Multiscale Modeling for Treatment Discovery in Duchenne Muscular Dystrophy

 描述(申请人提供)：Duchenne肌营养不良症(DMD)是一种遗传性的严重肌肉退行性疾病，每3500名男孩中就有一人受到影响。普遍和进行性的骨骼肌萎缩和虚弱通常在3-5岁的患者中首次出现，使患者在12岁时被轮椅束缚，并最终导致在25岁左右因呼吸或心脏衰竭而死亡。目前还没有治愈DMD的方法，目前唯一的治疗方法是皮质类固醇，它针对肌肉退化中的炎症。然而，皮质类固醇只是治标不治本：它们只会将活动时间和寿命延长几年。此外，皮质类固醇有很大的麻烦的副作用，导致男孩体重增加，由于骨骼脆弱而极易骨折，并可能发展成严重的行为问题，所有这些都使男孩和家庭的生活极其困难。发起人 DMD的原因是由于dystrophin基因的突变，使肌肉纤维在日常运动中容易膜撕裂，并引发肌肉纤维坏死、慢性炎症，最终肌肉退化。这种病理性重塑事件的级联涉及跨越空间和时间尺度的多种不同机制，与生物力学信号和肌肉组织中的炎症有关。我们假设最终导致肌肉退变的是生物力学信号和炎症信号之间的反馈。我们假设，检验这一假设需要一个多尺度的计算模型。我们建议将生物力学建模与基于代理的建模相结合，以开发并实验验证统一的多尺度计算模型(目标1)。然后，我们建议使用我们的肌肉重塑多尺度模型来测试我们的假设，挑战该模型以预测对不同治疗干预的反应，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)。最后，我们建议制作多尺度模型的人类版本，基于在患有DMD的男孩中收集的新数据，并使用它来测试不同的领先治疗方法，这些治疗方法具有不同程度的疗效，并通过了解生物力学和炎症如何相互反馈导致这种可怕的疾病来识别新的治疗方法(目标3)。

 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).