# Neutrophil Activation after Traumatic Brain Injury

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2020 · $371,797

## Abstract

PROJECT SUMMARY
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 generation of neutrophil extracellular
traps (NETs) initiates a detrimental cascade that culminates in neurological deterioration after TBI. 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 neurological injury after TBI. Specific Aim 3 will test the hypothesis that degradation of
NETs improves neurovascular function after TBI. Proof of concept studies will demonstrate that targeted
degradation of NETs prevents cerebral microthrombus formation, leading to improved cerebral recirculation
and reduced edema after TBI. These findings will provide the rationale for clinical repurposing of recombinant
human DNase I (rhDNase1), a safe, FDA-approved therapeutic in widespread clinical use for non-neurological
diseases, in the management of acute TBI patients. Expected outcomes of the proposed research include the
identification of NETs as critical initiators of acute cerebrovascular dysfunction after TBI. In addition to
providing a mechanistic explanation for the deleterious effects of neutrophils after acute injury, our studies will
establish a critical framework for the development of targeted therapies to improve TBI outcomes.
.

## Key facts

- **NIH application ID:** 9834985
- **Project number:** 5R01NS110378-02
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** ALI SYED ARBAB
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,797
- **Award type:** 5
- **Project period:** 2018-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9834985

## Citation

> US National Institutes of Health, RePORTER application 9834985, Neutrophil Activation after Traumatic Brain Injury (5R01NS110378-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9834985. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*