Selective Glucocorticoid Action in the Developing Brain

早产儿（约占妊娠的12%）的生命、情绪和经济负担已通过产前合成糖皮质激素（sGCs）治疗大大减轻。产前sGCs加速组织发育，减少早产儿的呼吸窘迫综合征（RDS）和脑室内出血（IVH），但它们可以影响大脑的发育过程，并在以后的生活中引发不良的行为和代谢结果。虽然IVH和RDS的产后管理在过去40年中有了很大改善，但sGC的给药方案自成立以来一直保持不变。产前sgc的结果和婴儿死亡率也存在显著的性别差异。我们已经确定了一个新的影响胚胎神经干/祖细胞（NSPC）功能的sGC通路。具体来说，sgc激活的糖皮质激素受体（GR）的位点特异性磷酸化将其定向到特定的基因组靶点，其中一些靶点调节NSPC的增殖。我们假设，被产前sGCs激活的NSPCs中选择的基因组（磷酸化-GR靶基因）GR通路会影响性别特异性NSPC功能。提出的创新和最先进的方法将确定负责胎儿大脑中产前sgc的性别和剂量特异性效应的新分子靶点和途径。目的1将利用来自新生儿脐带血（UCB）的外周血单个核细胞（PBMC）来检查产前sGC治疗对人类GR基因靶点和位点特异性磷酸化的影响，这些基因靶点和位点特异性磷酸化先前被确定为神经精神疾病风险增加的成人PBMC生物标志物。体外UCB pbmc研究将揭示胎儿体内sGC暴露是否会对GR反应产生长期影响。目的2将通过调控脑内sGC积累的主要外排转运蛋白（Mdr-1家族），确定sGC在体外和体内对NSPC功能的剂量和性别特异性影响。目的3将确定GR丝氨酸220位点磷酸化对体外和体内NSPC功能的基因组效应。目的4将确定产前sGCs对成年后代情绪和认知行为的影响。从这些研究中，新的生物标志物将在独特的GR通路中被鉴定出来，这些通路与早产儿或足月婴儿产前sgc的性别特异性不良神经发育效应有关。

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.