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

Sepsis is a common and lethal syndrome caused by a severe whole-body inflammatory response to an infection, most commonly bacteria, but also fungi, parasites and viruses. Sepsis is one of the leading causes of death in modern intensive care units and is responsible for approximately 10,000 deaths in Canada each year. As the number of older adults increases in Canada, nearly 60% of sepsis cases occur in patients aged over 65 years. Mortality rates in sepsis remain high and are often associated with muscle dysfunction leading to respiratory insufficiency. However, the underlying mechanisms are still unclear and no specific anti-sepsis treatment exists. Autophagy is the catabolic process by which cells degrade their own components. The role of autophagy in sepsis-induced muscle dysfunction has largely been ignored, primarily due to an erroneous assumption that autophagy does not play an important role in protein degradation. Recent evidence point to the possibility that enhanced autophagy is an underlying cause of muscle dysfunction in sepsis. Therefore, a crucial step on the path to effective treatment is to further elucidate the underlying molecular mechanisms that are responsible for sepsis-induced skeletal muscle dysfunction. We will first, determine the extent and time course changes of autophagy and related biological processes in septic skeletal muscles of wild type animals. Then, using various transgenic animal models to modulate autophagy and its related biological processes, we will mechanistically define the role of autophagy in sepsis. As such, these findings will generate tremendous progress in the field of Critical Medical Care, and might allow the identification of direct therapeutic targets to limit sepsis-induced muscle dysfunction.