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（由适用提供）：Duchenne肌肉营养不良（DMD）是一种遗传性的严重肌肉退行性疾病，每3500名男孩中有一个。通常首先在3-5岁的患者中观察到普遍和进行性骨骼肌萎缩和无力，使患者轮椅受到12岁的束缚，并最终导致20年代中期因呼吸道或心脏衰竭而导致死亡。 DMD无法治愈，目前，唯一的治疗方法是皮质类固醇，其靶向肌肉变性。但是，皮质类固醇只是姑息治疗：它们将流动性和生命的时间延长了几年。此外，皮质类固醇具有重大麻烦的副作用，导致男孩体重增加，由于骨骼脆弱而变得高度骨折，并可能出现重大的行为问题，所有这些问题都使男孩和家庭的生活变得极为困难。发起 DMD的原因是由于肌营养不良蛋白基因的突变引起的，该突变使肌肉纤维容易发生在每天运动中的膜撕裂，并引发一系列级联的肌肉纤维坏死，慢性感染和最终的肌肉变性。一系列的病理重塑事件涉及多种不同的机制，这些机制涵盖了空间和临时尺度，并且与肌肉组织中的生物力学信号和感染有关。我们假设是生物力学信号和炎症信号之间的反馈最终导致肌肉变性。我们建议检验该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进行对，以开发并实验验证统一的多尺度计算模型（AIM 1）。然后，我们建议使用肌肉重塑的多尺度模型通过挑战该模型来预测对不同治疗干预措施的反应，并探讨为什么DMD最广泛使用的鼠模型，MDX小鼠，MDX小鼠，不良概括了人类疾病（AIM 2）。最后，我们建议根据DMD男孩收集的新数据制作人类版本的多尺度模型，并使用它来测试具有可变程度效率程度的不同前进疗法，并通过了解如何通过了解生物力学和感染反馈来互相引起这种可怕的疾病（AIM 3）来识别新的治疗方法。