# Leveraging multiomics and advanced mouse models to delineate mechanisms underlying sex‐specific differences in recovery and repair after neonatal hyperoxia exposure in the developing lung

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $384,700

## Abstract

Bronchopulmonary dysplasia (BPD) is a debilitating lung disease with long-term
consequences and is one of the most common causes for morbidity in premature
neonates. Postnatal exposure to high concentrations of oxygen (hyperoxia) contributes
to the development of BPD. Despite the well-established sex-specific differences in the
incidence of BPD and impaired lung function in males, the molecular mechanism(s)
behind these are not completely understood. Our laboratory has been focused on the
study of sex-specific differences in neonatal hyperoxic lung injury. Endothelial to
mesenchymal transition (EndoMT) contributes to the development of pathologic
pulmonary fibrosis, but the role of EndoMT in BPD has not been determined. Critically,
we have found that neonatal female mice show decreased expression of pro-fibrotic
markers and improved alveolarization and pulmonary vascular development compared
to their male littermates in a murine model of BPD. Furthermore, we show pre-clinical
and clinical evidence of Endo-MT in BPD. Analysis of the pulmonary transcriptome
identified the anti-fibrotic miRNA, miR-30a, as one of the candidates driving these sex-
specific differences. Compellingly, the female advantage in alveolarization and
vascular development is lost in miR30a-/- mice and miR30a expression is decreased in
human BPD lungs. miR30a inhibits both the transcriptional regulator Snai1, as well as
Dll4 (which encodes a Notch ligand). Activation of Snai1 and Dll4/Notch pathway
promote fibrosis through EndoMT. We hypothesize that in hyperoxic female neonates,
miR30a attenuates pathological fibrosis in the developing lung through downregulation
of Dll4-Notch signaling and decreased Snai1 expression. The above hypothesis will be
tested by the following specific aims: Aim 1: Define the contribution of EndoMT and miR-
30a in neonatal hyperoxic lung injury. Aim 2: Determine if miR-30a represses EndoMT
and BPD in females by repressing endothelial Dll4-Notch signaling. Aim 3: Determine if
miR-30a mediated suppression of endothelial Snail1 impacts hyperoxia-induced
EndoMT in BPD. This proposal will address knowledge gaps in the molecular
mechanisms behind the sexual divergent incidence of bronchopulmonary dysplasia and
lay the foundation for future sex-specific treatment strategies.

## Key facts

- **NIH application ID:** 9937967
- **Project number:** 1R01HL146395-01A1
- **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:** $384,700
- **Award type:** 1
- **Project period:** 2020-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937967

## Citation

> US National Institutes of Health, RePORTER application 9937967, Leveraging multiomics and advanced mouse models to delineate mechanisms underlying sex‐specific differences in recovery and repair after neonatal hyperoxia exposure in the developing lung (1R01HL146395-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9937967. Licensed CC0.

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