Multiscale Modeling for Treatment Discovery in Duchenne Muscular Dystrophy

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 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).