DP ARF Ultrasound for Monitoring Muscle Degeneration in Duchenne Muscular Dystrop

DP ARF 超声监测杜氏肌营养不良症患者的肌肉退化

• 批准号: 8517226
• 负责人: Caterina M Gallippi
• 金额: $ 42.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517226
• 关键词: Acoustics; Address; Adult; Affect; Age; Area; Canis familiaris; Cardiac; Cephalic; Child; Clinic; Clinical; Clinical Trials; Complex; Cross-Sectional Studies; Crossbreeding; Data; Deposition; Development; Disease; Duchenne muscular dystrophy; Dystrophin; Enrollment; Event; Failure; Fatty acid glycerol esters; Genes; Goals; Growth; Human; Hypertrophy; Image; Individual; Investigation; Laboratories; Lead; Life; Link; Longitudinal Studies; Lung; Magnetic Resonance Imaging; Measures; Mechanics; Membrane; Methods; Modeling; Molecular; Monitor; Muscle; Muscle Weakness; Muscular Dystrophies; Myocardium; Natural History; Newborn Infant; Outcome; Outcome Measure; Pathologic; Patients; Property; Proteins; Radiation; Research; Research Proposals; Sartorius Muscle; Seminal; Sensitivity and Specificity; Skeletal Muscle; Staging; Teenagers; Testing; Time; Tissues; Translating; Translations; Ultrasonography; United States National Institutes of Health; Validation; Variant; Walking; boys; human male; imaging modality; in vivo; muscle degeneration; muscle strength; myostatin; novel; programs; rectus femoris; respiratory; response; therapy development; tool; trend; vastus lateralis; volunteer

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.

描述（由申请人提供）：杜氏肌营养不良症 (DMD) 是一种 X 连锁隐性遗传病，影响 3,500 名新生男性中的大约 1 名，骨骼和心肌逐渐退化，并被纤维组织和脂肪取代。受影响的男孩通常在 5 岁时出现肌肉无力，这些男孩通常在 10 岁时无法行走，并在十几岁或二十岁出头时死亡。12-15 目前尚无治疗方法可以阻止或逆转 DMD 的进展，但许多重要的分子发现已经带来了广泛的治疗前景。16-22 然而，由于对个体缺乏敏感性的结果测量不足，将这些前景转化为临床试验已被推迟。 无法与改变生活的事件（例如丧失行走能力）相关联，和/或直到疾病发展的后期才提供有意义的测量。2 传统测试未能作为具有临床意义的结果的早期和具体指标，这表明在儿童和成人中实现 DMD 和其他 30 多种类型的肌营养不良症的新疗法方面存在重大差距。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进行有效的、非侵入性的测量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型双推 (DP) 声辐射力 (ARF) 超声成像方法，该方法可非侵入性地集中区分肌肉的机械特性，以描绘与 DMD 相关的成分和结构变化。30 我们在金毛寻回犬肌营养不良症 (GRMD) 犬（人类 DMD 的相关模型）中的初步数据31-36 支持这一点 DP ARF 可区分受影响狗的股直肌 (RF) 中的纤维沉积和颅缝肌 (CS) 肌肉中的真正肥大，37 这与这些肌肉的先前病理研究一致。31,33,34 在具有肌生长抑制素抑制作用的杂交 GRMD 狗中获得了类似的 DP ARF 结果，38-40 表明这种趋势 正如预期的那样，纤维沉积（RF）和真正的肥大（CS）在促进肌肉生长的情况下得以保留。进一步开发 DP ARF 超声作为一种经过验证的工具，用于无创监测营养不良性肌肉的退行性机械和成分变化是该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 用于描述营养不良的肌肉机械特性和组成。我们的研究将遵循两个并行的方向：1）在 UNC-CH 的 NIH 国家 DMD 犬模型中心对 GRMD 狗进行体内成像，并进行病理验证并与 MRI 进行比较；2）在 UNC-CH 的肌营养不良协会 (MDA) 诊所和 Wellstone 肌营养不良合作研究中心对 DMD 男孩进行体内成像，并与标准定量肌肉相关 测试（QMT）和定时功能测试（TFT）。我们预计，这种方法虽然在范围上具有挑战性，但如果某个领域出现问题，将使项目的各个部分能够协同工作，而不会相互依赖来完成。我们假设 DP ARF 超声描述了个体营养不良性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。