Endothelial regulation of inflammation in trauma and hemorrhagic shock

Complications that arise secondary to an exaggerated innate immune response, such as multiple organ failure, are a major cause of late-stage mortality in trauma patients. My overall goal is to initiate an innovative and translational research program focused on elucidating mechanisms through which the vascular endothelium regulates the host inflammatory response to severe trauma. In particular, my research is focused on the immunomodulatory functions of the antithrombin (AT)-heparan sulfate system. AT elicits anti-inflammatory signaling upon binding to specific heparan sulfate proteoglycan (HSPG) receptors on the endothelial surface that contain a 3-0-sulfate (3-0S) modification. Our ongoing experiments demonstrate that dysregulation of the ATHSPG system is a novel mechanism driving inflammation and organ injury following severe trauma and hemorrhagic shock. However, the mechanisms that govern 3-0S HSPG expression and AT binding following trauma is a major knowledge gap in the field. Understanding these mechanisms will enable us to develop novel clinical tools to attenuate aberrant inflammation following trauma and treat or prevent subsequent organ failure. The next 5 years of my proposed research program will focus on 3 developing programmatic areas that seek to elucidate 1) mechanisms that mediate 3-0S HSPG degradation; 2) mechanisms that regulate 3-0S HSPG biosynthesis; and 3) the biological role and therapeutic potential of unique AT variants capable of regulating inflammation when 3-0S HSPG expression is reduced. Results of these investigations have broad-reaching implications for many conditions in which inflammation contributes to the pathogenesis, such as sepsis, transplantation, and COVID-19. Funding from this R35 award will 1) enable the establishment of my highly innovative, long-term research program that is guided by the NIGMS mission; 2) advance our basic understanding of the host inflammatory response to trauma; and 3) create novel therapeutics to improve longterm survival and quality of life for the critically ill.