DP ARF Ultrasound for Monitoring Muscle Degeneration in Duchenne Muscular Dystrop

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种x连锁隐性疾病，影响大约3500名新生儿男性中的1名，骨骼肌和心肌逐渐退化，并被纤维组织和脂肪取代。随之而来的肌肉无力通常在5岁时出现在受折磨的男孩身上，他们通常在10岁时无法行走，在十几岁或二十岁出头时死亡。目前还没有任何治疗方法可以阻止或逆转DMD的进展，但一系列重要的分子发现带来了广泛的治疗前景。然而，将这些前景转化为临床试验一直被延迟，因为不充分的结果测量缺乏对个体肌肉的敏感性，不能与改变生活的事件（例如失去行走能力）相关联，和/或直到疾病发展的晚期才提供有意义的测量常规测试无法作为临床有意义结果的早期和具体指标，这是实现DMD和其他30多种儿童和成人肌肉营养不良症新疗法的主要差距。对于肌营养不良蛋白缺乏对个体肌肉的组成和功能的影响的一种有效的、无创的测量方法的需求尚未得到满足。为了满足这一需求，我们的实验室正在开发一种新的双推力（DP）声辐射力（ARF）超声成像方法，该方法无创地局部区分肌肉的机械特性，以描绘与肌肉萎缩症（GRMD）相关的成分和结构变化。一个相关的人类DMD模型，31-36支持DP ARF区分受影响犬的股直肌（RF）纤维沉积和颅缝肌（CS）的真正肥大，这与先前对这些肌肉的病理研究相一致在肌肉生长抑制素抑制的GRMD杂交犬中获得了类似的DP ARF结果，38-40表明，正如预期的那样，在促进肌肉生长的背景下，纤维沉积（RF）和真正的肥大（CS）的趋势得到了保留。进一步发展DP ARF超声作为无创监测营养不良肌肉退行性力学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第一步，拟议研究的目标是证明DP ARF用于描述营养不良肌肉的力学特性和组成。我们的研究将遵循两个平行的重点：1)在UNC-CH的NIH国家犬类DMD模型中心对GRMD犬进行体内成像，并进行病理验证和与MRI的比较；2)在UNC-CH的肌肉萎缩协会（MDA）诊所和Wellstone肌肉萎缩症合作研究中心对DMD男孩进行体内成像，与标准定量肌肉测试（QMT）和定时功能测试（TFTs）相关。我们预计，这种方法虽然在其范围内具有挑战性，但如果在一个领域出现问题，它将使项目的各个部分能够协同工作，而不是相互依赖以完成。我们假设DP ARF超声描述了个体营养不良肌肉的肌肉成分和功能的变化，从疾病发展的早期到晚期，这些变化与患者志愿者的行动能力丧失时间有关。

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. PUBLIC HEALTH RELEVANCE: Duchenne muscular dystrophy (DMD) leads to muscle weakness in afflicted boys who are generally unable to walk by age 10 and die by their late teens or early twenties. A wide range of treatment prospects exist, but their translation to clinical use has been delayed by insufficient testing methods. The objectives of this research proposal are to demonstrate a new noninvasive imaging method - Double Push (DP) Acoustic Radiation Force (ARF) ultrasound - as a better test of DMD progression and response to treatment.