Dr. Stark's laboratory focuses on the inflammatory effect of infection on an often overlooked component of innate immunity, the endothelium. Specifically, he and his team are investigating how endothelial cells are affected during infection, with specific focus on endothelial nitric oxide synthase (eNOS) dysfunction. Nitric oxide produced by eNOS regulates many key functions of endothelial cells, namely vasomotor tone, cellular adhesion to myeloid cells and endothelial permeability. During severe systemic infections, known as sepsis, these functions are disturbed and contribute to the clinical findings of sepsis such as hypotension, capillary leak and microvascular thrombosis. The lab is currently trying to understand how infections induce changes in eNOS function, which will provide a framework towards combating the detrimental effects of endothelial dysfunction during sepsis. Additionally, the lab has examined how priming of the endothelium with a toll-like receptor 4 (TLR4) agonist, monophosphoryl lipid a (MPLA), alters the pro-inflammatory responses of activated endothelial cells in a models of burn-injury and acquired infections. TLRs are a major class of pattern recognition receptors crucial for innate immunity. There are several TLRs known in humans that respond to different pathogen associated molecular patterns (PAMPs). TLR4 is unique by its ability to cross-react with other TLRs due to its two downstream signaling cascades, MyD88 and TRIF. Current work is exploring how MPLA can retrain endothelial cells to become tolerant to subsequent infectious challenges. The long term goal of this work is to understand the mechanisms of endothelial dysfunction during infections and find modalities to mitigate the effects of infection on endothelial activation through the use of immunomodulators.

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