权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Placental epigenetic mechanisms contributing to sex-specific impacts of maternal stress on fetal development

胎盘表观遗传机制导致母体压力对胎儿发育的性别特异性影响

基本信息

批准号：
10563162
负责人：
Tracy L Bale
金额：
$ 52.36万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-11 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10563162
关键词：
Affect Attention deficit hyperactivity disorder Biochemical Birth Brain Cells Development EZH2 gene Environment Epigenetic Process Female Fetal Development Fetus Gene Expression Gene Targeting Genes Genetic Genetic Transcription Glucocorticoids Growth Histones Human Hypothalamic structure Link Metabolic Metabolic dysfunction Methods Methylation Methyltransferase MicroRNAs Mitochondria Modeling Molecular Molecular Target Mus Neurodevelopmental Disorder Neurons Nuclear O-GlcNAc transferase Outcome Perfusion Phenotype Placenta Predictive Factor Pregnancy Proteomics Puberty Regulation RiboTag Risk Sex Bias Sex Chromosomes Sex Differences Sex Ratio Signal Transduction Stress Testing Time Tissues Transcriptional Regulation Transferase Transgenic Mice Transgenic Organisms Weaning Weight autism spectrum disorder boys disorder risk ex vivo perfusion fetal gene repression genome wide screen genome-wide girls in utero innovation male maternal stress metabolomics mitochondrial dysfunction mitochondrial messenger RNA mouse model offspring outcome prediction prenatal prenatal stress programs resilience response sex steroid hormone transcriptome trophoblast

项目摘要

Defining the mechanisms by which stress in the environment during pregnancy promotes changes in development is critical in identifying factors predictive of disease risk or resilience. One major consistency across prenatal insults is the increased vulnerability of males. In this proposal, we utilize our mouse model of early prenatal stress (EPS) to examine sex-specific placental transcriptional regulation. In our EPS model, male, but not female, offspring present with increased stress sensitivity, including increased HPA stress axis activity, reduced post-weaning growth, and hypothalamic mitochondrial dysfunction. Sex differences in the placental function are likely to produce sex-specific transplacental signals to the developing fetal brain. Sex differences in the placenta begin with sex chromosomes. Through a genome-wide screen following maternal stress, we identified the X-linked gene, OGT, as causal in programming the male-specific stress phenotype via its regulation of the histone transcriptional repressive mark, H3K27me3. This proposal uses innovative approaches to determine the mechanisms by which the female placenta is able to restrict transcriptional responses to stress in the environment, where males are not, thus placing the male developing brain at greater risk prenatally. The transplacental signals received by the developing brain appear to be related to energy availability and impact metabolic and mitochondrial programming. Of key translational importance, we have also found the same biochemical and molecular outcomes are predicted by fetal sex in human placental tissue. Therefore, our proposal will focus on defining the causal importance of H3K27me3 in risk for developmental changes in response to stress, identify the sex-specific transplacental signals resulting from these changes in placental function using ex vivo perfusion, and determine the cellular compartment and mechanism by which these changes promote hypothalamic mitochondrial reprogramming and the EPS phenotype.

确定怀孕期间环境中的压力促进以下变化的机制：发展对于确定疾病风险或复原力的预测因素至关重要。一个主要的一致性在产前侮辱中，男性的脆弱性增加了。在这个提议中，我们利用我们的小鼠模型，早期产前应激（EPS）检查性别特异性胎盘转录调控。在我们的EPS模型中，雄性（而非雌性）后代表现出应激敏感性增加，包括HPA应激轴增加活动、断奶后生长减少和下丘脑线粒体功能障碍。性别差异胎盘功能可能产生性别特异性的经胎盘信号给发育中的胎儿大脑。性胎盘的差异开始于性染色体。通过全基因组筛查，压力，我们确定了X连锁基因，OGT，作为因果程序的男性特异性压力表型，通过其对组蛋白转录抑制标记H3K27me3的调节。该提案采用创新的确定女性胎盘能够限制转录的机制的方法对环境中压力的反应，而男性没有，因此使男性发育中的大脑处于更高的水平。产前风险发育中的大脑接收到的经胎盘信号似乎与能量有关可用性和影响代谢和线粒体编程。关键的翻译重要性，我们有还发现，人类胎盘组织中的胎儿性别可以预测相同的生化和分子结果。因此，我们的建议将侧重于确定H3K27me3在发展风险中的因果重要性。应激反应的变化，识别由这些变化引起的性别特异性经胎盘信号，胎盘功能，并确定细胞室和机制，这些变化促进下丘脑线粒体重编程和EPS表型。