Our Research
Emergency medical providers have long struggled to manage the acute trauma-induced inflammation and coagulopathy which occurs in as many as one-fourth of patients after severe multi-system trauma. Refractory coagulopathy prevents optimal surgical management and can lead to death from otherwise survivable injuries. This is a complex physiological problem, involving multiple organ systems, with important public health significance. We study the basic mechanisms that drive acute inflammation and injury to small blood vessels, including the microvasculature of the lung, gut and brain. We are using this information to develop novel therapeutics targeting endothelial health that will ultimately help trauma patients survive and recover.
Endotheliopathy of Trauma
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 this project is to understand vascular inflammation and endotheliopathy in trauma, so that we can improve outcomes. This research is delivering 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.
Endothelial Repair in Trauma Induced Coagulopathy (TIC)
Affecting as many as 30% of critically ill trauma patients, trauma-induced coagulopathy (TIC) represents a spectrum of coagulation phenotypes ranging from early impaired hemostasis to later thrombotic complications. Through randomized controlled trials testing prehospital plasma as a resuscitation tool, we have identified that plasma transfusion can reduce endothelial injury, even in the patients with the highest injury severity. Plasma transfusion reduces mortality after severe trauma, but the exact mechanism of benefit is unknown. In this project, we are characterizing the role of the endothelium as the regulator of maladaptive response and a crucial interface for thrombosis-inflammation crosstalk. We utilize a “cue, signal, response” framework to robustly characterize the molecular pathways activated in the endothelial and how the endothelial response interfaces with changes in the coagulation response. Finally, we will define the “reparative phenotype” that plasma transfusion creates, restoring the endothelium to homeostasis. This is the critical next step needed to develop targeted therapies in trauma resuscitation for endothelial health.
“Next-Gen” mRNA Vaccines for Trauma
3K3A-activated protein C (APC), an engineered cell-signaling analogue of the serine protease APC, has cytoprotective effects in brain injury and ischemia and is currently in phase III human trials as a neuroprotectant for patients with ischemic stroke. We are studying 3K3A-APC as a novel drug to prevent endothelial dysfunction and immune storm, mitigate TIC, and help set the ‘inflammatory thermostat’ allowing causalities sufficient time to reach definitive care and achieve recovery without thromboinflammatory morbidity and mortality. As a therapeutic, 3K3A-APC can be shelf stable and administered early and far forward even in an autoinjector self given by the injured. This makes it an ideal ‘resuscitation in a syringe’ providing TIC mitigating and inflammamodulatory treatment directly after injury. While treatment after injury will provide benefit, successful prophylactic delivery of therapeutic levels of protective recombinant proteins to at-risk military personnel immediately before deployment with mRNA vaccines will herald the next generation of precision therapeutics custom-designed to protect troops from any specific acute threat including not only polytrauma but also exposure to chemicals, radiation, or pathogens. Building on recent advances in mRNA vaccines and materials science, we are conducting a preclinical trial of mRNA/LNPs designed to deliver payloads of 3K3A-aAPC for treatment of endotheliopathy and TIC in polytrauma. This novel mRNA therapeutic will provide a shelf-stable immune modulator and “trauma vaccine” delivering endothelial and immune therapy in a single dose administered (1) immediately after injury or (2) prophylactically to at-risk military personnel before deployment.
