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

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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.