Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy and is associated with significant morbidity, mortality and cost. Its pathogenesis remains poorly understood and predictors of the disease remain to be identified. Dr. Mestan is committed to elucidating the mechanisms that lead to BPD so that preventive strategies could be developed to decrease its incidence. Her short term goal is to investigate the epidemiologic associations of BPD with biomarkers (8-isoprostane and 8-hydroxydeoxyguanosine (8- OHdG)) and gene polymorphisms implicated in pathways of oxidant stress, under the primary mentorship of Dr. Xiaobin Wang. This award would allow Dr. Mestan to gain the necessary skills to develop her research program and become an independent investigator. Her career development plan involves a multi-disciplinary program of didactic training and closely mentored molecular and genetic epidemiological research experiences. Her central hypothesis is that peripartum and postnatal oxidant stress, as measured by cord blood and urinary 8-isoprostane and 8-OHdG, and specific gene polymorphisms can independently or interactively affect the development of BPD. Her proposed study will employ the resources of two birth centers: The Boston Medical Center (BMC) birth cohort was established by Dr. Wang and colleagues in 1998, and is one of the largest ongoing birth cohorts in the U.S.;The Northwestern Memorial Hospital (NMH) cohort was initiated locally by Dr. Mestan in 2006, and will be developed further under the guidance of her mentors. Using a 1:2 case-control design of 1,200 preterm infants, she will investigate the following Specific Aims: 1) To identify relationships between cord blood and urinary biomarkers of oxidant stress and the development of BPD;and 2) To assess genetic associations of promising candidate genes (GSTP1, SOD3) with the risk of BPD, with adjustment for important clinical variables, population admixture, and multiple testing. Upon completion of this project, Dr. Mestan will have acquired essential experience in biochemical assay and genotyping techniques, and advanced statistical and genetic analyses, for the design and conduction of future studies of BPD and its outcomes. Project Narrative: Upon the identification of predictive biochemical and genetic markers of BPD, we will be better able to identify high-risk infants, provide earlier and more targeted interventions, and ultimately reduce the incidence and severity of BPD. In turn, this will improve the long-term outcomes of BPD patients, positively impact their families, and minimize the financial burden to society in managing this complex disease.

Public Health Relevance

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National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-R (F1))
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Colombini-Hatch, Sandra
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Children's Memorial Hospital (Chicago)
United States
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Mestan, K K; Check, J; Minturn, L et al. (2014) Placental pathologic changes of maternal vascular underperfusion in bronchopulmonary dysplasia and pulmonary hypertension. Placenta 35:570-4
Voller, Stephannie Baehl; Chock, Susanne; Ernst, Linda M et al. (2014) Cord blood biomarkers of vascular endothelial growth (VEGF and sFlt-1) and postnatal growth: a preterm birth cohort study. Early Hum Dev 90:195-200
Berkelhamer, Sara K; Mestan, Karen K; Steinhorn, Robin H (2013) Pulmonary hypertension in bronchopulmonary dysplasia. Semin Perinatol 37:124-31
Check, J; Gotteiner, N; Liu, X et al. (2013) Fetal growth restriction and pulmonary hypertension in premature infants with bronchopulmonary dysplasia. J Perinatol 33:553-7
Mestan, Karen; Matoba, Nana; Arguelles, Lester et al. (2012) Cord blood 8-isoprostane in the preterm infant. Early Hum Dev 88:683-9
Mestan, Karen K; Ilkhanoff, Leonard; Mouli, Samdeep et al. (2011) Genomic sequencing in clinical trials. J Transl Med 9:222
Mestan, Karen K; Steinhorn, Robin H (2011) Fetal origins of neonatal lung disease: understanding the pathogenesis of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 301:L858-9