通过病理验证并与MRI比较，在北卡罗来纳州国立卫生研究院国家犬科中心对GRMD犬进行体内成像，并与MRI进行比较；2)在肌肉营养不良协会(MDA)诊所和北卡罗来纳大学韦尔斯通肌营养不良合作研究中心对DMD男孩进行活体成像，并与标准定量肌肉测试(QMT)和定时功能测试(TFTs)相关联。我们预计，这种方法虽然在范围上具有挑战性，但如果一个领域出现问题，将使项目的各个部分能够相互协同，而不是相互依赖才能完成。我们假设，DP ARF超声描绘了个体营养不良肌肉从疾病发展的早期到晚期的肌肉成分和功能的变化，这些变化与患者志愿者失去行走的时间相关。

DESCRIPTION (provided by applicant): In Duchenne muscular dystrophy (DMD), an X-linked recessive disorder affecting approximately 1 of 3,500 newborn human males, skeletal and cardiac muscles progressively degenerate and are replaced by fibrous tissue and fat. Consequent muscle weakness typically presents by age 5 in afflicted boys who are usually unable to walk by age 10 and die by their late teens or early twenties.12-15 No treatment currently halts or reverses DMD progression, but a host of important molecular discoveries have lead to a wide range of treatment prospects.16-22 However, translating these prospects to clinical trials has been delayed by inadequate outcome measures that lack sensitivity to individual muscles, fail to correlate to life altering events (e.g. loss of ambulation), and/or do not provide meaningful measures until late stages of disease development.2 The failure of conventional tests to serve as early and specific indicators of clinically meaningful outcomes represents a major gap in realizing new treatments for DMD and the other 30+ types of muscular dystrophies in children and adults. There is an unmet need for a validated, noninvasive measure of the impact of dystrophin deficiency on the composition and function of individual muscles. To address this need, our laboratory is developing a novel double-push (DP) acoustic radiation force (ARF) ultrasound imaging method that noninvasively and focally discriminates the mechanical properties of muscle to delineate compositional and structural changes associated with DMD.30 Our preliminary data in Golden Retriever Muscular Dystrophy (GRMD) dogs, a relevant model of human DMD,31-36 supports that DP ARF discriminates fibrous deposition in the rectus femoris (RF) and true hypertrophy in the cranial sartorius (CS) muscles of affected dogs,37 which is consistent with prior pathologic studies of these muscles.31,33,34 Comparable DP ARF results were obtained in a crossbred GRMD dog with myostatin inhibition,38-40 indicating that this trend towards fibrous deposition (RF) and true hypertrophy (CS) is preserved in the context of promoted muscle growth, as expected. Further developing DP ARF ultrasound as a validated tool for noninvasively monitoring degenerative mechanical and compositional changes in dystrophic muscles is the long-term goal of this research program. As a critical first step toward achieving our long-term goal, the objectives of the proposed research are to demonstrate DP ARF for describing dystrophic muscle mechanical property and composition. Our investigation will follow two parallel thrusts: 1) in vivo imaging in GRMD dogs in the NIH National Center for Canine Models of DMD at UNC-CH with pathological validation and comparison to MRI, and 2) in vivo imaging in DMD boys in the Muscular Dystrophy Association (MDA) clinic and the Wellstone Muscular Dystrophy Cooperative Research Center at UNC-CH with correlation to standard quantitative muscle testing (QMT) and timed function tests (TFTs). We anticipate that this approach, while challenging in its scope, will allow the individual parts of the project to be synergistic without being interdependent on one another for completion, should problems arise in one area. We hypothesize that DP ARF ultrasound delineates changes in muscle composition and function in individual dystrophic muscles, from early through late stages of disease development, that correlate to time to loss of ambulation in patient volunteers.