# Mechanism of Inflammatory Related Brain Dysfunction after Spinal Cord Injury

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $431,648

## Abstract

Project Summary
Neuropsychological deficits have been reported after spinal cord injury (SCI) without concurrent head injury;
although most such studies reflect patient self-reports, more formal neuropsychological testing has
demonstrated performance impairments with an associated high risk of dementia including deficits in learning
and memory. On the other hand, patients with dementia, such as that resulting from Alzheimer’s disease (AD),
could have higher risk of falls, and therefore increased risk of SCI. Little research has addressed potential
mechanisms for such neuropsychiatric changes or their implications for targeted therapy. There is an urgent
need for such studies, as posttraumatic dementia such as cognitive and psychiatric changes negatively impact
rehabilitation and impair recovery. The purpose of this study is to identify the mechanisms responsible for
these less well examined yet important consequences of SCI and test the hypothesis that SCI-triggered
release of CCL21 in the brain contributes to spreading neuroinflammation with cognitive dysfunction and
depressive-like behavior, which can be improved by targeting specific mechanisms of neuroinflammation.
 We will use transgenic mice and molecular interventions to delineate the role of CCL21 as a key
regulator of brain microglial activation and related down-stream injury mechanisms in SCI. Aim 1 will identify
that SCI-induced CCL21 elevation mediates detrimental microglial activation in the brain
through NOX2 activity. Multiple quantitative assessments of microglia activation will be combined with a
molecular/genetic intervention targeting CCL21 to test the hypothesis that SCI-induced release of CCL21 in
key regions of the brain contributes to detrimental microglial activation through NOX2 activity. Aim 2 will
demonstrate that genetic depletion or pharmacological inhibition of CCL21/NOX2 reduces
detrimental microglial activation, resulting in improved cognitive decline and depressive-like
behavior. Complimentary pharmacological, molecular, and genetic approaches will be used to test the
hypothesis that brain CCL21/NOX2-mediated inflammation after SCI causes chronic neurodegeneration
associated with cognitive decline and depressive-like behavior. Aim 3 will determine that genetic or
pharmacological microglial ablation after SCI reduces brain neuroinflammation leading to
improved functional recovery. Using genetic or pharmacological microglia-deletion, we will examine the
role of resident microglia in SCI-mediated neuroinflammation in the brain and functional outcomes.
 The information gained from these studies would have an important positive impact by identifying the
key mechanisms involved in important yet largely ignored brain changes after SCI and identifying potential
therapeutic interventions.

## Key facts

- **NIH application ID:** 10380183
- **Project number:** 5R01NS110635-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** ALAN Ira FADEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $431,648
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380183

## Citation

> US National Institutes of Health, RePORTER application 10380183, Mechanism of Inflammatory Related Brain Dysfunction after Spinal Cord Injury (5R01NS110635-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10380183. Licensed CC0.

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