Hemolysis-Mediated Endothelial Dysfunction and Organ Injury in Trauma - Project Summary Trauma is a leading cause of death and long-term disability in the United States. Among survivors of severe injury, nearly one in four develops systemic complications such as organ failure, thrombosis, or infection. Emerging evidence suggests that trauma-induced hemolysis—the destruction of red blood cells and release of free hemoglobin into the bloodstream—may drive these complications by disrupting nitric oxide signaling, promoting oxidative stress, and impairing endothelial function. The central hypothesis of this K08 proposal is that hemolysis after trauma depletes nitric oxide and promotes endothelial activation, leading to microvascular dysfunction, impaired tissue perfusion, and organ injury. Further, individual genetic differences in haptoglobin phenotype may influence the capacity to neutralize circulating free hemoglobin, modulating susceptibility to hemolysis-mediated complications. Aim 1: Use human endothelial cell models to define how free hemoglobin alters nitric oxide bioavailability and triggers endothelial injury, and to assess how haptoglobin mitigates these effects. Aim 2: Leverage a multicenter observational trauma cohort to determine the association between haptoglobin genotype, hemolysis markers, endothelial dysfunction, and clinical outcomes. Aim 3: Conduct a prospective study of injured patients to evaluate how hemolysis affects nitric oxide signaling, vascular function, and tissue perfusion in vivo using biospecimens, transcriptomics, and near- infrared spectroscopy. This proposal directly aligns with NIGMS priorities by investigating fundamental mechanisms of redox signaling, vascular injury, and immune dysregulation in critical illness. Through integration of cellular, translational, and patient-based approaches, the project will identify new mechanistic targets and predictive biomarkers of trauma complications. A structured career development plan will provide the candidate with mentorship, formal training, and hands- on research experience in vascular biology, immunology, and translational research. This K08 award will position Dr. Ross to launch an independent research program focused on trauma pathophysiology and precision therapies.
