Selective Glucocorticoid Action in the Developing Brain

糖皮质激素在大脑发育中的选择性作用

基本信息

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
项目类别：
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

项目摘要

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.

早产的威胁，情绪和经济负担（占怀孕的12％）已通过合成糖皮质激素（SGC）的产前治疗极大地缓解了生命。产前SGC加速组织发育可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中的发育过程并触发后期生活后期的不良行为和代谢成果。在过去40年中，IVH和RDS的产后管理大大改善，但自成立以来，SGC剂量方案一直保持不变。响应产前SGC的结果和婴儿死亡率也存在显着的性别差异。我们已经确定了一种影响胚胎神经茎/祖细胞（NSPC）功能的新型SGC途径。具体而言，糖皮质激素受体（GR）的SGC激活部位特异性磷酸化将其引导到特定的基因组靶标，其中一些靶标会调节NSPC增殖。我们假设在产前SGC激活的NSPC中，选择基因组（磷酸靶基因）GR途径会影响性别特异性的NSPC功能。提出的创新和最先进的方法将确定胎儿大脑产前SGC的性别和剂量特异性作用的新型分子靶标和途径。 AIM 1将利用新生脐带血液（UCB）的外周血单核细胞（PBMC）检查癌产前SGC治疗对人类对GER靶标的GER靶标和先前确定的现场特异性磷酸化的影响。通过UCB PBMC进行的体内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。 AIM 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对NSPC功能的剂量和性别特异性作用。 AIM 3将确定丝氨酸220在体外和体内NSPC功能上GR磷酸化的基因组效应。 AIM 4将确定产前SGC对成人后代情绪和认知行为的影响。从这些研究中，将在独特的GR途径中鉴定出新型的生物标志物，这些途径与产前SGC在早产或全年婴儿中的性别特异性，不良神经发育作用相关。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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