This proposal outlines a 5 year training program for the development of an academic career in Respiratory Medicine. The candidate has completed training in Pediatrics and a fellowship in Respiratory Medicine. He is now in the midst of enhancing the requisite skills for success as an independent investigator. Dr. Lloyd Cantley, an expert in organ injury and repair will mentor the candidate's scientific development. A prestigious advisory committee (Drs. Jack Elias, Clifford Bogue and Scott Rivkees) drawn from the faculty at Yale with expertise in diverse aspects of lung development, injury, repair and oxygen toxicity will monitor and provide scientific and career guidance to the applicant's project. Bronchopulmonary dysplasia (BPD) is a result of ung injury in infants requiring mechanical ventilation and supplemental oxygen. The goal of this research project is to understand the regulatory mechanisms of injury and protection in the developing lung during hyperoxia. Preliminary results show that embryonic lung explants cultured under hyperoxic conditions exhibit developmental failure that is partially reversible by recombinant vascular endothelial growth factor (VEGF) 165. In addition, it was found that VEGF 188 is the most predominant isoform during lung development. This proposal will determine the airway cellular type that responds to hyperoxic stimuli (epithelial, endothelial and or mesenchymal) and establish the role of VEGF in ameliorating this injury Specific Aim (SA) 1. To address this hypothesis, lung explant models will be exposed to hyperoxia and different cellular responses (apoptosis vs cell proliferation) in the presence or absence of VEGF will be identified by immunostaining and gene expression. Finally, we will investigate specific VEGF isoforms (120,164 and 188) in regulating embryonic lung development and response to hyperoxia (SA 2). To determine the role of these isoforms, transgenic mice that express single VEGF isoforms (e.g.VEGF 188 +/+ will be VEGF120-/- and VEGF164 -/-) will be utilized.This work will provide understanding of the mechanisms leading to hyperoxic injury and may suggest a new treatment strategy through VEGF 188. Yale University is a world leader in biomedical research, and the Department of Pediatrics has proven itself to be an ideal setting to train pediatric physician-scientists.

Public Health Relevance

Bronchopulmonary dysplasia (BPD) occurs primarily in preterm infants who require mechanical ventilation and supplemental oxygen. High inspired oxygen levels can cause arrested lung development. My ultimate goal is to design strategies to treat preterm infants who are at risk for BPD in a manner that promotes normal lung development in the face of therapeutic interventions including supplemental oxygen .

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-O (O1))
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Colombini-Hatch, Sandra
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Esquibies, Americo E; Karihaloo, Anil; Quaggin, Susan E et al. (2014) Heparin binding VEGF isoforms attenuate hyperoxic embryonic lung growth retardation via a FLK1-neuropilin-1-PKC dependent pathway. Respir Res 15:32
Ishak, Marleine; Zambrano, Eduardo V; Bazzy-Asaad, Alia et al. (2012) Unusual pulmonary findings in mucolipidosis II. Pediatr Pulmonol 47:719-21