Role of Vitamin D in Lung Development and Bronchopulmonary Dysplasia

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The Clinical Problem: Bronchopulmonary dysplasia (BPD), the chronic lung disease of preterm infants is associated with significant respiratory complications that continue into adulthood. BPD results from a disruption in pulmonary vascular and alveolar growth. Recent studies suggest vitamin D plays a role in fetal lung development and enhances lung development in an animal model of chorioamnionitis. However, the mechanisms through which vitamin D enhances vascular and alveolar growth remain unknown. The Candidate: I am an Assistant Professor in the Department of Pediatrics, and board certified Neonatologist at the University Colorado School of Medicine. My studies on the effects of vitamin D on lung growth and function were the first to demonstrate a striking protective effect of early vitamin D treatment in an animal model of BPD, and further show that at least part of these effects are mediated through enhanced or preserved pro-angiogenic signaling mechanisms after lung injury. My short-term goals: 1) advance my understanding and use of mouse genetics to study mechanistic regulation of vitamin D and lung development; 2) develop new skills to analyze and interpret genomic and genetic data to determine vitamin D-sensitive pathways during fetal lung development; 3) expand my understanding and skills in statistics and bioinformatics. My long-term career goal is to become an independent physician scientist who will effectively translate mechanistic basic studies in pulmonary vascular development into new insights regarding the pathogenesis and potential treatment of BPD. During the fourth year of this award period, I will submit my first R01 application. The Research: Based on current literature and our preliminary data, the central hypothesis to this proposal is that abnormal vitamin D signaling in experimental BPD contributes to abnormal vascular and alveolar growth, causes PH, and increases susceptibility to the adverse effects of perinatal injury on lung structure and that the pro-angiogenic effects of vitamin D in the developing lung are mediated through increased PPARγ and VEGF signaling. We propose the following specific aims: Aim #1: To determine whether fetal vitamin D deficiency impairs endothelial cell growth, function, and angiocrine signaling pathways, which causes abnormal vascular and airspace structure, and increases susceptibility to postnatal hyperoxia; Aim #2: To determine whether perinatal vitamin D signaling enhances lung structure by preserving PPARγ – VEGF signaling in the fetal rat lung after endotoxin exposure and prevents BPD and PH; Aim #3: To determine whether impaired vitamin D signaling due to EC-specific vitamin D receptor deficiency disrupts lung growth, causes PH and increases the severity of lung injury to antenatal (ETX) or postnatal (hyperoxia) stress. The Environment: I have strong multidisciplinary mentorship by established investigators (University of Colorado School of Medicine and Purdue University). My mentoring team has extensive experience in basic vascular pulmonary and vitamin D biology research and a strong track record of prior successful mentorship.