# Mechanisms of type I interferon neuropathology following traumatic brain injury

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $452,462

## Abstract

Abstract
This proposal seeks to determine the regulation of microglial type I interferon signaling following traumatic
brain injury (TBI) and to identify how this affects neuroinflammation, neurodegeneration, and the
neurocognitive sequelae following TBI. TBI is a major public health problem, representing a leading cause of
death and disability from childhood through middle adulthood. Unfortunately, pharmacologic therapies for TBI
are non-existant. Treatment strategies that target specific secondary injury cascades like dysregulated
neuroinflammation are critically needed. Microglia, the primary immune cells of the CNS, persist in an activated
state for months and years following a single TBI and are associated with neurodegeneration. Mechanisms
that result in sustained, damaging neuroinflammation vs resolution of inflammation are unclear. Our recently
published work, however, demonstrated that the microglial transcriptome at a subacute time point following TBI
was highly enriched for type I interferon stimulated genes raising the question of if type I interferons are key
signaling molecules resulting in sustained, dysregulated microglial activation. The types and cell sources of
type I interferons activating microglia following TBI are unknown. Similarly, the specific effects of type I
interferons on sustained microglial reactivity and the subsequent mechanisms of microglial mediated
neurodegeneration and neurologic dysfunction following TBI remain unknown. Using a lateral fluid percussion
injury model of TBI in mice, combined with sophisticated mouse genetics, our data will uncover cell-specific
effects of type I interferon signaling on secondary injury. The hypothesis of this proposal is that multiple type I
IFNs drive development of dysregulated microglia subsets, immune cell recruitment, and the subsequent
neurodegeneration and neurobehavioral impairments that occur after TBI. In the first aim, we will identify the
types and cell-sources of type I IFNs driving persistent microglial and CNS interferon stimulated gene
expression following TBI. In the second aim, we will determine the impact of type I IFN signaling on microglial
subsets and their transcriptional activation following TBI. Finally, in the third aim, we will determine the
mechanisms by which type I interferon activated microglial impact neuropathology and neurocognitive
dysfunction following TBI, including through their recruitment of CD8+ T cells. As TBI is a leading, untreatable
cause of death and disability in the US, there is a critical need for further study of the specific mechanisms of
secondary injury so that ultimately, new therapies may be discovered.

## Key facts

- **NIH application ID:** 10930897
- **Project number:** 5R01NS127844-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Elizabeth Newell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $452,462
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930897

## Citation

> US National Institutes of Health, RePORTER application 10930897, Mechanisms of type I interferon neuropathology following traumatic brain injury (5R01NS127844-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10930897. Licensed CC0.

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