# Novel mechanisms suppressing the pro-resolving phenotype of peripheral innate immunity following traumatic brain injury

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2022 · $400,000

## Abstract

ABSTRACT
Neuroinflammation has emerged as a critical component of secondary injury and disease progression following
brain trauma. Recent pre-clinical studies have shed light on the neurotoxic effects of peripheral innate immunity.
Our preliminary findings suggest this overzealous response may be mediated by EphA4/mTOR signaling which
negatively regulates the anti-inflammatory state of peripheral-derived monocyte/macrophages (PDMs). The
research objective of this application is to characterize the cellular and molecular mechanism(s) underlying
innate immunity and PDM polarization status in the regulation of tissue damage and functional recovery following
TBI. Our proposal builds upon extensive preliminary and published data demonstrating a distinct protective and
reduced pro-inflammatory response in the absence of peripheral EphA4 using chimeric mice following controlled
cortical impact (CCI) injury. Interestingly, PDMs-derived from EphA4null mice directly confer neuroprotection and
blood brain-barrier preservation in a model of monocyte depletion and replacement. Moreover, we discovered
that PDM-specific EphA4 suppresses phosphorylation of key proteins involved in the mTOR pathway, a novel
mediator of the pro-resolving state of PDMs. We hypothesize that EphA4 mediates the pro-inflammatory innate
immune response by suppressing mTOR signaling, which induces PDM infiltration, polarization and phenotypic
behaviors that drive neurovascular dysfunction following TBI. We will employ cell-specific depletions, and PDM
replacement as well as novel transgenic murine models. These approaches will include rigorous behavioral,
histological and innovative low-input genome-wide epigenomic and transcriptomic assessment of the relevance
and mechanism(s) of PDM behaviors. We will also provide a framework for retooling the neuroinflammatory
response to accelerate recovery and dampen pro-inflammatory processes after TBI.

## Key facts

- **NIH application ID:** 10409794
- **Project number:** 5R01NS121103-02
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Michelle Lee Theus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $400,000
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409794

## Citation

> US National Institutes of Health, RePORTER application 10409794, Novel mechanisms suppressing the pro-resolving phenotype of peripheral innate immunity following traumatic brain injury (5R01NS121103-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10409794. Licensed CC0.

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