# CTBI: Tauopathy in Mice and Human: Effects of Open-Field Low-Intensity Blast on Brain Ultrastructure and Outcomes in Mild Traumatic Brain Injury

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2021 · —

## Abstract

Project Summery
Overall Research Strategy: Traumatic brain injury (TBI) from open-field blast or repetitive mild head impact to
human tau transgenic mice will induce Alzheimer-relevant, tau-dependent pathology, that can be rescued by
suppression of tau expression or tau aggregation inhibitors. Blast-induced tau-related pathological changes will
be analyzed in brains from veterans and mice exposed to blast, and biomarkers for TBI, chronic traumatic en-
cephalopathy (CTE) and Alzheimer-pathology will be identified in mice and validated in humans. TBI caused by
explosive weaponry is the most prominent type of injury that occurs in military personnel. Over 82% of combat-
related TBIs are classified as mild TBIs (mTBI)—the “signature injury” of recent wars. Service members with
mTBI, often undetectable by conventional brain imaging techniques, do not realize they have sustained this
injury. This “invisible injury” can lead to the development of lifelong disabilities, including neuropsychiatric
and/or neurodegenerative diseases, imposing socioeconomic burdens on patients, families, and society. To-
date, our understanding of the mechanisms by which open-field low-intensity blast (LIB) causes mTBI and sub-
sequent neurological deficits remains inadequate. Thus, there is an urgent need for investigation of LIB-in-
duced pathogenesis using reliable and “real world” animal models. Here, we have assembled a team of investi-
gators with cross-disciplinary expertise and unique blast and in vivo imaging research facilities available at the
Harry S. Truman Veterans Hospital and the affiliated University of Missouri. We have developed a platform us-
ing pressure sensor instrumentations and high-speed cameras to reproduce and record open-field blast expo-
sures with high-explosive velocity C4 detonation. Our preliminary studies show that LIB-exposed mice results
in reduced locomotor/exploratory activity, but with no mortality or other impact/acceleration-mediated bodily
injuries. Using transmission electron microscopy (TEM), we observed mitochondrial damage in cell bodies and
defected myelin in selected brain areas. Further omics and biochemistry analyses indicated mitochondrial dys-
function and increase in phospho-tau protein levels. We propose to test the hypothesis that LIB-induced neu-
ropathology in a human tau transgenic mice is initiated by mitochondrial dysfunction associated with
oxidative stress responses and bioenergetic impairment, which in turn, induces ultrastructural dam-
ages and tau-related pathology leading to metabolic and behavioral deficits. This study will use the trans-
genic mice expressing regulatable human tau (rTg-hTau) exposed either to a single or repetitive blasts in our
well established platform, and investigate effects of mitochondrial dysfunction associated oxidative stress re-
sponses in the mouse brain. Specifically, Aim-1 will evaluate effects of LIB-induced mTBI on ultrastructure in
specific brain areas over time, assess beha...

## Key facts

- **NIH application ID:** 10044404
- **Project number:** 5I01BX004313-02
- **Recipient organization:** HARRY S. TRUMAN MEMORIAL VA HOSPITAL
- **Principal Investigator:** Zezong Gu
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044404

## Citation

> US National Institutes of Health, RePORTER application 10044404, CTBI: Tauopathy in Mice and Human: Effects of Open-Field Low-Intensity Blast on Brain Ultrastructure and Outcomes in Mild Traumatic Brain Injury (5I01BX004313-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10044404. Licensed CC0.

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