Modulation of Neonatal Hyperoxic Lung Injury by the Aryl Hydrocarbon Receptor

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DESCRIPTION (provided by applicant): I am an Assistant Professor in Pediatrics at Baylor College of Medicine (BCM) with a long-standing research interest in hyperoxic lung injury. My main career goal is to become an established investigator with a focus on understanding the role of aryl hydrocarbon receptor (AhR) in hyperoxia-induced developmental lung injury. The primary objective of my K08 proposal is to obtain the career development award that values protected research time and the involvement of senior mentors to formulate an educational curriculum and oversee my research progress, both of which are crucial in attaining my career goals. As a postdoctoral fellow, I investigated the molecular mechanisms of hyperoxic lung injury in adult mice and laid the groundwork for the proposed research. I have enrolled for a PhD offered by Clinical Scientist Training Program at BCM, where I will be educated and trained in molecular methods, molecular genetics, biostatistics, grant writing, and ethics in research to enhance my career development. The renowned BCM provides an outstanding core of mentors and an enriched environment to support my training and research. My primary mentor, Dr. Bhagavatula Moorthy, is a renowned researcher with successful funding in determining the mechanistic roles of cytochrome P450 1A enzymes in hyperoxic lung injury, and the regulation of AhR by the polycyclic aromatic hydrocarbons. In addition to Dr. Moorthy, my advisory committee consists of Drs. Stephen Welty, Francesco DeMayo, David Moore, and E. O'Brian Smith of BCM who are leaders in research related to this proposal. We observed that omeprazole, a proton pump inhibitor, attenuates hyperoxic lung injury in adult wild type mice and oxygen toxicity in adult human lung cells via activation of the AhR. Whether AhR activation results in a similar effect in newborn mice and in newborn human lung cells are unknown. My research will test the central hypotheses that the proton pump inhibitors (PPIs), i.e. omeprazole and lansoprazole, protect against hyperoxia-induced alveolar simplification in newborn mice in vivo and against oxygen toxicity in neonatal human lung cells in vitro via activation of the pulmonary AhR. I will test this hypothesis by pursuing the following 3 specific aims: 1. Determine the effects of the PPIs on alveolarization and pulmonary vascularization in hyperoxia-exposed newborn mice. 2. Determine the effects of the PPIs on the activation of pulmonary AhR in newborn wild type (WT) mice. 3. Determine the effects of PPI-mediated activation of the AhR on hyperoxia exposed human neonatal lung cells. The lungs of the air- or hyperoxia-exposed newborn WT and AhR-null mice treated with PPIs will be assessed for AhR activation, alveolarization, pulmonary vascularization, oxidative stress and inflammation. Air- or hyperoxia- exposed neonatal human pulmonary microvascular endothelial and alveolar epithelial cells treated with PPIs in the presence or absence of the AhR will be analyzed for AhR activation, oxidative stress, inflammation, apoptosis and necrosis. I anticipate that the results will support my hypotheses, which will lead to novel strategies in the prevention and treatment of BPD in premature infants.