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：
10359743
负责人：
Tracy L Bale
金额：
$ 24.81万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359743
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 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 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.

明确怀孕期间环境中的应激通过哪些机制促进在确定疾病风险或复原力的预测因素时，发展至关重要。一个主要的一致性在产前侮辱中，男性的脆弱性增加了。在这个提案中，我们利用我们的鼠标模型早期产前应激(EPS)以检查性别特异的胎盘转录调节。在我们的EPS模型中，雄性，但不是雌性，后代具有更高的应激敏感性，包括HPA应力轴增加活动减少，断奶后生长减少，以及下丘脑线粒体功能障碍。男女学生的性别差异胎盘功能可能会向发育中的胎儿大脑产生性别特异性的跨胎盘信号。性胎盘的差异始于性染色体。通过全基因组筛查关注母体应激，我们确定X连锁基因OGT是通过以下途径编程男性特有的应激表型的原因它对组蛋白转录抑制标记H3K27me3的调控。这项提案使用了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，而男性不是这样，因此将男性发育中的大脑置于更大的在产前有风险。发育中的大脑接收到的胎盘信号似乎与能量有关。可获得性和影响代谢和线粒体编程。关键的翻译重要性，我们有还发现在人类胎盘组织中，胎儿性别可以预测相同的生化和分子结果。因此，我们的建议将集中于定义H3K27me3在发育风险中的因果重要性。应激反应的变化，确定由这些变化引起的性别特异性的胎盘信号胎盘功能的体外灌流，并确定细胞隔间和机制这些变化促进了下丘脑线粒体重编程和EPS表型。