Grant: CIHR Fellowship

The organism is normally programmed to turn off inflammatory and/or immune reactions. If a dysbalance between pro- and anti-inflammatory factors takes place, this 'auto' anti-inflammatory response fails, leading to chronic inflammation, and further major associated-disorders like arteriosclerosis or ischemic stroke. Chronic inflammation occurs in type 2 diabetes (T2D), which associates hyperglycemia and various lipid disorders. Additionally, elements of the immune system have been shown to be altered in obesity/T2D, with elevated circulating levels of pro-inflammatory molecules. These changes occur in the adipose tissue, the liver, and the pancreas as well as in blood vessels and immune cell populations. Generation of inflammatory factors depends on the activation of a multi-protein complex termed the inflammasome. Inflammasomes sense various stressor or danger signals, including high glucose concentrations or free fatty acids. Lipid mediators may also play a role in inflammasome activation. They have privileged interactions with cytokines and some of them can promote inflammation, while others lower it. As a potent novel therapeutic strategy for cardiovascular disease, inducing some of those peculiar lipid mediators may improve cardiovascular disorders during obesity-related disease like T2D in human and potentially lead to enhancement of cardiometabolic therapeutics. We hypothesize that lipid mediators play a crucial role in inflammasome regulation at the vascular level in the context of obesity/T2D. Hence in this project, we aim at investigating first the inflammasome activation/deactivation pathways in research model of human vascular cells and its potential underlying mechanisms during metabolic stress (mimetic of diabetic milieu). In a second study, we will evaluate the effects of blocking lipid mediator activity on inflammasome activation. Future directions will include in vivo validation of these findings.