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

基本信息

批准号：
8704340
负责人：
Caterina M Gallippi
金额：
$ 43.13万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/8704340
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 in vivo imaging muscle degeneration muscle strength myostatin novel programs rectus femoris respiratory response therapy development tool trend vastus lateralis volunteer

项目摘要

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Duchenne肌肉营养不良（DMD）中，一种X连锁的隐性疾病，影响3500名新生的人类男性中约1个，骨骼和心脏肌肉逐渐退化，并被纤维组织和脂肪所取代。随之而来的肌肉无力通常按5岁的男孩呈现，他们通常无法在10岁之前行走并在十几岁或二十多岁时死亡。12-15目前没有治疗停止或逆转DMD的进展，许多重要的分子发现导致了各种各样的治疗前景。肌肉与改变生活事件（例如失去行动）和/或在疾病发育的晚期之前不提供有意义的措施。2传统测试未能作为临床上有意义的早期有意义的结果指标，这代表了实现DMD和其他30多种肌肉类型的儿童的新疗法的主要差距。对肌营养不良蛋白缺乏症对单个肌肉组成和功能的影响的验证的无创测量的需求未满足。为了满足这一需求，我们的实验室正在开发一种新型的双刺（DP）声学辐射力（ARF）超声成像方法，该方法无创，局部区分肌肉的机械特性，以描绘与DMD相关的构成和结构变化。30我们的狗的初步数据，即狗的前期数据，31-人类dogs dogs dogs dogs dogs dogs dogs dogs dogs dogs dogs dogs dogs dogny dogs dogs dods dods dods dods dods dods dods dods dods dods dods dods dods dods dods dods a dody dods dods dods n of 31- 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如预期的那样，在促进肌肉生长的背景下，保留了纤维沉积（RF）和真正的肥大（CS）。该研究计划的长期目标是进一步开发DP ARF Ultrasound作为验证的工具，用于非侵入性监测营养不良肌肉的退化机械和组成变化。作为实现我们长期目标的关键第一步，拟议的研究的目标是证明DP ARF来描述营养不良的肌肉机械性能和组成。 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测试（QMT）和定时功能测试（TFTS）。我们预计，这种方法在其范围上具有挑战性，但如果在一个领域出现问题，那么项目的各个部分就可以保持协同作用而不会相互依存。我们假设DP ARF超声描述了从疾病发育的早期到晚期的单个营养不良肌肉中肌肉组成和功能的变化，这些肌肉与患者志愿者的流动丧失相关。