We want to know more about...

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 se x-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.

Premature Lung

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.

Currently funded projects:

Mechanisms of sex differences in neonatal pulmonary oxygen toxicity.

Bronchopulmonary dysplasia (BPD), a debilitating lung disease with long-term consequences, is the most common morbidity in extremely premature neonates. Male babies have a higher incidence of BPD compared to females. In this proposal, we will study how small RNAs lead to sex-specific differences in lung injury in repair. This will lead to the development of novel approaches and individualized therapeutic options for BPD.

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

Bronchopulmonary dysplasia (BPD), a debilitating lung disease with long-term consequences, is the most common morbidity in extremely premature neonates. Male babies have a higher incidence of BPD compared to females. In this proposal, we will study how lung injury and repair is different between male and female neonates and elucidate the molecular mechanisms modulating these sex-specific differences.

Sex as biological variable in Bronchopulmonary Dysplasia: Role of the Notch pathway.

Bronchopulmonary dysplasia (BPD), a debilitating lung disease with long-term consequences, is the most common morbidity in extremely premature neonates. Male babies have a higher incidence of BPD compared to females. In this proposal, we will study how the Notch pathway could lead to sex-specific differences in lung repair after exposure to hyperoxia. This will lead to the development of novel approaches and individualized therapeutic options for BPD.

Projects in pipeline:

Single cell Seq experiment to look at heterogeneity in different lung cell subpopulations and sex-specific differences.

Use the Four Core Genotype mice to delineate the role of sex hormones versus sex chromosomes on lung development, injury and repair.

Lineage Tracing Models to study the cell fate of endothelial cells in lung injury and repair.

Use Endothelial cell specific AAV to deliver therapies or to temporally turn off or turn on key genes to study their role in neonatal lung injury and repair.