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Principal Investigator: Christopher David Barrett
Organization: UNIVERSITY OF NEBRASKA MEDICAL CENTER
Fiscal Year: 2024
Award: $166,644
Funding agency: National Heart Lung and Blood Institute
Project Summary
The leading cause of death from ages 1-44 years in the United States is traumatic injury, responsible for
millions of hospital encounters at a cost of over $4 trillion annually. Unfortunately, outcomes in trauma patients
who survive the initial injury have not seen the marked improvements observed in other fields of medicine
recently, so more research is critical. It is known that a key driver of delayed mortality after injury is organ
failure, where a marked inflammatory response and dynamic coagulopathy are both implicated. Approximately
1 in 4 patients who suffer from major trauma have a detectable coagulopathy on clinical coagulation testing,
and even more have a perturbation in fibrinolysis, a process mediated by the protease plasmin. A major
inflammatory signaling pathway in the blood circulation is called complement, a protease cascade that shares
a number of cleavage specificities with the coagulation system with increasing recognition the two processes
heavily influence one another. It logically follows that acute traumatic coagulopathy and inflammatory organ
failure may therefore be related processes, with complement-mediated inflammation being a key link. In
support of this, the extant literature has shown the degree of complement activation correlates with both organ
failure and mortality, but the primary mechanism of complement activation after trauma remains unknown. Our
preliminary results and prior work suggest that the observed complement activation may occur as a direct
result of plasmin cleavage of complement proteins, where plasmin is known to be generated in large amounts
in trauma patients with severe shock. In addition, we also know that after trauma the vascular endothelium
sheds its glycocalyx into the circulation, which may serve to activate complement via the lectin pathway, which
is a complement activation pathway that binds to specific glycans and causes robust complement activation.
To further elucidate the mechanism of complement activation after trauma, we are now proposing 3 Aims. In
Aim 1, we propose a focused protein and glycan biomarker investigation of plasma from human trauma
patients to test whether plasmin generation or circulating endothelial glycocalyx molecules correlate with
degree of complement activation. In Aim 2, we will use a human endothelial cell culture model designed to
mimic traumatic shock to elucidate whether plasmin, endothelial glycocalyx molecules and the lectin pathway,
or both are capable of generating robust complement activation in the absence of other complement pathways
to delineate relative contributions and mechanism of activation. Finally, in Aim 3, we will directly investigate the
role of complement in generating organ failure in trauma using a mouse model of trauma comparing mice
deficient in complement proteins C3 and C5 with wild-type mice. The results of this Aim would highlight the
potential role of anti-complement therapies for future clinical study considerations. Taken together, this
research program will improve our understanding of the mechanisms of complement activation and
inflammatory organ injury after trauma in this leading cause of death in the United States.
Terms: <Acquired brain injury><Acute><Age><Alteplase><Animals><Antibodies><Antigens><Assay><Award><Binding><Bioassay><Biological Assay><Biological Markers><Bleeding><Blood Circulation><Blood Coagulation Disorders><Blood Plasma><Bloodstream><Brain Injuries><Bypass><Cause of Death><Cell Coat><Cell Culture Techniques><Cessation of life><Circulation><Circulatory Collapse><Clinical><Clinical Research><Clinical Study><Clotting><Coagulation><Coagulation Disorder><Coagulation Process><Coagulopathy><Complement><Complement Activation><Complement Proteins><Coupled><Data><Death><Development><Dryness><Endothelial Cells><Endothelium><Esteroproteases><Experimental Designs><Fibrinolyses><Fibrinolysin><Fibrinolysis><Foundations><Future><Generations><Glu-Plasmin><Glycans><Glycobiology><Glycocalyx><Goals><Hemorrhage><Hemorrhagic Shock><Hospitals><Human><Immune system><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Infection><Inflammation><Inflammatory><Inflammatory Response><Injury><Investigation><Ischemia><KO mice><Kidney><Kidney Urinary System><Knock-out Mice><Knockout Mice><Knowledge><Lectin><Life><Link><Literature><Lung><Lung Respiratory System><Lung damage><Mannan-Binding Lectin><Mannan-Binding Protein><Mannose Binding Lectin><Mannose-Binding Protein><Mannose-Specific Lectin><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measurement><Mediating><Medicine><Mentors><Mentorship><Methodology><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Multiple Injuries><Multiple Trauma><Murine><Mus><Null Mouse><Organ failure><Outcome><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peptidases><Peptide Hydrolases><Plasma><Plasma Serum><Plasmin><Polysaccharides><Process><Protease F><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Recombinant Tissue Plasminogen Activator><Research><Reticuloendothelial System, Serum, Plasma><Role><Sampling><Scientist><Series><Shock><Signal Pathway><Specificity><Stimulus><Surgeon><System><T-Plasminogen Activator><Testing><Therapeutic><Tissue Activator D-44><Tissue Plasminogen Activator><Tissue-Type Plasminogen Activator><Trauma><Trauma patient><Traumatic Shock><Traumatic injury><United States><Vascular Endothelium><Wild Type Mouse><Work><ages><bio-markers><biologic marker><biomarker><bleeding disorder><blood loss><brain damage><brain-injured><career><cell culture><cell cultures><circulatory shock><clotting disorder><complement pathway><complement pathway regulation><complement system><complementation><cost><critical injury><devastating injury><developmental><exposed human population><fighting><hemodynamics><human exposure><hypoperfusion><immunogen><improved><improved outcome><indexing><injuries><injury response><injury to organs><innovate><innovation><innovative><lung injury><microbial><model design><mortality><mouse model><murine model><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><organ injury><pathway><patient oriented outcomes><polytrauma><prevent><preventing><programs><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><randomized, clinical trials><renal><response><response to injury><severe injury><shocks><skill acquisition><skill development><skills><social role><t-PA><therapeutic target><trauma induced coagulopathy><traumatic coagulopathy><wildtype mouse>