PROJECT SUMMARY/ABSTRACT Multi-organ failure as a result of the systemic inflammatory response to injury (SIRS) is the leading cause of late complications and death after severe trauma and burn injury. Despite decades of research, therapeutics that limit the SIRS response following injury remains an unmet clinical need. Emerging research points to the contribution of human-specific differences in our immune system that distinguish the human injury response from that observed in other species. These species-specific differences may explain why therapies that are widely successful in animal models used for preclinical research fail in human clinical studies. Uniquely human genes (UHGs), with expression that frequently tracks to human immune cells, may account for some of these differences in human SIRS after injury. The overarching goal of my research program is to systematically define factors that distinguish the human immune response from other species, characterize the contribution of UHGs to human SIRS, and understand how these genes effect therapeutics that target anti-inflammatory signaling pathways. To this end, we have recently discovered a novel role for the uniquely human CHRFAM7A gene that is a variant of the conserved α7 nicotinic acetylcholine receptor (α7nAchR) that mediates cholinergic anti-inflammatory signaling. In addition to decreasing the ability of therapeutics to target the α7nAchR, unexpectedly, we have demonstrated that human CHRFAM7A expression functions in transgenic mouse mice to cause increased monocyte mobilization to lung and decreased acute lung injury in a model of severe burn injury. Our research focus in this MIRA proposal is to identify the function and mechanism of action of UHGs that are highly expressed in monocytes/macrophages and relevant in the injury response. To demonstrate the functional relevance of UHGs, we will use a combination of precision animal models, genetic approaches in human induced pluripotent stem (iPS) cells, and clinical samples from trauma and burn patients. In this research program, we propose to 1) test cell-specific UHG function in an animal model of severe injury; 2) develop an iPS cell system for mechanistic studies in human macrophages; 3) determine how UHGs alter the effect of therapeutics that target anti-inflammatory signaling pathways; and 4) evaluate how relative UHG expression alters the inflammatory phenotype of monocytes from injured patients. Understanding how UHGs make the human immune response to injury unique may allow for the development of novel therapeutic interventions aimed at modulating SIRS and decreasing organ dysfunction after severe trauma and burn.