One of the major goals of my research is to delineate the molecular mechanisms behind sexual dimorphism in neonatal mortality and morbidity. In the long-term, our research is aimed at improving lung health in premature babies and identifying new therapeutic targets. 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. Male sex is considered an independent predictor for 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. The NF?B families of transcription factors regulate diverse cellular processes including cell proliferation, survival, and angiogenesis. There is data to support a role for NF?B in postnatal angiogenesis and alveolarization in neonatal mice; both of these processes are impaired in BPD. The role of the NF?B pathway in modulating sex-specific differences in neonatal hyperoxic lung injury and pulmonary angiogenesis has not been investigated. The objective of this application is to delineate the mechanisms of sex-specific differences in neonatal hyperoxic lung injury. The overall hypotheses of the research proposed in this application is that differential sex-specific activation of the NF-kB pathway a) will promote alveolar and vascular development and prevent PH in a hyperoxia-induced BPD model in female neonatal mice and b) decrease oxygen toxicity in human female pulmonary microvascular endothelial cells in vitro.
Aim 1 : To determine the mechanistic role of NF?B pathway in the sex-specific differences in neonatal hyperoxic lung injury. Male and female p50-/-, p50 +/+ and NF-?B/luciferase (NF-?B /luc) transgenic mice will be exposed to hyperoxia (95% FiO2; PND 1-5) after birth. Expression and activity of the NF-?B pathway, inflammation, oxidant stress, alveolarization and angiogenesis will be measured (PND 6 and 21). In addition, markers of PH will be quantified (PND21).
Aim 2 : To determine if the NF?B pathway differentially modulates cell viability, oxidative stress, and angiogenesis in male and female human pulmonary microvascular endothelial cells and elucidate the underlying regulatory mechanism(s) in an in vitro model of 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. Understanding the sex-specific differences in the modulation of the NF-kappaB pathway, as proposed in this application, will lead to the development of novel approaches and individualized therapeutic options for BPD.
