Oxygen-Mediated Regulation of PDE5 in the Developing Pulmonary Vasculature

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DESCRIPTION (provided by applicant): This proposal describes a five year training program for the development of an academic career in Neonatology. The principal investigator has completed structured fellowship training in Neonatology and now, will expand upon her scientific skills through a unique integration of basic science and translational resources. This program will promote our understanding of oxygen-mediated cellular signaling, as applied to pulmonary vascular biology and the clinical care of critically ill neonates. Robin H. Steinhorn will mentor the principal investigator's scientific development. Dr. Steinhorn is a recognized leader in the field of neonatal pulmonary vascular biology. She is the Division Head of Neonatology and has trained numerous clinical fellows, postdoctoral fellows, and graduate students. To enhance the training, the program will enlist the expertise of Paul Schumacker, Professor of Pediatrics. Dr. Schumacker is a nationally known expert in mechanisms of oxygen-sensing within the cell. In addition, an advisory committee of highly regarded medical scientists will provide scientific and career advice. Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening clinical syndrome of newborn infants, characterized by failed transition of the pulmonary vasculature from intrauterine to extrauterine life. Although ventilation with 100% oxygen and inhaled nitric oxide (iNO) is standard therapy for infants with PPHN, there is growing evidence that exposure to hyperoxia may have lasting effects on a cellular level. Our long-term research goal is to better understand the pathogenesis of PPHN and to develop novel therapies to improve the outcomes of infants with PPHN. One potential target for intervention is the major phosphodiesterase isoform in the lung, phosphodiesterase 5 (PDE5). Our central hypothesis is that PDE5 is a critical mediator of neonatal pulmonary vascular tone, and that its expression and activity are impacted by PPHN pathogenesis as well as PPHN therapies, such as oxygen. Understanding oxygenmediated regulation of PDE5 will play a critical role in understanding PPHN pathogenesis and will impact clinical management, as PDE5 may prove to be an important therapeutic target. The major goal of this project is to delineate the effects of oxygen and its downstream targets on PDE5 gene expression and activity, both in the healthy perinatal pulmonary vasculature and in PPHN. The successful completion of the studies presented here will impact public health by providing a basic science foundation for clinical trials of both targeted antioxidants and PDE5 inhibitors to prevent oxygen-mediated damage to the pulmonary vasculature. These drugs have the potential to not only improve outcomes for infants with PPHN, but for all infants and children who require ventilation with high levels of oxygen, regardless of the etiology of their underlying disease. (End of Abstract)