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.

Grant Number: 5R35GM146859-05
NIH Institute/Center: NIH
Principal Investigator: Jessica Cardenas