Project 461254

Regenerative medicine is a branch of translational research aiming to replace, engineer or regenerate human cells, tissues and organs to re-establish normal function. Since this entire process occurs naturally during the repair of tissues by the activation of adult stem cells after injury, the knowledge gained from the study of adult stem cells will accelerate regenerative medicine. The remarkable capacity for stem cell mediated tissue regeneration is illustrated by the activity of the muscle stem cell, which is normally a rare cell resting within muscle, but is activated in response to injury to expand a population of muscle cells needed for repair. Nevertheless, skeletal muscle remains affected by untreatable muscle disease. Duchenne muscular dystrophy (DMD), affects approximately 1 in 5000 boys worldwide, is marked by chronic degeneration of muscle that causes muscle stem cell exhaustion. The resulting decline in muscle regeneration coincides with infiltration of muscle with fat and fibrotic tissue. We therefore aim to discover novel mechanisms, potentially targeted by drugs, which maintain muscle stem cell numbers and function. In this project, we focus on understanding the receptors on the exterior of cells that respond to changes in the muscle environment. We use genetic tools in a mouse model of DMD to demonstrate that inactivation of these receptors exacerbates the progression of DMD. Furthermore, we use 'biosensors' to determine how these receptors communicate to the muscle stem cell and modify its behaviour. We expect our characterization of the receptor in MuSCs will provide a framework to manipulate stem cell behaviour in a therapeutic context, which we also investigate in the preclinical mouse model of DMD.