Developing models of placenta-driven developmental lung injury in human preeclampsia

About This Grant

PROJECT SUMMARY The following proposal is a 5-year career development and training plan that will prepare Dr. Taglauer for a career as an independent clinician-scientist and leader in the field of neonatal lung disease. The chronic lung disease of prematurity, (i.e. bronchopulmonary dysplasia) causes significant impairment to the short-term and long-term health of neonates. To date, most studies on bronchopulmonary dysplasia (BPD) pathogenesis have focused on postnatal lung injury. However, the antenatal determinants predisposing infants to BPD have been less well-defined. Among these, the pregnancy disease of preeclampsia has a strong clinical association with BPD. Multiple studies have identified that premature infants born to mothers with preeclampsia have a significant risk of developing BPD postnatally. The primary source of preeclamptic disease is the placenta. In preeclampsia, placental dysregulation causes the release of anti-angiogenic and proinflammatory factors. Dr. Taglauer’s long term research goal is to characterize and address developmental lung injury caused by human preeclampsia. Dr. Taglauer has previously identified in a rodent model of experimental preeclampsia that pups born to preeclamptic mothers have changes in lung morphology and alterations in key developmental gene expression. During her K08 award period, Dr. Taglauer will expand upon these findings by evaluating the influence of human preeclampsia on fetal lung development. Dr. Taglauer will test the hypothesis that the human preeclamptic placenta releases pro-inflammatory and anti-angiogenic signaling proteins into the fetal compartment that cause specific injury to alveolar epithelium and pulmonary vasculature. Specifically, she will 1) identify human preeclampsia-specific placental proteins in the fetal circulation involved in lung developmental injury pathways; 2) develop an in vitro model to evaluate the impact of human preeclamptic placental proteins on human alveolar epithelial and pulmonary vascular endothelial cells; and 3) establish an in vivo rat pregnancy model to examine the effect of human preeclamptic placental proteins on postnatal lung development. Dr. Taglauer has 75% protected research time from the Department of Pediatrics at Boston Medical Center to accomplish these project aims under the guidance of co-mentors Dr. Darrell Kotton at the Center for Regenerative Medicine at Boston University/Boston Medical Center and Dr. Steve Abman at the University of Colorado School of Medicine. She has assembled an excellent scientific advisory committee with diverse expertise to guide her scientific research and career development. Dr. Taglauer has also created a comprehensive training plan that includes mentored research in the Kotton and Abman labs, didactic coursework, presentations at national scientific meetings, manuscript preparation and acquisition of additional grant funding leading to an R01. Dr. Taglauer has the strong commitment from her institution to accomplish these goals and transition to an independently funded physician scientist by the end of this award.