_____ __________________________________________ __ Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability worldwide. Over 1.7 million Americans suffer a TBI annually and up to 2% of the population currently lives with the long-term neurological consequences of a previous TBI, placing a $76.5 billion annual economic burden on society. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized TBI patients die from injuries that are secondary to the initial trauma. Cerebral edema is a life-threatening neurological complication that promotes elevated ICP and leads to clinical deterioration in the hours and days after a TBI. Unfortunately, neurosurgical approaches to control elevated ICP are limited and efficacious medical therapies to control cerebral edema are lacking, presenting a critical barrier to improving patient prognoses after TBI. The objective of this proposal is to test the overarching hypothesis that activation of neutrophilic toll-like receptor 4 (TLR4) promotes the formation of neutrophil extracellular traps (NETs) after TBI, initiating a detrimental immune cascade that culminates in neurological deterioration.
Specific Aim 1 will test the hypothesis that TLR4 activation mediates NET formation after TBI. Proposed mechanistic studies will demonstrate a key regulatory role for activation of the TLR4 signaling pathway in the formation of NETs after TBI.
Specific Aim 2 will test the hypothesis that peptidylarginine deiminase 4 (PAD4) promotes cerebral edema after TBI. Proposed mechanistic studies will use genetic and pharmacological approaches to implicate PAD4, a mediator of TLR4-induced histone hypercitrullination in human and mouse neutrophils, in NET formation and neurovascular injury after TBI.
Specific Aim 3 will test the hypothesis that NETs trap macrophages in the brain after TBI. These studies will identify NETs as a novel mediator of brain macrophage infiltration/polarization after TBI. Proposed translational studies also will support the repurposing of recombinant human DNase (rhDNase), a safe, FDA-approved therapeutic in widespread clinical use for non- neurological diseases, allowing rapid clinical translation into TBI patients. Expected outcomes of the proposed research include the identification of NETs as a functional initiator of secondary neurological injury after TBI, establishing a framework for the development of innovative therapeutics to reduce neurovascular injury and improve patient outcomes after TBI. .

Public Health Relevance

___________ _____________________________________ Traumatic brain injury (TBI), a leading cause of mortality and long-term disability worldwide, is a significant public health issue, debilitating or killing more individuals that breast cancer, AIDS, multiple sclerosis, and spinal cord injury combined. Cerebral edema is a life-threatening neurological complication that develops in the hours and days after TBI and contributes to poor clinical outcomes. In this project, we will implicate the release of neutrophil extracellular traps (NETs) from activated neutrophils in the initiation of secondary neurovascular injury after TBI. Our conceptually and technically innovative studies will establish a mechanistic framework for the development of novel therapeutic approaches and will identify a potential biomarker to prospectively identify patients at high risk for neurological deterioration.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bellgowan, Patrick S F
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Augusta University
Schools of Medicine
United States
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Vaibhav, Kumar; Braun, Molly; Khan, Mohammad Badruzzaman et al. (2018) Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation. J Exp Med 215:2636-2654