Grant: Foundation Grant

<html> <body> <p>Skeletal muscle has the remarkable capacity to regenerate itself after injury, and serves as a highly useful model for studying stem cell function <i>in vivo</i> and <i>ex vivo</i>. Muscle stem cells, also called satellite cells (SCs), reside along myofibers where they are maintained in a quiescent state. Upon injury, SCs are activated and undergo a multi-step process ultimately leading to either self-renewal to maintain their population or differentiation to establish new myofibers. While Duchenne Muscular Dystrophy (DMD) is caused by specific mutations in the dystrophin gene, the severity of disease progression results from exhaustion of SCs due to incessant muscle damage. This suggests that therapies allowing for the mobilization of SCs during regeneration have the potential to provide increased life expectancy and improved quality of life for DMD patients. The development of such therapies requires a detailed understanding of the molecular mechanisms directing cell fate decisions such as self-renewal or differentiation. Previous studies have shown that epigenetic enzymes play important roles in cell fate determination through the establishment of cell-specific transcriptional programs. The <b>overarching goal</b> of my research career is to decipher the molecular mechanism controlling cell fate determination in SCs such that epigenetic-based therapies can be developed to treat muscle diseases.<br> <br> Towards this goal, I have established a dynamic research program that builds upon the broad range of skills developed during my PhD and post-doctoral training. Using a combination of biochemistry, cell biology and mouse genetics, my research group has made seminal contributions to the understanding of mechanisms that mediate changes in gene expression during different stages of muscle regeneration. Moving forward, I plan to continue exploiting the strength of my lab in the basic sciences to further characterize mechanisms controlling cell fate determination, while pushing our basic discoveries towards development of novel therapeutic approaches for muscular dystrophies. Our team will use cutting-edge proteomic and genomic technologies, as well as chemical library screening, to identify epigenetic enzymes involved in controlling transitions between alternate muscle fates. Inhibition of these epigenetic enzymes will then be examined as a potential therapy to improve SC-mediated muscle repair in pre-clinical models of muscular dystrophy. To complete these studies, I have assembled an international team of scientists that includes key collaborations with expertise in mouse models of epigenetics (Kai Ge, Bethesda), proteomics (Marjorie Brand, Ottawa), high-throughput screening of shRNA libraries (Evi Soutoglou, Strasbourg), muscular dystrophies with access to patient biopsies (Davide Gabellini, Milan; and Jean Mah, Calgary), and structural biology to aid in the development of novel epigenetic therapeutics (Cheryl Arrowsmith, Toronto).<br> <br> Trainees in my lab will be mentored in the latest technologies used to study the epigenetic of gene regulation and will have the opportunity to interact with some of the top scientists in their respective fields, pushing their basic science discoveries through to the clinic. Completion of our research is expected to provide new mechanistic insight into the role of epigenetic enzymes in fate determination, while paving the way for the development of novel epigenetic therapies to treat muscle diseases.<br> </p> </body> </html>