Project Summary/Abstract: Mutations in collagen VI cause a spectrum of muscle disease ranging from severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy. The three protein components of collagen VI encoded by COL6A1, COL6A2, and COL6A3, undergo extensive assembly after translation before being excreted and incorporated into the extracellular matrix (ECM). Collagen VI is an integral component of the ECM, making collagen VI related dystrophies prototypical disorders of the muscle ECM. However, how these mutations result in muscle weakness, atrophy, degeneration and fibrosis remains unknown and no specific therapies are available that can alter the natural history of this disease. In this study, we propose to characterize the histologic and functional changes in skeletal muscle of a new mouse model of collagen VI related dystrophies with homozygous deletion of the Col6a2 alleles, paying special attention to dysregulation of growth factor pathways associated with these changes. For the interventional phase of this study, we propose to test effectiveness of medications in treating the manifestation of disease in this animal model. This study will also provide funding for in depth training of an early career clinician scientist with prior neuromuscular medicine training to develop laboratory techniques and scientific skills to conduct translational research and pre-clinical studies of animal models of muscular dystrophies.