Multiscale Modeling for Treatment Discovery in Duchenne Muscular Dystrophy

杜氏肌营养不良症治疗探索的多尺度建模

基本信息

批准号：
9345312
负责人：
Silvia Salinas Blemker
金额：
$ 52.47万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-09 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9345312
关键词：
12 year old 5 year old Acute Adrenal Cortex Hormones Adverse effects Affect Age Anti-Inflammatory Agents Anti-inflammatory Behavior Behavioral Biological Markers Biomechanics Blood Cell membrane Cells Cessation of life Chronic Clinic Clinical Treatment Communication Complex Computer Simulation Consensus Cytoskeleton DNA Sequence Alteration Data Degenerative Disorder Disease Duchenne muscular dystrophy Dystrophin Elements Event Extracellular Matrix Family Feedback Fibroblasts Fibrosis Fracture Genes Goals Grant Heart failure Hereditary Disease Human Inflammation Inflammatory Inflammatory Response Inherited Intervention Life Link Lower Extremity Magnetic Resonance Imaging Measurement Mechanics Membrane Modeling Modification Motion Movement Mus Muscle Muscle Cells Muscle Contraction Muscle Fibers Muscle Weakness Muscular Atrophy Muscular Dystrophies Mutation Necrosis Pathologic Patients Pharmaceutical Preparations Process Property Proteins Protocols documentation Publishing Respiratory Diaphragm Respiratory Failure Running Signal Transduction Stress Teenagers Testing Time Tissues Transcend Translating Translations Walking Wasting Syndrome Weight Gain Wheelchairs Work base biomechanical model bone boys drug discovery empowered exon skipping experimental study human data human disease in vivo macrophage mdx mouse mechanical properties mini-dystrophin models and simulation mouse model multi-scale modeling muscle degeneration muscle strength muscle stress neutrophil novel palliative pre-clinical predicting response public health relevance respiratory satellite cell simulation skeletal muscle wasting stem cell therapy treatment effect treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is an inherited, severe muscle degenerative disease that affects one in every 3,500 boys. Pervasive and progressive skeletal muscle atrophy and weakness is generally first observed in patients at 3-5 years of age, leaves patients wheelchair bound by age 12 years, and ultimately leads to death due to respiratory or cardiac failure by the mid-20s. There is no cure for DMD, and currently, the only treatment is corticosteroids, which targets inflammation in muscle degeneration. However, corticosteroids are merely palliative: they extend the time of mobility and life by only a few years. Furthermore, corticosteroids have major troublesome side effects, causing boys to gain weight, become highly prone to fractures due to brittle bones, and potentially develop significant behavioral issues, all of which make lives of boys and families extremely difficult. The initiating cause of DMD is due to a mutation in the dystrophin gene, which renders muscle fibers prone to membrane tearing during everyday movements and initiates a cascade of muscle fiber necrosis, chronic inflammation, and ultimately muscle degeneration. This cascade of pathological remodeling events involves multiple different mechanisms that span spatial and temporal scales and pertain to biomechanical signals and inflammation in the muscle tissue. We hypothesize that it is the feedback between biomechanical signals and inflammatory signals that ultimately leads to muscle degeneration. We posit that testing this hypothesis requires a multiscale computational model. We propose to couple biomechanical modeling with agent-based modeling to develop and then experimentally validate a unified multiscale computational model (Aim 1). We then propose to use our multiscale model of muscle remodeling to test our hypothesis by challenging the model to predict the response to different treatment interventions and to explore why the most widely used murine model of DMD, the mdx mouse, poorly recapitulates human disease (Aim 2). Finally, we propose to make a human version of the multiscale model, based on novel data collected in boys with DMD, and use it to test different front-running treatments that have had variable degrees of efficacy and to identify new treatments that are informed by understanding how biomechanics and inflammation feedback on one another to cause this terrible disease (Aim 3).

描述（由申请人提供）：杜氏肌营养不良症 (DMD) 是一种遗传性严重肌肉退行性疾病，每 3,500 名男孩中就有一人患有普遍且进行性的骨骼肌萎缩和无力，通常首先在 3-5 岁的患者中观察到。，让患者在 12 岁时就必须坐在轮椅上，最终导致 20 多岁时因呼吸或心力衰竭而死亡。唯一的治疗方法是皮质类固醇，它针对的是肌肉退化的炎症。然而，皮质类固醇只是姑息治疗：它们只能将活动时间和寿命延长几年。此外，皮质类固醇有严重的副作用，导致男孩体重增加、体重增加。由于骨骼脆弱，容易发生骨折，并可能出现严重的行为问题，所有这些都使男孩和家庭的生活变得极其困难。 DMD 的病因是肌营养不良蛋白基因突变，导致肌纤维在日常运动中容易发生膜撕裂，并引发一系列肌纤维坏死、慢性炎症，最终导致肌肉退化。这种级联病理重塑事件涉及多种不同的过程。跨越空间和时间尺度并与肌肉组织中的生物力学信号和炎症有关的机制我们探索了生物力学信号和炎症信号之间的反馈最终导致肌肉退化。假设测试这个假设需要一个多尺度计算模型，我们建议将生物力学建模与基于代理的建模结合起来，然后通过实验验证一个统一的多尺度计算模型（目标 1）。通过挑战模型来预测对不同治疗干预措施的反应来检验我们的假设，并探索为什么最广泛使用的 DMD 小鼠模型（mdx 小鼠）不能很好地概括人类疾病（目标 2）。多尺度模型的版本，基于在患有 DMD 的男孩中收集的新数据，并用它来测试具有不同程度功效的不同领先治疗方法，并通过了解生物力学和炎症如何反馈来确定新的治疗方法另一个导致这种可怕疾病的因素（目标 3）。