Grant: Master's Award: Canada Graduate Scholarships

IL-1β is a potent cytokine that is released as a part of the innate defense mechanism to invading pathogens. Activation of the NLRP3 inflammasome plays a crucial role in appropriate secretion of IL-1β, and its malfunctioning is a driver of autoimmune diseases like gout, rheumatoid arthritis, and lupus. Understanding how NLRP3 inflammasomes are regulated is important for developing novel therapeutics targeting these diseases. Research from my lab has shown that the protein TRAF1 is also an important regulator of inflammation in diseases like rheumatoid arthritis by controlling the subsequent activation in response to both signals (via two independent mechanisms) required for IL-1β secretion. My project will elucidate whether TRAF1 controls NLRP3 inflammasome activation in vivo, as earlier experiments have involved in vitro analysis, and determine whether that alters the severity of inflammasome-driven disease models. I will employ two inflammasome-driven disease models by injecting monosodium urate crystals (MSU) into the knee joints and peritoneum of the mice, which will cause rheumatoid arthritis and peritonitis, respectively. Subsequent analysis will help us determine the effect that TRAF1 has on controlling NLRP3 inflammasome activation in relevant models of inflammatory disease. We hypothesize that mice lacking TRAF1 will exhibit increased inflammasome activation and worsened disease outcome in the rheumatoid arthritis and peritonitis models, including excessive inflammation, suggesting its crucial role in controlling diseases characterized by aberrant inflammasome activation. These studies may showcase the possibility of inflammasomes and TRAF1 as therapeutic targets in diseases characterized by aberrant inflammation, like rheumatoid arthritis and peritonitis.