Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Duchenne muscular dystrophy (DMD) is a debilitating disease affecting one in 4200 boys which leads to death within the second decade of life. It is characterized by progressive muscle weakness and respiratory failure due to the absence of a protein called dystrophin in the muscle fibers. Currently, there is no cure for DMD, and steroid treatments only serve to modestly increase lifespan. Therefore, research is needed to better understand the disease. Recent studies from our lab have shown that muscle stem cells in mice suffering from DMD (mdx mice) do not divide properly and are less efficient at regenerating muscle following injury. A more recent study has linked DMD to the mis-regulation of a protein called CARM1. We know from previous work that CARM1 normally methylates PAX7, a gene that is absolutely required for normal muscle stem cell function. Methylated Pax7 then binds a protein complex that modifies chromatin to properly program the expression of genes, Therefore, we believe PAX7 exists in an unmethylated form in muscle stem cells from mdx mice. Consequently, we sought to study the effect of this modification in the context of DMD. To this end, we used CRISPR-Cas9, a new and exciting gene editing technology, to mutate PAX7 directly in mice, preventing its methylation by CARM1, and hopefully mimicking its state in DMD. We will use this mouse to study the effects the mutation will have on muscle regeneration and muscle stem cell divisions, as well as comparing the effect to mdx mice. Lastly, drug treatments to increase PAX7 methylation levels will be looked at as a potential treatment to ameliorate muscle stem cell function in mdx mice.