Genomic determinants of bronchopulmonary dysplasia development in humans and an animal model

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PROJECT SUMMARY . The purpose of this Mentored Patient-Oriented Research Career Development Award (K23) is to provide Alvaro Moreira, MD, MSc, Assistant Professor at the University of Texas Health Science Center at San Antonio with the knowledge and skills requisite to develop into an independent academic physician scientist. His long-term career goal is to understand the pathologic processes that correlate with the development of bronchopulmonary dysplasia (BPD), a disease with high morbidity and mortality in premature neonates. To this avail, Dr. Moreira is incorporating the use of high-fidelity technology to validate two genomic signatures (n=20 genes) that he and his mentoring team have identified as strong predictors for BPD susceptibility. To achieve this goal, Dr. Moreira and his mentoring team have devised a comprehensive plan based on: (1) an in-depth hands on training in genomics and bioinformatics; (2) didactic and experiential instruction in advanced immunology, and (3) rigorous training in clinical trials. This platform will provide the basis for Dr. Moreira to gain the skills, knowledge and experience needed to formulate and test incisive hypotheses that will bolster advances in neonatal lung disease. Neonates diagnosed with BPD are at increased risk for systemic (blindness, mental deficiency) and site-specific complications (asthma, recurrent respiratory infections, pulmonary hypertension). BPD is characterized by an aberrant lung development secondary to chronic exposure to hyperoxia and ventilator-induced injury. Despite advances in neonatal medicine, current therapies are limited and largely ineffective. Thus, there is an urgency to adopt novel tactics to mitigate and prevent BPD. Significant gaps in understanding the underlying mechanisms in BPD are attributed to an operational definition, a lack of robust neonatal tissue biorepositories, and animal models that do not recapitulate the intricacies of human physiology. Translational genomics holds significant promise as an approach to overcome these barriers. Indeed, in a discovery cohort of 120 preterm neonates, Dr. Moreira and his mentoring team have identified genomic signatures that predict BPD and stratifies BPD endotypes in a neonate's first 5 days of life. In this revised application Dr. Moreira plans to validate two genomic signatures in a large prospective preterm neonatal cohort (Year 1, 2). In Year 3, he will test the ability of a customized genomic array, based on his signatures, to provide a quick and reliable BPD risk stratification. Furthermore, Dr. Moreira's studies will evaluate the safety and efficacy of an FDA-approved biologic in a one of a kind large animal model mimicking BPD. This monoclonal antibody targets a modifiable process found to be highly predictive for BPD in his genomic profile from the discovery cohort. Dr. Moreira's K23 studies will produce a rich learning and educational framework directly informing his future R01 proposal aimed at primary prevention strategies for BPD.