# The role of monocyte and microglia interaction in the evolution of traumatic brain injury-induced neurodegeneration

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $509,187

## Abstract

Project Summary/Abstract
Traumatic brain injury (TBI) is a growing and under-recognized public health threat. The Centers for Disease
Control and Injury Prevention estimate that 2.5 million Americans sustain a traumatic brain injury each year. In
fact, TBI-related healthcare costs eclipse 80 billion dollars annually. There are currently no effective therapies
for TBI and supportive care remains the mainstay of treatment. The impact of TBI is highlighted not only by its
high mortality but also by the significant long-term neurologic impairment complications suffered by survivors.
The immune response to TBI plays a fundamental role in the development and progression of this subsequent
neurologic impairment and represents a complex interplay between infiltrating monocytic cells and the resident
immune system of the injured brain—microglia. Despite this, reciprocal action between monocytes and
microglia is poorly understood and the molecular mechanisms driving their interaction remain largely unknown.
Preliminary work has generated head-shielded bone marrow chimeric mice allowing for the unambiguous
differentiation between infiltrating monocytes and microglia after TBI. Using this model, we have shown that
non-classical monocytes are essential for neutrophil recruitment into the injured brain after TBI and that their
targeted depletion results in improved functional and anatomic outcomes after injury. Furthermore, this model
has allowed for the sorting of isolated populations of microglia after TBI. Transcriptional profiling of these
microglia has implicated longitudinal changes in microglial gene expression in the development of long-term
neurodegenerative changes. Taken together, we that infiltrating monocytes shape the microglial
response to injury altering gene expression, anatomic, and functional outcomes after TBI. To test this
hypothesize
hypothesis, we will determine whether microglia adopt a TBI-associated phenotype after TBI and whether
infiltrating monocytes are required for their generation. Additionally, our Preliminary Data has identified
progressively increased expression of genes involved in synaptic plasticity in the microglia of TBI mice. In
particular, Striatal-enriched protein tyrosine phosphatase (STEP) was identified as a key protein in this
process. STEP is important in several other neurocognitive disorders, but has not been investigated in TBI.
We will determine whether STEP, and other regulators of synaptic plasticity, contribute to the development and
degree of neurocognitive dysfunction after TBI with the use of knockout and transgenic mice. Lastly, we will
obtain monocytes from traumatically brain-injured human patients to develop a humanized mouse model of
TBI. Using this model, we will determine whether autonomous changes in monocytes from TBI patients direct
microglia to adopt a TBI-associated phenotype as compared to monocytes from healthy controls. Collectively,
the proposed studies will identify key molecular events...

## Key facts

- **NIH application ID:** 10224682
- **Project number:** 5R01GM130662-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** STEVEN J SCHWULST
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $509,187
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224682

## Citation

> US National Institutes of Health, RePORTER application 10224682, The role of monocyte and microglia interaction in the evolution of traumatic brain injury-induced neurodegeneration (5R01GM130662-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10224682. Licensed CC0.

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