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
• 负责人: Tracy L Bale
• 金额: $ 42.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755571
• 关键词: Paternal; stress; epigenetic; programming; offspring

Parental lifetime exposures to perturbations such as stress, infection, malnutrition, and to advanced age have been linked with an increased risk for neurodevelopmental disorders in their children. While maternal insults during pregnancy can directly impact fetal development, the mechanisms by which paternal lifelong experiences can alter germ cell programming and affect offspring neurodevelopment are not known. However, transmission of these epigenetic marks to the next generation can significantly elevate disease risk, and if programmed into the germline can affect future generations as well. Using male stress experience as a model in which we can examine mechanisms involved in offspring neurodevelopmental programming, we found that paternal stress significantly altered offspring HPA stress axis regulation and reprogrammed the hypothalamus. Mechanistically, we identified 9 specific miRNAs in the mature sperm from stressed males that contributed to the offspring phenotype. Further, we were able to completely recapitulate the offspring phenotype by microinjection of these 9 miRNAs into fertilized zygotes. Using single-cell amplification technology, we were identified a novel role for these miRNAs to significantly affect post-fertilization embryo development, providing substantial evidence that sperm miRNAs are programmable by the environment and are able to transmit this information allowing for paternally directed embryo development. Therefore, our proposal will utilize our mouse model of paternal stress to examine: 1) the mechanisms whereby stress alters paternal germ cell miRNA that affect neurodevelopment and give rise to the offspring phenotype, 2) the transgenerational transmission of stress dysregulation to a second generation programmed by paternal stress and sperm miRNAs, and 3) the mechanism within the offspring brain that promotes the paternal stress phenotype through increased BBB permeability and repressive histone epigenetic programming.

父母终身暴露于压力，感染，营养不良和高龄等扰动 与儿童神经发育障碍的风险增加有关。孕产妇的侮辱 怀孕期间可以直接影响胎儿发育，这是父亲终生的机制 经验可以改变生殖细胞编程，并影响后代神经发育。然而， 将这些表观遗传标记传播到下一代可以显着提高疾病的风险，如果 被编程到种系也可能影响子孙后代。使用男性压力体验作为模型 在其中我们可以检查涉及后代神经发育编程的机制，我们发现 父亲应力显着改变了后代HPA应力轴调节，并重新编程了下丘脑。 从机械上讲，我们从应力的雄性中鉴定出成熟精子中的9个特定miRNA，这有助于 后代表型。此外，我们能够通过 将这9个miRNA的显微注射到受精的Zygotes中。使用单细胞扩增技术，我们是 确定了这些miRNA的新作用，以显着影响后有胚胎的胚胎发育，提供 大量证据表明精子miRNA是由环境编程的，并且能够传播 允许亲子定向的胚胎发育的信息。因此，我们的建议将利用我们的鼠标 父亲应力的模型要检查：1）压力改变父亲生殖细胞mirna的机制 影响神经发育并引起后代表型，2） 压力失调对由父亲应力和精子miRNA编程的第二代，以及3） 后代大脑内的机制通过增加的BBB来促进父亲应力表型 渗透性和抑制性组蛋白表观遗传编程。