Injury and trauma are common conditions that encompass a considerable burden of illness and account for a major component of health care costs. Endothelial cells (ECs) are the nexus between the blood and the body, and disruption of endothelial function in trauma leads to a syndrome of endothelipathy characterized by impaired microvascular blood flow, barrier integrity and coagulation. Our lack of understanding of how ECs translate the signals of trauma into changes in vasodilatory, barrier and coagulation functions represents a significant void— but also an opportunity for clinical intervention. The central theme of my lab is to understand endotheliopathy in trauma and inflammation, so that we can improve outcomes. This research program will deliver a molecular model of the mechanisms by which histones cause both immediate and sustained effects on vascular endothelium that explain oscillating clotting responses seen in trauma patients. This project will also test novel strategies to protect and/or rescue endothelial dysfunction after trauma. The proposed research is expected to significantly advance the continuum of research needed to improve diagnosis and management of acute endotheliopathy in trauma. Moreover, it has the potential to radically change our view of endothelial biology. This research will provide an enduring and sustained impact on understanding the role of the endothelium in health and disease.