# Microglial process convergence following brain injury

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $557,339

## Abstract

Project Abstract
Traumatic brain injury (TBI) produces significant pathology, including post-injury inflammation (particularly
within the thalamus), that can lead to long-term morbidities. Microglia, the innate immune cells of the brain, are
critical mediators of neuroinflammation that can have either neurotoxic or neurotrophic effects. Progress has
been made investigating TBI-induced neuroimmune responses in rodents and therapies showing great
promise have moved to clinical trials but failed to translate into beneficial interventions for humans suffering
TBI. However, therapies targeting processes that occur in higher order mammals, with immune responses,
cytoarchitecture, and metabolic rates similar to humans, such as pigs, would be more likely to translate to the
clinic successfully. The neuroinflammatory progression following brain injury in pigs, however, is not well-
understood. Our preliminary data demonstrated that microglial processes converge onto injured axonal
swellings (microglial process convergence; MPC) in the thalamus of micro pigs, that is not recapitulated in rats,
following diffuse TBI but does appear to occur in humans. Studies in mice indicate that this microglial process
convergence (MPC) requires functional P2Y12R, however, the mechanisms behind MPC in higher order
mammals is currently unknown. Both our preliminary data and previous studies indicate that MPC may be an
ameliorative process, promoting axonal outgrowth acutely post-injury. Therefore, the goal of this study is to
assess the roles of microglial changes on pathological progression in a pig model of diffuse TBI.
Studies indicate that males have greater pro-inflammatory responses and less axonal outgrowth compared to
females. However, there are no known studies evaluating sex as a biological variable in MPC. Accordingly, the
current study will address the following specific aims 1) to evaluate the effects of inflammatory and
P2Y12R modulation on MPC, neuronal survival and axonal outgrowth/retraction following injury and 2)
to assess the prevalence of MPC in human brain tissue following diffuse TBI and other CNS
injuries/diseases. To address these aims we will complete quantitative 3D assessments of multiplexed
immunohistological samples for microglial-axonal interactions in vitro and in pigs to determine the degree of
MPC in relation to axonal outgrowth/retraction changes, P2Y12R expression, and sex-related variability. As the
prevalence of MPC following brain injury in the human population is currently unknown, we will also probe for
the degree of MPC onto injured axonal swellings, neuronal survival, axonal outgrowth/retraction, and spatially
resolved RNA profiles in a unique cohort of postmortem brain tissue. This study is significant because
understanding microglial-neuronal interactions and repair mechanisms in higher order species and humans of
both sexes will translate into therapeutics strategies for the treatment of TBI.

## Key facts

- **NIH application ID:** 10876937
- **Project number:** 5R01NS128104-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Audrey D Lafrenaye
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $557,339
- **Award type:** 5
- **Project period:** 2023-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876937

## Citation

> US National Institutes of Health, RePORTER application 10876937, Microglial process convergence following brain injury (5R01NS128104-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10876937. Licensed CC0.

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