Salivary miRNAs as Prognostic Markers of Pulmonary Hypertension Associated with Bronchopulmonary Dysplasia in Extremely Low Gestational Age Infants

PROJECT SUMMARY/ABSTRACT With recent advances in neonatal care, there is improved survival of extremely premature babies with very low birth weight, although the complications of bronchopulmonary dysplasia (BPD) remain. One of the most severe of these complications is pulmonary hypertension (BPD-PH). The true incidence of BPD-PH in preterm babies is unknown, but prevalence is estimated to range from 17-40%. BPD and BPD-PH are typically diagnosed at 36 weeks postmenstrual age (PMA). BPD-PH leads to more days in the neonatal ICU, increased days of ventilator and oxygen requirement, and the need for tracheostomy and home ventilator support. Furthermore, these infants continue to have high mortality and morbidity with increased hospital readmissions in their first 2 years of life. Some clinical parameters and qualitative markers help predict development of BPD-PH at 36 weeks PMA, such as infants born small for gestational age, maternal history of preeclampsia, chorioamnionitis, and early periods of ventilator support at 7 and 28 days of life. However, we lack quantitative markers to predict development or long-term outcomes such as death, re-hospitalization, or response to therapies. A non-invasive quantitative predictor would help stratify these infants early on and be appropriate for these frequently intubated and medically fragile infants. In our preliminary study among infants with BPD-PH, we non-invasively obtained tracheal aspirate and identified a specific panel of microRNAs (small noncoding RNAs) associated with hypoxic stress response and angiogenic pathways. We have further conducted preliminary studies correlating tracheal aspirate samples with that of saliva from extreme preterm infants. In this proposed K23 project, the Candidate (with advice from an outstanding multidisciplinary team of mentors) will study salivary samples of extreme preterm infants for early identification of target miRNAs that could predict development of BPD-PH and its long-term outcomes. This will be a prospective study of infants born <28 weeks of gestation; saliva samples will be collected at 7 and 28 days of age and analyzed for markers that could predict BPD-PH at 36 weeks of gestation. The Candidate will evaluate miRNA expression in infants with BPD-PH over the first year of life and identify markers that predict diagnosis and outcomes, based on their echocardiogram findings and oxygen requirements. By the end of this K23, the Candidate will have learned how to design and carry out future miRNA studies and analyze their results. She also will have completed selected relevant courses as part of her Master’s Degree in Clinical Research and received guidance on career development. Data will be disseminated at meetings and published in peer-reviewed journals. In summary, this project will provide a strong platform for future R01-type applications and help continue the Candidate’s positive career trajectory and ultimate goal to become an independent physician-scientist and nationally recognized expert in BPD-PH in premature infants.