# S-nitrosoglutathione reductase and airways hyperreactivity in murine bronchopulmonary dysplasia

> **NIH NIH K08** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $163,603

## Abstract

Project Abstract/Summary:
 This proposal describes a five-year mentored research and training plan that will facilitate the development
of Dr. Thomas Raffay, MD to an independent investigator in neonatal pulmonary disease. Building upon Dr.
Raffay's background as a clinical neonatologist and a basic scientist in airways reactivity and neonatal
bronchopulmonary dysplasia (BPD), he will attain expertise in S-nitrosothiol biology, flow-cytometry, conditional
transgenic animal models, pharmacology, and translational science through structured mentorship, rigorous
hands-on laboratory experiences, didactics teaching, and formal classwork and skills training at Case Western
Reserve University/Rainbow Babies and Children's Hospital, the Mayo Clinic Rochester, and the University of
Windsor. Dr. Benjamin Gaston, a pioneer in S-nitrosothiol signaling in pediatric lung disease, and Dr. Richard J
Martin, an international leader in neonatal airways disease and BPD, will provide their expertise and an
established track record of mentorship to this project and Dr. Raffay's transition to research independence. In
the United States, 14,000 new diagnoses of the pediatric lung disease, BPD, are made annually in surviving
premature infants, with costs exceeding $2.5 billion. Treatment options are limited for the severe
bronchospasms and life-long airway obstruction that characterize BPD. Using a neonatal hyperoxia mouse
model of BPD and airways hyperreactivity, Dr. Raffay's new data identify a viable therapy. Treatment with a
single aerosol of S-nitrosoglutathione (GSNO) reverses airways hyperresponsiveness in juvenile BPD mice
and room air recovered adults. GSNO is a potent endogenous bronchodilator, critical for the airways diseases
of asthma and cystic fibrosis. In this model, neonatal hyperoxia increases the catabolic breakdown of GSNO
caused by increased expression and activity of the enzyme, S-nitrosoglutathione reductase (GSNOR), at least
in part through hyperoxic downregulation of a microRNA (miR-342-3p). This study will test the overall
hypothesis that loss or inhibition of GSNOR activity will protect against BPD airways hyperreactivity in juvenile
and adult mice. This proposal will evaluate the effects of neonatal hyperoxia on BPD airways hyperreactivity
and parenchymal lung remodeling utilizing global GSNOR knockout mice (Aim 1A); identify the lung tissues
involved in GSNOR and miR-342-3p expression utilizing fluorescence-activated cell sorting and develop and
test conditional GSNOR knockout mice (Aim 1B); test a pharmaceutical-grade GSNOR inhibitor drug in wild-
type mice to alleviate acute bronchoconstriction (Aim 2a) and chronically to attenuate the BPD phenotype (Aim
2b). In a translational human aim (Aim 3): GSNOR levels, real-time fluorescent GSNO catabolism, and
microRNA expression will be measured in human fetal airway smooth muscle exposed to hyperoxia; and
GSNO and GSNOR inhibitors will be tested as a treatment for attenuation of oxygen induced h...

## Key facts

- **NIH application ID:** 10208930
- **Project number:** 5K08HL133459-05
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Thomas Michael Raffay
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $163,603
- **Award type:** 5
- **Project period:** 2017-07-14 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10208930

## Citation

> US National Institutes of Health, RePORTER application 10208930, S-nitrosoglutathione reductase and airways hyperreactivity in murine bronchopulmonary dysplasia (5K08HL133459-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10208930. Licensed CC0.

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