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: 10089223
• 负责人: Donald B DeFranco
• 金额: $ 50.93万
• 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/10089223
• 关键词: Ablation; Adult; Adult Children; Affect; Behavior; Behavior Control; Behavioral; Behavioral Paradigm; Biological Markers; Brain; Cell Culture Techniques; Cell Differentiation process; 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; Nervous System control; Neuraxis; Neurons; Newborn Infant; Outcome; Pathway interactions; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Pregnancy; Premature Birth; Premature Infant; Premature Labor; Race; Regimen; Research; Respiratory distress; Risk; Rodent; Role; Serine; Sex Differences; Site; Small Interfering RNA; 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; neurodevelopmental effect; neuropsychiatric disorder; novel; novel marker; outcome prediction; postnatal; predictive marker; prenatal; prenatal exposure; racial difference; relating to nervous system; respiratory distress syndrome; response; sex; side effect; stem; stem cell function; stem cell proliferation; stem cells; 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.

早产（约12%的妊娠）的生命威胁，情感和经济负担已大大减轻了产前治疗与合成糖皮质激素（sGC）。胎儿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），但它们可影响大脑发育过程，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年中有了很大改善，但sGC给药方案自成立以来一直保持不变。在产前sGC的结果和婴儿死亡率方面也存在显著的性别差异。我们已经确定了一种新的sGC途径，影响胚胎神经干/祖细胞（NSPC）的功能。具体而言，糖皮质激素受体（GR）的sGC激活的位点特异性磷酸化将其引导至特定的基因组靶点，其中一些靶点调节NSPC增殖。我们假设，选择基因组（磷酸-GR靶基因）GR通路在NSPCs激活产前sGC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新的分子靶点和途径，负责胎儿大脑中产前sGC的性别和剂量特异性效应。目的1将利用来自新生儿脐带血（UCB）的外周血单核细胞（PBMC）来检查人类产前sGC治疗对GR基因靶点和位点特异性磷酸化的影响，这些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。UCB PBMC的离体研究将揭示产前sGC体内暴露是否对GR反应产生长期影响。目的2将通过操纵调节sGC在脑中蓄积的主要外排转运蛋白（Mdr-1家族），在体外和体内确定sGC对NSPC功能的剂量和性别特异性效应。目的3将在体外和体内确定GR在丝氨酸220处磷酸化对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，将在独特的GR通路中鉴定新的生物标志物，这些通路与早产儿或足月儿中产前sGC的性别特异性不良神经发育影响相关。

项目成果

Butyrate suppresses experimental necrotizing enterocolitis-induced brain injury in mice.

• DOI: 10.3389/fped.2023.1284085
• 发表时间: 2023
• 期刊: Frontiers in pediatrics
• 影响因子: 2.6

Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum.

• DOI: 10.1016/j.nbd.2021.105422
• 发表时间: 2021-08
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Jaumotte JD;Franks AL;Bargerstock EM;Kisanga EP;Menden HL;Ghersi A;Omar M;Wang L;Rudine A;Short KL;Silswal N;Cole TJ;Sampath V;Monaghan-Nichols AP;DeFranco DB
• 通讯作者: DeFranco DB