Impaired angiogenesis in preterm infants after maternal complications of pregnancy

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 DESCRIPTION (provided by applicant): The Clinical Problem: 10% of all children born in the United States suffer from preterm birth and 10% of these develop bronchopulmonary dysplasia (BPD), the chronic lung disease associated with significant respiratory complications that continue into adulthood. BPD results from a disruption in pulmonary vascular and alveolar growth. Epidemiological studies have shown that maternal complications of pregnancy, such as preeclampsia, chorioamnionitis, and intrauterine growth restriction (IUGR), increase the risk for BPD. However, the mechanisms through which maternal complications of pregnancy lead to more severe BPD are unclear. We speculate that maternal complications of pregnancy disrupt angiogenesis in preterm newborns resulting in more severe BPD. The Candidate: I am an assistant professor in the Department of Pediatrics and board certified in pediatric pulmonary medicine. As an NIH K12 award recipient, I performed basic science research in endothelial progenitor cell (EPC) biology and became proficient in EPC isolation and characterization. My past studies demonstrated that EPCs from preterm infants are highly proliferative and uniquely susceptible to oxidative stress. I then showed that cord blood EPCs are decreased in preterm infants who later develop BPD. These findings inspired my current research interest, to utilize advanced biostatistical methods to link epidemiological risk factors for BPD with angiogenic biomarkers to suggest mechanisms of BPD pathogenesis and identify those preterm infants at greatest risk. I have described a focused career development plan that will enable me to independently conduct clinical-translational research. This K23 Career Development Award application will provide three years of critical support so that I may achieve my short-term goals: 1. To learn state-of-the-art quantitative applied biostatistical methods. 2. To apply statistical mediation analysis to test my specific hypothesis. This will enable me to attain my long-term career goal of becoming an independent clinician scientist who will effectively translate mechanistic basic studies in pulmonary vascular development into new insights regarding the pathogenesis and potential treatment of bronchopulmonary dysplasia (BPD). During the second year of this award period, I will submit my first R01 application concerning angiogenic biomarkers and BPD outcomes in childhood. The Research: Based on the current literature and our preliminary data, the central hypothesis to this proposal is that maternal complications of pregnancy alter angiogenic biomarkers in preterm infants suggesting a disruption in EPC- mediated angiogenesis that results in severe BPD. In this study, we will utilize an integrated translational approach to connect epidemiological risk factors for BPD with novel mechanistic biomarkers and longitudinal assessments of BPD severity in a well-characterized cohort of mothers and their preterm newborns. To test the hypothesis above, we propose the following specific aims: Aim 1: To determine whether specific maternal complications of pregnancy are associated with altered cord blood angiogenic biomarkers. We will test the hypothesis that antenatal complications of pregnancy decrease cord blood angiogenic biomarkers (ECFCs, CPC:non-CPC, angiogenic cytokines), disrupt ECFC function in vitro, and increase endothelial microparticles, an independent marker of vascular injury, providing further evidence that angiogenesis is disrupted in the lungs of preterm infants who develop BPD. Aim 2: To determine whether peripheral blood angiogenic biomarkers are associated with BPD severity during the first year of life. We will test the hypothesis that circulating ECFCs are decreased and ECFC function is disrupted in preterm infants who develop severe BPD with chronic hypoxemia, hospital readmissions/ED visits, and pulmonary hypertension by echocardiography during early life. Aim 3: To perform statistical mediation analysis to determine whether BPD is associated with maternal complications of pregnancy through impaired angiogenesis as suggested by angiogenic biomarkers. We will utilize novel biostatistical methods to test the hypothesis that maternal complications of pregnancy are associated with BPD through disrupted angiogenesis in preterm infants. This research plan represents the logical next step for my research. As I perform the outpatient follow-up visits, I will have direct interaction with the study participants The Environment: As described in this proposal and the letters of support, I have strong multidisciplinary mentorship by established investigators (from the Departments of Pediatrics in the University of Colorado School of Medicine, the Colorado School of Public Health, and the Colorado Clinical Translational Sciences Institute). My mentoring team has extensive experience in clinical translational research and a strong track record of prior successful mentorship. This environment has enabled me to develop the skills needed to perform the angiogenic assays, to develop a clinical database, and will ensure the success of this proposal to prepare me for independent research.