Critical developmental windows and underlying processes in extremely low gestational age neonates' immune trajectories

About This Grant

Abstract Since the medical breakthroughs of surfactant and synchronized mechanical ventilation in the 1990’s, there have been few new interventions that have substantially impacted morbidity and mortality of infants born at extremely low gestational ages (ELGANs), resulting in stalled even increased common morbidities. The most common ELGAN morbidities, including central white matter disease, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy and sepsis share features of inflammation, suggesting immune-mediated damage may be a common causal pathway. However, there are major gaps in our understanding of normal human fetal and postnatal immune development in full-term infants, and even more so in preterm infants, which are born at a development stage of the immune system which was not meant to encounter the non-sterile extra-uterine environment. These gaps have limited our ability to discern, let alone treat harmful activated immune pathways. To make matters even more complicated in ELGANs, some age-associated immune pathways are necessary for sustained organ development, as evidenced by our previous work showing that ELGANs whose T cells do not follow an expected pattern of change over time are at higher risk for respiratory illnesses later in infancy. Thus, there is a critical need to understand both the molecular program that defines normal immune maturation, as well as the earliest timing during which abnormally developing immune pathways are likely to respond to intervention postnatally. The overall goal of the project is to identify key age-associated immune pathways in ELGANs T cells that can be targeted for treatments. We hypothesize that there is an underlying immune program that meets the unique demands of a developing fetus, but this program is vulnerable to disruption by common postnatal exposures, including antibiotics, during the first postnatal month. To address this hypothesis, we aim to 1) model typical and atypical longitudinal age-determined T cell subset trajectories in ELGANs, 2) frame a postnatal window during which immune trajectories are susceptible to modulation using discovery proteomics, 3) determine the gene regulatory program in ELGANs using single cell genomics, 4) Identify immune changes associated with a common exposure, antibiotics, and potential gene targets to mitigate their harmful effects. Successful completion of this study will provide the highest resolution immune trajectories during the most dynamic period of postnatal immune system development. These results will enable us to direct novel immunomodulatory therapies at the appropriate postnatal age in order to promote normal immune system development in ELGANs.