# Hyperoxic Modulation of Thioredoxin Signaling

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $379,150

## Abstract

PROJECT SUMMARY
Fetal transitioning from the relatively hypoxic in utero environment to an oxygen-rich perinatal atmosphere
represents an oxidative burden on the developing lung. Preterm lungs are already deficient in antioxidants and
are poorly equipped to deal with this oxidative transition following parturition even before considering the
adverse effects of therapeutic oxygen and ventilation required to treat poor respiratory function. Sustained
therapeutic oxygen may result in bronchopulmonary dysplasia (BPD), a significant morbidity and mortality in
preterm infants marked by alveolar simplification and dysmorphic vascular growth. It is imperative to identify
and define how oxygen-sensitive signaling pathways contribute to alveolar growth and injury in settings of
altered oxygen tension. Reversible oxidation of cysteine thiols has emerged as an important signaling
paradigm to modulate protein activity in response to redox perturbations. Such thiol switches are regulated by
the enzyme activities of thioredoxin and glutathione superfamilies. We recently identified thioredoxin-1 (Trx1)
and thioredoxin-2 (Trx2) as critical regulators of cysteine oxidation during hyperoxic injury. We hypothesize that
Trx1 and Trx2 act as molecular sensors of atmospheric oxygen tension that modulate alveolar development
and injury/repair responses during redox perturbations associated with developmental oxidative transitions
during parturition and hyperoxic injury. However, the physiological contribution of redox signaling via
thioredoxin-dependent thiol switches is unknown since genetic disruption of either Trx1 or Trx2 expression is
embryonic lethal and in vivo data are exclusively generated with overexpression of transgenes. The following
Aims investigate how
thioredoxin regulation thiol switches influences tissue and cellular physiologies and
molecular functions in response to redox perturbations caused by
atmospheric oxygen tension Determine if
: (1)
Trx1 activity influences alveolar growth and injury during oxygen transitions, (2) Identify oxygen-sensitive Trx1-
dependent signaling pathways regulated via reversible oxidation of cysteine thiols, and (3) Examine how Trx2
regulates oxygen-induced mitochondrial injury and lung epithelial cell death.
Fundamental knowledge gained
from this project will provide new understanding on thioredoxin-dependent thiol switches regulation of
responses during redox perturbations. The overarching goal of this project is to
accelerate the discovery of key thioredoxin regulatory nodes of redox-dependent signaling networks and
harness this information for the development of new diagnostic and therapeutic approaches for BPD.
alveolar
development and injury

## Key facts

- **NIH application ID:** 10261027
- **Project number:** 7R01HL135112-05
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Peter Vitiello
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $379,150
- **Award type:** 7
- **Project period:** 2017-08-10 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10261027

## Citation

> US National Institutes of Health, RePORTER application 10261027, Hyperoxic Modulation of Thioredoxin Signaling (7R01HL135112-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10261027. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*