# Mechanisms of sex differences in neonatal pulmonary oxygen toxicity

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $537,886

## Abstract

Bronchopulmonary dysplasia (BPD) is a debilitating lung disease with long-term
consequences in premature neonates. Postnatal exposure to high concentrations of
oxygen (hyperoxia) contributes to the development of BPD. Premature male neonates
are at a greater risk of developing BPD. The reasons underlying sexually dimorphic
outcomes in premature neonates are not known. Pulmonary vascular development in
neonatal mice exposed to hyperoxia is better preserved in females. Our preliminary
analysis of the pulmonary transcriptome demonstrates that angiogenesis is differentially
modulated between hyperoxia-exposed neonatal male and female mice. Suggestively,
many of these differentially regulated angiogenic transcripts contained a seed sequence
for the pro-angiogenic miRNA, miR-30a, within their 3’ UTR. The role of miRNAs in
mediating sex biases in BPD is understudied. Relatedly, female lungs had increased
miR-30a expression following early exposure to hyperoxia. Compellingly, our
preliminary data indicate that protection from neonatal hyperoxic lung injury is lost in
female miR30a-/- mice. Hif-1α increases miR-30a expression and plays an important
role in post-natal lung development, especially in recovery from hyperoxic injury. HIF-1α
binding to its target genes is greater in female lungs after hyperoxia exposure. miR-30a
downregulates Delta like ligand 4 (Dll4), which encodes a ligand for the Notch family of
receptors. Increased DLL4/Notch activity decreases, while blockade enhances
angiogenic sprouting and branching. Decreased miR-30a levels and increased Dll4 and
Notch expression are seen in human BPD patient lungs. We hypothesize that higher
miR-30a expression through HIF-1α preserves lung vascular development by
downregulation of Dll4-Notch signaling in females. The above hypothesis will be tested
by the following specific aims: Aim 1: Establish the role of miR-30a in neonatal
pulmonary angiogenesis after hyperoxia exposure. Aim 2: Define the sex-specific
mechanisms governing transcriptional regulation of miR-30a by HIF-1α during recovery
from neonatal hyperoxic lung injury. Aim 3: Determine the impact of endothelial DLL4
suppression by miR-30a in the neonatal lung exposed to hyperoxia. This proposal will
address knowledge gaps behind the sexual divergent incidence of bronchopulmonary
dysplasia and lay the foundation for future sex-specific treatment strategies.

## Key facts

- **NIH application ID:** 9948751
- **Project number:** 5R01HL144775-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Krithika Lingappan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $537,886
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948751

## Citation

> US National Institutes of Health, RePORTER application 9948751, Mechanisms of sex differences in neonatal pulmonary oxygen toxicity (5R01HL144775-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9948751. Licensed CC0.

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