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:
    10112935
  • 负责人:
  • 金额:
    $ 48.48万
  • 依托单位:
  • 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 2024-02-29
  • 项目状态:
    已结题

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。

项目成果

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Tracy L Bale其他文献

Sex as a Biological Variable: Who, What, When, Why, and How
性别作为一个生物学变量:谁、什么、何时、为何以及如何
  • DOI:
    10.1038/npp.2016.215
  • 发表时间:
    2016-09-23
  • 期刊:
  • 影响因子:
    7.100
  • 作者:
    Tracy L Bale;C Neill Epperson
  • 通讯作者:
    C Neill Epperson
Sex differences in the programming of stress resilience
压力恢复能力规划中的性别差异
The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming
胎盘作为应激对神经发育重编程影响的介质
  • DOI:
    10.1038/npp.2015.231
  • 发表时间:
    2015-08-07
  • 期刊:
  • 影响因子:
    7.100
  • 作者:
    Stefanie L Bronson;Tracy L Bale
  • 通讯作者:
    Tracy L Bale

Tracy L Bale的其他文献

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{{ truncateString('Tracy L Bale', 18)}}的其他基金

Paternal stress epigenetic programming of offspring neurodevelopment
父系应激对后代神经发育的表观遗传编程
  • 批准号:
    10656492
  • 财政年份:
    2023
  • 资助金额:
    $ 48.48万
  • 项目类别:
Paternal stress epigenetic programming of offspring neurodevelopment
父系应激对后代神经发育的表观遗传编程
  • 批准号:
    10755571
  • 财政年份:
    2023
  • 资助金额:
    $ 48.48万
  • 项目类别:
Extracellular vesicles as biomarkers of trauma exposure and PTSD risk
细胞外囊泡作为创伤暴露和 PTSD 风险的生物标志物
  • 批准号:
    10420911
  • 财政年份:
    2022
  • 资助金额:
    $ 48.48万
  • 项目类别:
Stress modeling of the human sperm sncRNA transcriptome and causal importance of dynamic miRNA in reproductive and developmental outcomes
人类精子 sncRNA 转录组的压力模型以及动态 miRNA 在生殖和发育结果中的因果重要性
  • 批准号:
    10707015
  • 财政年份:
    2022
  • 资助金额:
    $ 48.48万
  • 项目类别:
Stress modeling of the human sperm sncRNA transcriptome and causal importance of dynamic miRNA in reproductive and developmental outcomes
人类精子 sncRNA 转录组的压力模型以及动态 miRNA 在生殖和发育结果中的因果重要性
  • 批准号:
    10442142
  • 财政年份:
    2022
  • 资助金额:
    $ 48.48万
  • 项目类别:
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
  • 批准号:
    10359743
  • 财政年份:
    2019
  • 资助金额:
    $ 48.48万
  • 项目类别:
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
  • 批准号:
    9891086
  • 财政年份:
    2019
  • 资助金额:
    $ 48.48万
  • 项目类别:
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
  • 批准号:
    10743792
  • 财政年份:
    2019
  • 资助金额:
    $ 48.48万
  • 项目类别:
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
  • 批准号:
    10563162
  • 财政年份:
    2019
  • 资助金额:
    $ 48.48万
  • 项目类别:
Female preconception stress programming of offspring neurodevelopment
女性孕前压力编程对后代神经发育的影响
  • 批准号:
    9360959
  • 财政年份:
    2017
  • 资助金额:
    $ 48.48万
  • 项目类别:

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