# Aging Exacerbates Neutrophil Persistence and Negatively Impacts Stroke Outcomes

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2024 · $440,000

## Abstract

PROJECT SUMMARY
Stroke is a major cause of disability in the U.S., disproportionately impacting older adults.
Ischemic stroke accounts for over 75% of stroke subtypes, but the only approved treatments rely
on blood flow restoration (reperfusion). Significant gains made in acute stroke treatments have
increased the number of patients undergoing acute reperfusion treatment. Despite successful
reperfusion, most patients still suffer from post-stroke disability, driven in part by
ischemia/reperfusion (I/R) injury. Activation of the inflammatory response following ischemic
stroke is known to cause further neurologic injury, and impairs recovery. Neutrophils are the initial
cell type involved in this inflammatory response, however our understanding of neutrophil-
mediated brain injury following ischemic stroke is lacking. Therapeutic advancements for I/R injury
are unlikely without better understanding the neutrophil-mediated injury following ischemic stroke.
By leveraging publicly available gene expression datasets, we found a potentially critical
transcription factor, nuclear receptor Nr4a2, was upregulated in neutrophils. Nr4a2 is widely
expressed in several types of leukocytes, but universally serves as a regulator of lifespan and
longevity. Nr4a2 is also upregulated in circulating neutrophils in aged mice and humans,
suggesting that neutrophils from older adults may persist once entering the ischemic brain.
We hypothesize that 1.) Neutrophils persist in the ischemic brain following I/R in aged brains
compared to younger brains due to increased neutrophil Nr4a2 expression, and 2.) Increased
Nr4a2 expression in recruited neutrophils contribute to impaired neutrophil function and increased
injury following ischemic stroke, leading to worse outcomes.
Aim 1 will focus on how NR4A2 affects the spatiotemporal recruitment and persistence of
neutrophils following ischemic stroke. Aim 2 will determine how NR4A2 impacts neutrophil
function and overall outcomes following ischemic stroke. These aims will be tested using a murine
transient middle cerebral artery occlusion model with young and aged wild-type C57Bl/6 Catchup
mice crossed with Nr4a2 knockout mice.
The proposed studies will fill an important knowledge gap regarding the neutrophil-response
following acute I/R and address the discrepancy in this response in aged brains. Findings from
these studies will inform development of novel therapies targeting neutrophil-mediated
mechanisms of brain injury. The proposed study has the potential for expanding treatment
approaches for ischemic stroke beyond blood flow restoration and has broad potential translation
to other aging-related brain disorders.

## Key facts

- **NIH application ID:** 10864541
- **Project number:** 1R21AG086751-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Ayush Batra
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $440,000
- **Award type:** 1
- **Project period:** 2024-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10864541

## Citation

> US National Institutes of Health, RePORTER application 10864541, Aging Exacerbates Neutrophil Persistence and Negatively Impacts Stroke Outcomes (1R21AG086751-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10864541. Licensed CC0.

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