Selective Glucocorticoid Action in the Developing Brain

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The life-threatening, emotional and economic burdens of premature birth (~12% of pregnancies) have been greatly alleviated by antenatal treatment with synthetic glucocorticoids (sGCs). Antenatal sGCs accelerate tissue development reducing respiratory distress syndrome (RDS) and intraventricular hemorrhage (IVH) in premature infants, but they can affect developmental processes in the brain and trigger adverse behavioral and metabolic outcomes later in life. While postnatal management of IVH and RDS has greatly improved over the last 40 years, sGC dosing regimens have remained the same since their inception. There are also significant sex differences in outcome and infant mortality in response to antenatal sGCs. We have identified a novel sGC pathway that impacts embryonic neural stem/progenitor cell (NSPC) function. Specifically, sGC-activated site-specific phosphorylation of glucocorticoid receptor (GR) directs it to specific genomic targets, some of which regulate NSPC proliferation. We hypothesize that select genomic (phospho-GR target genes) GR pathways in NSPCs activated by antenatal sGCs impact gender-specific NSPC function. The innovative and state-of-the-art approaches proposed will identify novel molecular targets and pathways responsible for sex- and dose-specific effects of antenatal sGCs in fetal brain. Aim 1 will utilize peripheral blood mononuclear cells (PBMCs) from newborn umbilical cord blood (UCB) to examine the impact of antenatal sGC treatment in humans on GR gene targets and site-specific phosphorylation previously established to be PBMC biomarkers in adults with increased risk for neuropsychiatric disorders. Ex vivo studies with UCB PBMCs will reveal whether antenatal sGC exposure in vivo generates long-term effects on GR response. Aim 2 will identify dose- and sex-specific effects of sGCs on NSPC function in vitro and in vivo through manipulation of the major efflux transporters (Mdr-1 family) that regulate sGC accumulation in the brain. Aim 3 will determine the genomic effects of GR phosphorylation at serine 220 on NSPC function in vitro and in vivo. Aim 4 will determine effects of antenatal sGCs on emotional and cognitive behavior in adult offspring. From these studies, novel biomarkers will be identified in unique GR pathways that are associated with sex-specific, adverse neurodevelopment effects of antenatal sGCs in preterm or full term infants.