ABSTRACT/PROJECT SUMMARY
Bronchopulmonary dysplasia (BPD), a chronic lung disease, is the most common major complication of preterm
birth affecting at least one fourth of infants born with a birth weight less than 1500g. Many premature infants with
BPD will continue to have persistent respiratory symptoms and decreased lung function into adulthood. These
life-long complications of BPD create significant health burden and necessitate extensive health care utilization.
Currently, there is no effective prevention or personalized treatment for BPD. Not every premature infant
develops BPD, and this individual variability in BPD susceptibility is likely explained by complex interactions
between environmental, cellular, genetic, and epigenetic factors. Supplemental oxygen administration, while
lifesaving in the neonatal period, remains a key determinant of BPD pathophysiology. Exposure of the immature
lung to increased levels of oxygen elicits an inflammatory response resulting in abnormal lung development.
However, the lung immune cells, specifically those involved in the innate immune response, and their
accompanying gene expression programs that provide protection against BPD are not completely known. The
overall objective of this proposal is to identify and characterize specific lung myeloid cells and their gene
programs that provide protection to oxygen-induced lung injury. Our hypothesis is that the innate immune
response activated in the lung differs between premature infants who develop BPD and those that are resilient
to disease. Based on our novel finding that genetic loss of function of Triggering Receptor Expressed on Myeloid
cells 2 (TREM2) is protective in hyperoxia-induced lung injury, we propose that inhibition of TREM2 signaling
may be exploited to modulate the innate immune response to prevent abnormal lung development. In Aim 1 we
will employ single cell RNAseq and TREM2-deficient mice to define how TREM2 regulates gene expression and
severity of lung injury after neonatal hyperoxia exposure. In Aim 2 we will apply novel approaches using myeloid
p53-deficient mice exposed to neonatal hyperoxia and interrogate epigenomic modifications using ATACseq and
ChIPseq to identify the regulatory mechanisms by which TREM2 directs a pathogenic immune response on a
transcriptional level. Lastly, to establish proof-of-principle for the translational potential of therapeutic targeting
of TREM2 we will test a TREM2 blocking antibody in vivo and assess recovery from hyperoxia in room air (Aim
3). Further investigations of the conservation of gene regulatory pathways between mice and humans will provide
a sound rationale to use these gene pathways to develop targeted therapies. This project will identify unique
gene regulatory networks of lung myeloid cells that support a regenerative immune response in the developing
lung. These findings will elucidate novel pathways of neonatal lung resilience after hyperoxia, which will inform
the development of more targeted management of multifactorial BPD.
