Chronic lung disease (CLD) represents an important cause of morbidity and mortality in preterm infants. Although advances in neonatal care have decreased the incidence of chronic lung disease in preterm infants, a subset of these infants remain dramatically affected, developing ?severe? lung pathologies along with other organ associated complications. Currently, few clinically useful strategies have been developed to identify and treat the infants at greatest risk. We hypothesize that the severe pulmonary disease in preterm infants is a result of epigenetic changes caused by events in utero which primes them for exacerbated responses to interventions after birth. MicroRNAs (miRs) are epigenetic regulators involved in growth, development, and repair processes, however dysregulation of miRs are associated with pulmonary disease. We have identified a microRNA, miR-29b, that is suppressed at birth in preterm infants that go on to develop chronic lung disease. The central hypothesis of this proposal is that restoration of pulmonary expression of microRNA-29b will attenuate morbidites associated with newborn chronic lung disease. To test our hypothesis, we will use our extensively characterized murine model; systemic maternal LPS followed by exposure of the pups to hyperoxia for 14 days. The objective of this proposal is to test novel therapeutic strategies to reverse epigenetic changes resulting from exposure to perinatal inflammation. To accomplish this we propose three Aims:
Aim 1 will test the hypothesis that AAV9-mediated delivery of miR-29b to newborn mouse pups will rescue the phenotype caused by perinatal inflammation and neonatal hyperoxia. To test this hypothesis, we will build upon our preliminary data using an innovative delivery strategy, adeno-associated virus, to restore the pulmonary expression of miR-29b which plays an essential role in lung development and fundamental signaling pathways.
Aim 2 will test the hypothesis that miR-29b can be efficiently delivered to the lungs of a newborn mouse using lipid-based vehicles. We will investigate relevant alternative delivery strategies including liposomal nanoparticles and surfactant suspension that could be directly translated into therapies for infants.
Aim 3 will utilize bio-banked blood specimens obtained at delivery and at 36 weeks' corrected age to define the clinical characteristics of infants with decreased miR29b expression at birth and at the time of clinical determination of BPD status. Using existing biorespositories, we will investigate cord blood and infant samples for associations between clinical variables and neonatal miR expression to optimize identification of the population of infants that would most benefit from miR therapies. In summary, these studies will provide the framework for new and novel therapeutic approaches that include delivery of miRs to prevent pulmonary morbidities in newborn infants.

Public Health Relevance

Preterm infants are in danger of developing pulmonary morbidities. Currently, few clinically useful strategies have been developed to identify and treat the infants at greatest risk. We have identified a microRNA, miR-29b that is suppressed at birth in preterm infants that go on to develop chronic lung disease. We have developed a mouse model to mimic the pulmonary pathology observed in these infants and have partially rescued the phenotype by restoring miR levels. This proposal will investigate the therapeutic value of miR restoration in the context of newborn lung disease and identify clinically relevant vectors that could be used for delivery to human infants. Additionally, we will use cord blood samples from an existing biorepository to identify those infants that are at greatest risk for suppression of this microRNA and to identify the population that would most benefit from miR therapy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD088033-02
Application #
9394030
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ren, Zhaoxia
Project Start
2016-12-10
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Durrani-Kolarik, Shaheen; Pool, Caylie A; Gray, Ashley et al. (2017) miR-29b supplementation decreases expression of matrix proteins and improves alveolarization in mice exposed to maternal inflammation and neonatal hyperoxia. Am J Physiol Lung Cell Mol Physiol 313:L339-L349