# Neuroinflammatory Status as a Driver of Pathophysiology Following Repetitive Traumatic Brain Injury

> **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2024 · —

## Abstract

Traumatic Brain Injury (TBI) is caused by a mechanical insult to the head and often results in prolonged or
permanent brain dysfunction. TBI represents a major health and socioeconomic problem; in the U.S. over 2.8
million are affected annually. Even so-called “mild” TBI – otherwise known as concussion – may induce
neurophysiological deficits affecting learning, memory, and concentration that do not resolve in up to 15-20% of
patients. There are currently no approved treatments to improve recovery from TBI. Through previous extensive
neuropathological examinations, we have shown that mild TBI is associated with subtle changes in synaptic loss
or gain and neuronal hypertrophy occurring concomitantly with migration and activation of microglia – the
resident immune cell of the central nervous system. We have also detailed persistent changes to microglia
morphology in distinct white matter and gray matter regions after a single mild TBI. The objective of this proposal
is to establish the function of microglia and the overall neuroinflammatory response in secondary
pathophysiology for a range of TBI severities, with a particular focus on the role of hyper-ramified microglia on
responses to repeat TBI. To accomplish these objectives, we will utilize our porcine model of closed-head
rotational-acceleration-induced TBI, which closely replicates human head injury biomechanics that cannot be
reproduced in small animals. In Aim 1, we will characterize the effect of mild or moderate injury severity on TBI
pathology through transcriptomic profiling and immunohistochemical protein expression. In particular, RNA
sequencing will be performed to examine neurodegenerative and neuroinflammatory pathways followed by
immunohistochemistry to provide regional context to neuronal loss and immune cell activation, amongst other
pathologies. In Aim 2, animals will perform a battery of neurobehavioral tasks to assess spatial memory and
working memory. We will then create a statistical model to correlate the extent of behavioral and cognitive deficits
with transcriptomic and neuropathological changes post-TBI. Finally, in Aim 3, we will test the effect of repeat
TBI on neuroinflammatory states. We will subject pigs to a second TBI at either a timepoint shown to present
maximal elevations in hyper-ramified microglia or a timepoint where the density of this microglial phenotype has
returned to baseline. Changes in gene expression, neuropathology, and behavior will be assessed. Our
hypothesis is that repeat TBI during a period with elevated levels of hyper-ramified microglia will result in
excessive synaptic pruning/loss, exacerbated neuronal hypertrophy, and elevated deficits in hippocampal-
dependent cognitive tasks. Across these aims, we will use established methodologies to generate
comprehensive genomic, pathological, and cognitive profiling of clinically relevant TBI and create open access
datasets that other TBI researchers can interrogate against rodent and human model ...

## Key facts

- **NIH application ID:** 10916787
- **Project number:** 1I01BX006341-01A1
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** Daniel Kacy Cullen
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916787

## Citation

> US National Institutes of Health, RePORTER application 10916787, Neuroinflammatory Status as a Driver of Pathophysiology Following Repetitive Traumatic Brain Injury (1I01BX006341-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10916787. Licensed CC0.

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