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: 8326055
• 负责人: Caterina M Gallippi
• 金额: $ 43.78万
• 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/8326055
• 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）：在杜氏肌营养不良症（DMD）中，一种X连锁隐性疾病影响约1/3，500的新生男性，骨骼肌和心肌进行性退化，并被纤维组织和脂肪取代。患有DMD的男孩通常在5岁时出现痉挛性肌无力，这些男孩通常在10岁时无法行走，并在青少年后期或20岁出头死亡。12 -15目前没有任何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带来了广泛的治疗前景。由于缺乏对个体肌肉的敏感性，未能与改变生活的事件相关联，（例如，丧失安培），和/2常规检查未能作为有临床意义结果的早期和特异性指标，这代表了实现DMD新治疗方法的主要差距以及其他30多种儿童和成人肌营养不良症。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经验证的非侵入性测量存在未满足的需求。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，该方法非侵入性和局部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我们在金毛猎犬肌营养不良（GRMD）犬（人类DMD的相关模型）中的初步数据，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的杂交GRMD犬中获得了可比较的DP ARF结果，38-40表明在促进肌肉生长的背景下保持了这种纤维沉积（RF）和真正肥大（CS）的趋势，正如预期的那样。进一步开发DP ARF超声作为非侵入性监测营养不良肌肉中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性质和组成。我们的调查将沿着两个平行的方向进行：1）在UNC-CH的NIH National Center for Canine Models of DMD的GRMD狗中的体内成像，具有病理学验证和与MRI的比较，和2）肌营养不良协会（MDA）诊所和UNC-CH的Wellstone肌营养不良合作研究中心的DMD男孩体内成像与标准定量肌肉测试（QMT）相关和定时功能测试（TFT）。我们预计，这一办法虽然在范围上具有挑战性，但如果在一个领域出现问题，将使项目的各个部分能够发挥协同作用，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中肌肉组成和功能的变化，从疾病发展的早期到晚期，与患者志愿者中amorphin丧失的时间相关。