ABSTRACT The research and training plan put forth in this Diversity Supplement will build upon key findings generated under the parent application by the pre-doctoral candidate (Micah LaTrell Willis). This Research Plan and the Training Plan submitted will provide Mr. Willis with opportunities to not only build an intellectual and technical toolbox to propel him towards the next phase of his trainee/development but provide him the career development opportunities to ensure he obtains his short and long-term career goals. Thus, support from this this Diversity Supplement will empower Mr. Willis to own and drive his research, training, and career development plans. Severe burn injury is one of the most devastating forms of trauma, with mortality rates reaching up to 12% even in specialized burn centers. Combined inhalation injury further increases this mortality rate. The primary cause of mortality are opportunistic infections which occur days to weeks after the injury, often resulting in lethal pneumonias and/or sepsis from bacteremia. Burn-induced immune dysfunction underlies this prolonged susceptibility to infection. It is known that response to bacterial infections is induced and regulated by Toll-like Receptor (TLR) and associated MyD88 signaling, causing release of key inflammatory cytokines. With our parent NIGMS grant “Damage-Induced Activation of the TLR/mTOR/PPARg Axis Regulates the Immune Response After Burn and Inhalation Injury” (R01GM131124), we are currently investigating in human and pre-clinical studies that immune dysfunction after burn and inhalation injury involves aberrant MyD88-mediated TLR signaling by damage associated molecular pattern molecules (DAMPs) released after injury. This results in aberrant cytokine signaling, with macrophages, neutrophils and endothelial cells (EC) playing key roles. Extracellular vesicles have emerged as novel mediators of immune dysfunction across several immune pathologies. Microvesicles (MVs) are a class of extracellular vesicles that carry DAMPs, cytokines, and miRNAs, to regulate functions of recipient cells. We have found that MVs are a key reservoir for DAMPs, cytokines, and potent immune complexes after burn injury in humans and mice. Given our findings, and the key role of MVs in multiple immune conditions, we hypothesize that MVs drive the immune dysfunction associated with poor clinical outcomes in severe burn injury. These findings are highly synergistic with the Specific Aims of the parent grant. Using same patient and mouse tissue (utilizing our established pre-clinical model of burn and inhalation injury, and repository of human burn patient samples) derived during the parent grant’s experimental plan, we aim to further characterize the payload (Supplement Aim 1) and immune function (Supplement Aim 2) of MVs isolated from plasma after injury. This will allow us to incorporate MVs into the Immune Suppression Index (ISI) developed in the parent grant to identify burn patients at lo...