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

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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. Aberrant Notch signaling contributes to the pathogenesis of many chronic lung diseases and Notch activation is seen in lungs of human infants with BPD. The role of aberrant Notch signaling in pulmonary dysangiogenesis in BPD has not been determined. Critically, neonatal female mice have improved alveolarization and pulmonary vascular development, which is associated with, decreased Notch pathway activation and expression of the Notch ligand Dll4 compared to male littermates in a murine model of BPD. The overall aim of this innovative proposal is to define the role of sex-specific activation of Notch pathway in modulating pulmonary angiogenesis in neonatal hyperoxic lung injury. We hypothesize that decreased Notch activation secondary to lesser Dll4 expression preserves pulmonary angiogenesis in female neonates . The above hypothesis will be tested by the following specific aims: Aim 1: Elucidate the spatio-temporal role of endothelial DLL4 (Notch ligand) in modulating pulmonary angiogenesis. Aim 2: Determine the role pulmonary endothelial Notch signaling in modulating pulmonary angiogenesis in the developing lung exposed to hyperoxia. 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.