# Altering XOR Product Identity to Treat Ischemic Stroke

> **NIH NIH P20** · WEST VIRGINIA UNIVERSITY · 2020 · $262,960

## Abstract

Project Summary
Obesity is an imminent healthcare crisis in West Virginia as the number of obese citizens is
currently greater than 34% of the population. A crucial comorbidity allied to obesity is stroke as
central adiposity is reported to be strongly associated with greater risk for an ischemic event
and worse outcomes. The most common clinical treatment for stroke is administration of
recombinant tissue plasminogen activators (rtPAs) which is limited to a therapeutic window of
only a few hours post stroke affirming the urgent need for novel approaches to address this
clinical issue. By recognizing that key elements of the pathogenic processes leading to and
resulting from a stroke event are obesity, enhanced rates of reactive species generation and
elevated plasma levels of UA, we propose to target the intersection of these components,
xanthine oxidoreductase (XOR). XOR is a molybdopterin/flavin enzyme that is up-regulated in
obesity, is an abundant source of reactive species and the sole source of UA in mammals. We
provide preliminary data that demonstrates murine, diet-induced obesity results in enhanced
circulating XOR activity and UA levels and reveal that a novel tissue-specific, murine XOR
knockout maintains lean levels of circulating XOR and UA when obese. Importantly, we
demonstrate a XOR-dependent, nitrite-mediated, reduction in oxidative stress and UA levels in
rodent brain. Furthermore, these data are supported by ex vivo analysis of obese murine tissues
where significant rates of NO generation are catalyzed by XOR and nitrite. In aggregate, these
findings support our overarching hypothesis that diverting XOR activity from pro-
inflammatory products (oxidants and UA) to NO will improve ischemic stroke outcomes
in obesity. The following Aims will test this hypothesis: 1) Determine the relative impact of
XOR-derived ROS versus UA on ischemic stroke in obese mice and 2) Utilize obesity-
associated elevation of XOR to induce XOR-catalyzed NO generation and improve stroke
outcome.In toto, this proposal is designed to capitalize on obesity-associated elevation in XOR
by switching its product identity from oxidants to NO and thus improve stroke outcome.

## Key facts

- **NIH application ID:** 10025935
- **Project number:** 2P20GM109098-06A1
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Eric Eugene Kelley
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $262,960
- **Award type:** 2
- **Project period:** 2014-09-08 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10025935

## Citation

> US National Institutes of Health, RePORTER application 10025935, Altering XOR Product Identity to Treat Ischemic Stroke (2P20GM109098-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10025935. Licensed CC0.

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