Project Summary: This project proposes to study the role of Smad8 and muscle-enriched microRNAs, known as myomiRs, in Duchenne muscular dystrophy. Duchenne muscular dystrophy is a skeletal muscle wasting disease that is at least in part mediated by secondary effects from membrane fragility due to loss of dystrophin. These secondary effects include impairments in muscle proliferation, differentiation, and regeneration that are propagated by inflammation. This project has identified the TGF-associated transcription factor, Smad8, as markedly elevated and associated with the repression of myomiRs in Duchenne muscular dystrophy skeletal muscles. As such, the proposal will use cell culture and mouse models of Duchenne muscular dystrophy to molecularly map the role of Smad8 in skeletal muscle function and disease. The short-term goal is to identify the mechanisms by which TGF / Smad8 signaling might promote dystrophic processes by understanding its connection to myomiRs repression with a goal of identifying novel pathways for potential therapeutic intervention. For example, we will study the effects of over-expression and knockdown of Smad8 on key pathways like muscle proliferation, differentiation, and skeletal muscle regeneration. We will also study impact of Smad8 modulation on myomiRs and their downstream mRNA pathways. The long-term goal is to expand our understanding of TGF / Smad8 cell signaling and microRNA biology in skeletal muscle function in health and disease.