Medical advances have made it possible for premature infants to survive in increasing numbers. However, the increased survival at early gestational ages is accompanied with increased morbidity. Bronchopulmonary dysplasia (BPD) is the most prevalent major complication of premature birth affecting at least one quarter of infants born with a birth weight less than 1500g. Alarmingly, the rate of BPD is increasing, while rates of several other in-hospital complications of premature birth have dropped. BPD predisposes premature infants to a higher mortality and morbidity risk both in the immediate neonatal period as well as after discharge form the neonatal intensive care unit. Many survivors of premature birth will continue to have persistent respiratory symptoms and decreased lung function into adulthood. In addition to the respiratory complications, BPD is also one of the strongest predictors of neurodevelopmental impairment. These life-long complications of BPD create significant health burden and necessitate extensive health care utilization. Currently, there is no effective treatment for BPD. Key pathogenic mechanisms of the disease are not completely understood and therefore we lack a clear path for development of new therapies. One factor that plays a central role in the pathogenesis of BPD is oxygen administration, used as a life-saving intervention after premature birth. Exposure of the immature lung to increased levels of oxygen results in a profound inflammatory response that permanently disrupts normal lung development. However, not every premature infant is equally sensitive to oxygen-induced injury. Therefore, identifying the cellular and molecular mechanisms leading to oxygen induced inflammation and variance in individual susceptibility has the potential to establish new therapeutic targets. I propose to build on recent conceptual, technical and computational advances to identify the innate immune cells that initiate and maintain the pathologic inflammatory response in BPD. After identifying the disease-relevant cells, I will apply state of the art sequencing techniques to study their gene expression and the epigenetic mechanisms that regulate gene expression. Using computational analysis I will integrate the genetic and epigenetic data to identify candidate genes that are likely to drive the pathology in BPD and contribute to individual differences in disease susceptibility. Understanding the fundamental biology of gene expression and regulation in innate immune cells in the developing lung will not only benefit premature infants with BPD, but could be harnessed for therapeutic purposes in several other respiratory diseases.

Public Health Relevance

Exposure to excess oxygen causes inflammation and disrupts normal lung development in premature infants leading to bronchopulmonary dysplasia (BPD). In this project, I will apply next generation sequencing techniques and computational analysis to understand how hyperoxia exposure alters the normal postnatal development of lung mononuclear phagocytes and how gene-environment interactions correlate to susceptibility and/or resilience to lung remodeling. Identifying gene regulatory networks in disease relevant cells could lead to novel therapeutic targets for the treatment and prevention of BPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL140198-01
Application #
9431594
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Colombini-Hatch, Sandra
Project Start
2018-01-15
Project End
2022-12-31
Budget Start
2018-01-15
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093