Discover, optimize, and translate novel therapies for neurological and musculoskeletal disorders
Dr. Toshifumi Yokota, Ph.D.
The Friends of Garrett Cumming & Muscular Dystrophy Canada HM Toupin Neurological Science Research Chair
Our research currently focuses on following projects:
1. Antisense and Genome Editing Therapies
Antisense-mediated therapy is an exciting new approach to treat diseases using DNA-like molecules. These molecules act like a stitch or Band-Aid to mitigate the effects of genetic mutations and restore the gene function. We also employ CRISPR/Cas9-based genome editing to rescue these mutations. Our focus is on several rare genetic diseases.
2. Dystrophin Revertant Fibre Analysis
Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic disorders, occurring once per 3,500 male births, caused by a lack of a protein called dystrophin. Interestingly, in many DMD patients and animal models, a small proportion of muscle fibres show strong dystrophin positive staining called "revertant fibres". We previously identified the mechanism by which revertant fibres arise from spontaneous exon skipping (alternative splicing) and proliferate through muscle regeneration with activation of muscle precursor (stem) cells. The aim of the current project is to elucidate the mechanisms underlying generation and proliferation of revertant fibres. By analyzing these fibres, researchers may be able to identify new and more effective targets for treatments of DMD.
3. Muscle Membrane Imaging
Some forms of muscular dystrophy patients including limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), and distal myopathy with anterior tibial onset (DMAT) have a primary defect in skeletal muscle membrane repair. Their muscle fibres are unable to effectively repair the damaged muscle membrane. We analyze the molecular mechanisms involved in muscle membrane repair machinery with our state-of-the-art imaging infrastructure including multi-photon (two-photon) laser microscope. A better understanding of this process could lead to better treatments for patients. We are also developing antisense drugs to treat them.
4. Deciphering Molecular Mechanisms of Muscle Fatigue and Recovery
The cause of skeletal muscle fatigue has been investigated by researchers for more than 100 years, yet its molecular mechanisms remain poorly understood. Muscle fatigue is also a common complaint in muscular dystrophy patients, but it has not been well studied. Our recent studies indicate that dystrophin and dystrophin-associated proteins are involved in the recovery from muscle fatigue. Using transgenic and mutant mouse models, we focus on the role of dystrophin-associated proteins in the recovery from muscle fatigue.