Grant: CIHR Fellowship

Sepsis is a lethal syndrome of organ dysfunction resulting from a dysregulated immune response to infections including pneumonia, meningitis and influenza. Sepsis affects 250,000 Canadians each year and kills 35,000; children and older patients face a particularly increased risk. Sepsis is difficult diagnose and treat. Current medical management is entirely supportive; many survivors are left with severe disability and worse long term health outcomes. There is an urgent need for effective new treatments and diagnostic tests. Neutrophils (PMN) are white blood cells that play a key role in sepsis. While PMN combat infections, they can also harm healthy cells, leading to injury of the heart, lungs, liver, and kidneys and the need for life support in an intensive care unit (ICU). How PMN regulate their functions in sepsis is poorly understood. In this proposal, I aim to understand a novel mechanism underlying PMN dysfunction. We recently identified a PMN protein, TARM1, which can activate PMN anti-infectious functions, and is closely related to a previously described protein, SIRL1, that has inhibitory functions. Both are expressed on septic PMN and so may work together to regulate PMN responses. This study aims to 1) understand how changes in TARM1/SIRL1 expression on septic PMN influence their anti-microbial functions, 2) to determine how TARM1/SIRL1 activate intracellular signals for survival and functional activity in septic PMNs and 3) correlate TARM1/SIRL1 expression on PMNs with clinical outcomes in sepsis. Success in these studies will identify new approaches to identify, monitor and, importantly, tailor novel treatments to improve outcomes for septic patients.