Grant: Project Grant

Duchennes's Muscular Dystrophy is a disease of muscle that affects approximately 1 in 3500 boys. Disease starts early in life when young boys fail to reach key milestones in their motor development and it is progressive; children are soon bound to a wheelchair and most die in their 20s and 30s from cardiac and respiratory complications. At present there is no known cure for DMD. The underlying molecular biology of DMD is well-known: patients carry a mutation in the Dystrophin gene. Muscle cells fail to make Dystrophin protein and are not stable. Lack of Dystrophin leads to a breakdown of the Dystrophin Glycoprotein Complex and consequently results in muscle membrane fragility, damage, inflammation, and cell death. Recent technical developments in the areas of stem-cell therapy and gene editing have given renewed hope to developing a treatment for DMD. However, we Identify a knowledge gap in our understanding of the effects of DMD mutations on the physiology of human muscle and synapses. Our proposed experiments are designed to fill that gap and will subsequently direct our studies of therapeutic treatments, especially research into existing pharmaceutical approaches To enable this research, we have developed a pioneering 3D muscle cell culture system to analyze the neuromuscular physiology and structure of human muscle cells grown from healthy and DMD-patient stem cells. Such human muscle microtissues (hMMT) will serve as the model system in our studies. By completing this work we will derive new knowledge of the effects of DMD mutations on human neuro-muscular physiology and test therapeutic efficacy of compounds to improve performance of DMD-affected muscle.