Bronchopulmonary dysplasia (BPD) is a common morbidity in extremely low birth weight (ELBW) infants. Our research group has considerable expertise in translational research on BPD. We have: (a) developed models using only limited clinical information to predict BPD or death by postnatal age or respiratory illness severity in ELBW infants, (b) prospectively evaluated pulmonary hypertension in BPD and (c) identified biomarkers associated with BPD/death in a cohort of 1067 ELBW infants using multiple clinical variables and 25 cytokines in blood. More recently, we have made novel observations on the genetic basis of BPD by genome-wide analysis in 751 ELBW infants. In additional ongoing studies, we have identified novel proteomic biomarkers of BPD, and have determined alterations in the airway microbiome in BPD. The overall objective of STOP BPD (Signature of Top Omic Profiles in BPD) is to prospectively define and validate clinical and omic signatures associated with resilience against, or risk for development of BPD. To address this objective, we will build upon our recent studies on genomics, proteomics, respiratory microbiome, and model development in BPD. We will evaluate a prospective cohort (Generic Database or GDB cohort of the NICHD Neonatal Research Network) of 300 preterm infants <29 weeks gestation born in 2015-2017 (n=213 in 2013 alone, with 80%+ enrollment) by the following Specific Aims:
Specific Aim 1 - Development and validation of a personalized genomic risk/resilience score for BPD and severe BPD using a combination of genome-wide expression analysis and targeted SNP profiling in blood collected within 72h of birth Specific Aim 2 - (a) Development and validation of a personalized urinary proteomic risk/resilience score for BPD and severe BPD measured in the first postnatal week (b) Development and validation of a personalized plasma proteomic and cytokine risk/resilience score for BPD and severe BPD measured within 72h of birth Specific Aim 3 - Development and validation of a personalized airway microbiome risk/resilience score for BPD and severe BPD using tracheal aspirates collected in the first postnatal week Specific Aim 4 - Development of a combined Omic scoring system combining the genomic, proteomic, and microbiomic scores with the clinical model We will develop and determine the accuracy of the various models in the Development cohort (n=150), and validate them in the Validation cohort (n=150). These novel models can be used to define the target population for future interventions, assess efficacy of specific interventions, develop a lab on chip, and support future studies on the biology of BPD.

Public Health Relevance

Bronchopulmonary dysplasia (BPD) is a common respiratory disorder in very preterm infants, characterized by impaired lung development, and associated with long-term respiratory complications. In this study, we will evaluate 300 extremely preterm infants to determine alterations in gene expression, protein amounts, or microbial flora in the airway that are associated with resilience (resistance to development of severe BPD, even when considered to be at high risk due to clinical risk factors) or predisposition (higher rate of developing severe BPD even if not initially considered at high risk). (End of Abstract)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1)
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Natarajan, Aruna R
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University of Alabama Birmingham
Schools of Medicine
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Lal, Charitharth Vivek; Olave, Nelida; Travers, Colm et al. (2018) Exosomal microRNA predicts and protects against severe bronchopulmonary dysplasia in extremely premature infants. JCI Insight 3:
Lutful Kabir, Farruk; Ambalavanan, Namasivayam; Liu, Gang et al. (2018) MicroRNA-145 Antagonism Reverses TGF-? Inhibition of F508del CFTR Correction in Airway Epithelia. Am J Respir Crit Care Med 197:632-643
Kandasamy, Jegen; Olave, Nelida; Ballinger, Scott W et al. (2018) Reply to Shah et al.: Mitochondrial Dysfunction in Bronchopulmonary Dysplasia. Am J Respir Crit Care Med 197:1363-1364
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Kandasamy, Jegen; Olave, Nelida; Ballinger, Scott W et al. (2017) Vascular Endothelial Mitochondrial Function Predicts Death or Pulmonary Outcomes in Preterm Infants. Am J Respir Crit Care Med 196:1040-1049
Lal, Charitharth V; Xu, Xin; Jackson, Patricia et al. (2017) Ureaplasma infection-mediated release of matrix metalloproteinase-9 and PGP: a novel mechanism of preterm rupture of membranes and chorioamnionitis. Pediatr Res 81:75-79
Olave, Nelida; Lal, Charitharth V; Halloran, Brian et al. (2016) Regulation of alveolar septation by microRNA-489. Am J Physiol Lung Cell Mol Physiol 310:L476-87
Lal, Charitharth Vivek; Travers, Colm; Aghai, Zubair H et al. (2016) The Airway Microbiome at Birth. Sci Rep 6:31023
Ambalavanan, Namasivayam; Morty, Rory E (2016) Searching for better animal models of BPD: a perspective. Am J Physiol Lung Cell Mol Physiol 311:L924-L927
Panikkanvalappil, Sajanlal R; James, Masheika; Hira, Steven M et al. (2016) Hyperoxia Induces Intracellular Acidification in Neonatal Mouse Lung Fibroblasts: Real-Time Investigation Using Plasmonically Enhanced Raman Spectroscopy. J Am Chem Soc 138:3779-88

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