Endothelial regulation of inflammation in trauma and hemorrhagic shock
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Principal Investigator: Jessica Cardenas Organization: UNIVERSITY OF COLORADO DENVER Fiscal Year: 2024 Award: $390,000 Funding agency: National Institute of General Medical Sciences 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. Terms: <Anabolism><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Area><Attenuated><Automobile Driving><Award><Binding><Biological><COVID-19><CV-19><Cell Communication and Signaling><Cell Signaling><Clinical><Coronavirus Infectious Disease 2019><Critical Illness><Critically Ill><Endothelial Cells><Endothelium><Funding><Goals><HSPG><Hemorrhagic Shock><Heparan Sulfate><Heparan Sulfate Proteoglycan><Heparitin Sulfate><Immune response><Immunological response><Immunomodulation><Inflammation><Inflammatory Response><Injury><Innate Immune Response><Intracellular Communication and Signaling><Investigation><Knowledge><MOF syndrome><Mediating><Mission><Modification><Molecular Interaction><Morbidity><Morbidity - disease rate><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><NIGMS><National Institute of General Medical Sciences><Organ><Organ failure><Pathogenesis><Proteoheparan Sulfate><QOL><Quality of life><Receptor Protein><Regulation><Research><Role><Secondary to><Sepsis><Signal Transduction><Signal Transduction Systems><Signaling><Sulfate><Surface><System><Therapeutic><Thrombase><Thrombin><Translational Research Enterprise><Transplantation><Trauma><Trauma patient><Traumatic injury><Variant><Variation><Vascular Endothelium><attenuate><attenuates><biologic><biological signal transduction><biosynthesis><blood infection><bloodstream infection><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><driving><endothelial dysfunction><experiment><experimental research><experimental study><experiments><fibrinogenase><host response><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><injuries><injury to organs><innovate><innovation><innovative><mortality><multiorgan failure><multiple organ system failure><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><organ injury><prevent><preventing><programs><receptor><social role><tool><translation research enterprise><translational research program><transplant><vascular contributions>