# Role of Dual Oxidase in post-stroke brain inflammation and injury

> **NIH NIH R03** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $155,458

## Abstract

Project Summary
Ischemic brain damage remains a leading cause of long-term disability and death with limited treatment options.
Cerebral ischemic injury is strongly associated with excessive production of reactive oxygen species (ROS) that
contributes to endothelial dysfunction, blood brain barrier disruption, neuronal cell death, and worsened brain
damage. Thus, efforts to curtail ROS have major impact on improving stroke outcome. Dual oxidases (Duox) are
novel members of reduced nicotinamide dinucleotide phosphate oxidases family. The main function of Duox1 is
to generate hydrogen peroxide (H2O2)/ROS. Duox1 at low levels, is involved in essential cellular functions,
antimicrobial host defense, thyroid hormone production, and airway epithelial cell migration, and injury. However,
excessive production and activation of Duox1 may contribute to pathological events including inflammation,
apoptosis, hypertension, cancer, and tissue damage. The direct link between Duox1 and ROS in airway epithelial
cells was shown in our previous work. Pro-inflammatory cytokines and deranged calcium signaling increase the
activity and expression of Duox in airway epithelial cells and thyroid tissues. Interestingly, ischemic stroke causes
aberrant Ca2+ influx. Despite these compelling observations, the specific roles of Duox in the brain and cerebral
ischemia are largely unknown. We have recently identified that focal cerebral ischemia in rodents, and in-vitro
oxygen glucose deprivation rapidly induce the expression of Duox1 in endothelial and neuronal cells in
association with increased ROS production. However, pre-treatment of neuronal cells with Duox1 specific small
interfering RNA decreased Duox1 expression and ROS levels. These data led us to hypothesize that cerebral
ischemia evokes Duox1 over-expression which in turn increases ROS in the brain, leading to exacerbation of
pro-inflammatory and apoptotic processes that worsen the brain injury. We further propose that Duox1 inhibition
has a great potential to mitigate post-ischemic brain damage and neurological dysfunction. Accordingly, our
specific Aims are; To determine the spatiotemporal changes in the expression of Duox1 in brain following focal
cerebral ischemia/reperfusion; To determine if Duox1 inhibition or genetic loss of Duox1 decreases ROS, and
reduces ischemic brain damage, and thus improves post-stroke functional recovery; To investigate the role of
Duox1 as a key driver of inflammatory and apoptotic processes in ischemic brain. We will address these Aims
using a wide array of molecular, cellular, and biochemical approaches in both in vivo animal, and in vitro cell
culture models. Overall, this ‘proof of concept’ study will determine a previously unidentified role for Duox1 in
ischemic brain. These studies pave the way towards better understanding of the role of Duox1 mediated ROS
and neuro-inflammatory mechanisms in brain and may open up a promising new approach for treating cerebro-
vascular diseases...

## Key facts

- **NIH application ID:** 10214199
- **Project number:** 1R03NS118239-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** UMADEVI V WESLEY
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $155,458
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214199

## Citation

> US National Institutes of Health, RePORTER application 10214199, Role of Dual Oxidase in post-stroke brain inflammation and injury (1R03NS118239-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10214199. Licensed CC0.

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