MRI-based computer models of DMD gait to explain selective muscle degeneration

基于 MRI 的 DMD 步态计算机模型可解释选择性肌肉变性

• 批准号: 9232074
• 负责人: Silvia Salinas Blemker
• 金额: $ 17.38万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232074
• 关键词: Affect; Age; Animals; Birth; Cardiac; Caring; Child; Computer Simulation; DNA Sequence Alteration; Data; Development; Duchenne muscular dystrophy; Dystrophin; Evidence based practice; Exercise; Exhibits; Fatty acid glycerol esters; Gait; Genes; Goals; Guidelines; Health; Heart failure; Human; Impairment; Limb structure; Longevity; Lower Extremity; Magnetic Resonance Imaging; Medical Imaging; Movement; Muscle; Muscle function; Muscular Dystrophies; Musculoskeletal; Pathologic; Patients; Pattern; Phase; Physical activity; Quality of life; Regimen; Rehabilitation therapy; Relaxation; Research; Respiratory Failure; Self-Help Devices; Teenagers; Testing; Time; Walking; Work; base; boys; design; exercise regimen; experimental study; imaging biomarker; improved; innovation; male; mechanical properties; muscle degeneration; public health relevance; rehabilitation management; respiratory; simulation

 DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD), a genetic mutation in the dystrophin gene that affects 1 in 3500 male births, causes rapid progressive muscle degeneration. Boys with DMD gradually lose ambulation, often in their teens, and die of respiratory and cardiac complications by their twenties or thirties. Currently, there are no definitive effective cures for DMD. While potential treatments are in trial phases, priorities of care and exercise management for patients with DMD are to prolong ambulation, maintain quality of life and improve longevity. However, there is currently a paucity of scientifically base guidelines for prescribing safe exercise management for boys with DMD. A better understanding of how physical activity leads to muscle degeneration in DMD is critical for establishing evidence-based practices for maintaining ambulation as long as possible. It remains unclear why some lower limb muscles degenerate more quickly than others in DMD (selective degeneration), despite the fact that dystrophin is deficient in all lower limb muscles. Although multiple factors could affect the pace of degeneration, our central hypothesis is that specifically for lower limb muscles in DMD, differing degree of eccentric contraction during walking across muscles significantly contributes to the selective degeneration. The goal of our work is to develop computer models to predict the impact of various activities on the progression of muscle degeneration in DMD, thereby providing scientific guidelines for DMD care and exercise management. Since walking is the most frequent and essential activity for lower limb muscles, this exploratory project will test the hypothesis that eccentric contractions estimated from musculoskeletal simulations of walking predict the patterns of muscle degeneration in the lower limb of children with DMD. This work will lead to a more scientific basis for determining exercise and designing assistive devices that promote muscle health and mobility while minimizing damage in children with DMD. We propose to integrate computer simulations, gait experiments and magnetic resonance imaging (MRI) to achieve this goal with two specific aims. In aim 1, we will determine if muscle loads during gait - determined from computer simulations - predict selective degeneration of lower limb muscles in DMD. In aim 2, we will determine if impaired DMD gait leads to increased muscle loads during gait. This project will provide a new innovative framework for developing rehabilitation regimens that optimize gait and prolong ambulation. The experiment-simulation framework developed in this project can be further applied to understand the influences of various other activities on the progression of DMD, and potentially on the progression of other types of muscular dystrophy, such as Becker or Limb-Girdle. The research proposed here will be crucial to develop quantitative guidelines for care and exercise management as well as in designing assistive devices that would alleviate muscle degeneration, prolonging ambulation, maintaining quality of life and improving longevity.

 描述(申请人提供)：Duchenne肌营养不良症(DMD)是营养不良蛋白基因的一种基因突变，每3500名男性新生儿中就有一人受到影响，导致快速进行性肌肉退化。患有DMD的男孩通常在十几岁时逐渐失去行走能力，并在二十多岁或三十多岁时死于呼吸道和心脏并发症。目前，对于DMD还没有明确有效的治疗方法。虽然可能的治疗处于试验阶段，但DMD患者的护理和运动管理的优先事项是延长步行时间，保持生活质量和提高寿命。然而，目前缺乏为患有DMD的男孩开出安全运动管理处方的科学基础指南。更好地了解身体活动如何导致DMD的肌肉退化，对于建立尽可能长时间保持步行的循证实践至关重要。目前尚不清楚为什么在选择性退行性变(DMD)中，一些下肢肌肉比其他肌肉退化得更快，尽管Dstrophin在所有下肢肌肉中都是缺乏的。虽然多种因素可能会影响退化的速度，但我们的中心假设是 对于DMD患者的小腿肌肉，行走过程中不同程度的偏心收缩是导致选择性退行性变的重要原因。我们工作的目标是开发计算机模型来预测各种活动对DMD肌肉退变进程的影响，从而为DMD的护理和运动管理提供科学的指导。由于步行是腿部肌肉最频繁和最基本的活动，这个探索性项目将检验这样一个假设，即通过步行的肌肉骨骼模拟估计的偏心收缩可以预测DMD儿童下肢肌肉退化的模式。这项工作将为确定运动和设计辅助设备提供更科学的基础，这些辅助设备可以促进肌肉健康和活动，同时将DMD儿童的损害降至最低。我们建议结合计算机模拟、步态实验和核磁共振成像(MRI)来实现这一目标，具体有两个目标。在目标1中，我们将确定步态中的肌肉负荷--通过计算机模拟确定--是否可以预测DMD患者下肢肌肉的选择性退行性变。在目标2中，我们将确定DMD步态受损是否会导致步态中肌肉负荷的增加。该项目将为开发优化步态和延长步行的康复养生法提供一个新的创新框架。本项目开发的实验-模拟框架可以进一步应用于了解各种其他活动对DMD进展的影响，以及潜在地对其他类型的肌营养不良的进展的影响，如Becker或Limb-Girdle。这里提出的研究对于制定护理和运动管理的量化指南以及设计辅助设备将是至关重要的，这些辅助设备将缓解肌肉退化、延长步行时间、维持生活质量和提高寿命。