Selective Glucocorticoid Action in the Developing Brain

糖皮质激素在大脑发育中的选择性作用

• 批准号: 9236316
• 负责人: Donald B DeFranco
• 金额: $ 41.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236316
• 关键词: Ablation; Adult; Adult Children; Adverse effects; Affect; Behavior; Behavior Control; Behavioral; Behavioral Paradigm; Biological Markers; Brain; Cell Culture Techniques; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Cerebrum; ChIP-seq; Child; Clinical; Clinical Data; Cognitive; Communities; Development; Developmental Process; Dexamethasone; Disease; Dose; Economic Burden; Economically Deprived Population; Embryo; Emotional; Exposure to; Family; Female; Fetus; Gender; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Glucocorticoid Receptor; Glucocorticoids; Health; Hispanics; Histologic; Human; In Vitro; Infant; Infant Mortality; Knock-in Mouse; Knock-out; Life; Long-Term Effects; Mass Spectrum Analysis; Measures; Mental disorders; Metabolic; Metabolism; Molecular; Molecular Target; Morbidity - disease rate; Mus; Necrotizing Enterocolitis; Neonatal; Neuraxis; Neurons; Newborn Infant; Outcome; Pathway interactions; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Pregnancy; Premature Birth; Premature Infant; Race; Regimen; Research; Respiratory distress; Risk; Rodent; Role; Serine; Sex Characteristics; Site; Small Interfering RNA; Stem cells; Technology; Therapeutic; Tissues; Umbilical Cord Blood; Western Blotting; Woman; antenatal; behavioral response; behavioral study; clinically relevant; disorder risk; efflux pump; fetal; genome-wide; improved; in utero; in vivo; innovation; intraventricular hemorrhage; male; mortality; mouse model; nano-string; neonate; neurodevelopment; neuropsychiatric disorder; novel; novel marker; outcome prediction; postnatal; predictive marker; prenatal; prenatal exposure; racial difference; relating to nervous system; respiratory distress syndrome; response; sex; stem; transcriptome; transcriptome sequencing

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.

合成糖皮质激素 (sGC) 的产前治疗大大减轻了早产（约占妊娠的 12%）带来的危及生命、情感和经济负担。产前 sGC 可加速组织发育，减少早产儿呼吸窘迫综合征 (RDS) 和脑室内出血 (IVH)，但它们会影响大脑的发育过程，并在以后的生活中引发不良行为和代谢结果。虽然 IVH 和 RDS 的产后管理在过去 40 年里有了很大改善，但 sGC 的给药方案自诞生以来一直保持不变。产前 sGC 的结果和婴儿死亡率也存在显着的性别差异。我们发现了一种影响胚胎神经干/祖细胞 (NSPC) 功能的新 sGC 途径。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引导至特定的基因组靶标，其中一些靶标调节 NSPC 增殖。我们假设产前 sGC 激活的 NSPC 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。所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影响的新分子靶点和途径。目标 1 将利用新生儿脐带血 (UCB) 中的外周血单核细胞 (PBMC) 来检查人类产前 sGC 治疗对 GR 基因靶标和位点特异性磷酸化的影响，这些磷酸化先前被确定为神经精神疾病风险增加的成人中的 PBMC 生物标志物。 UCB PBMC 的离体研究将揭示体内产前 sGC 暴露是否会对 GR 反应产生长期影响。目标 2 将通过操纵调节大脑中 sGC 积累的主要外排转运蛋白（Mdr-1 家族）来确定 sGC 在体外和体内对 NSPC 功能的剂量和性别特异性影响。目标 3 将确定丝氨酸 220 处 GR 磷酸化对体外和体内 NSPC 功能的基因组影响。目标 4 将确定产前 sGC 对成年后代情绪和认知行为的影响。从这些研究中，我们将在独特的 GR 通路中鉴定出新的生物标志物，这些通路与早产儿或足月婴儿产前 sGC 的性别特异性、不良神经发育影响相关。