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.

父母一生中暴露于诸如压力、感染、营养不良和高龄等扰动， 与孩子神经发育障碍的风险增加有关。虽然母亲的侮辱 在怀孕期间可以直接影响胎儿的发育，父亲的终身机制， 经验是否会改变生殖细胞编程并影响后代神经发育尚不清楚。然而，在这方面， 这些表观遗传标记传递给下一代会显著增加疾病风险，如果 也会影响后代。以男性压力体验为模型 我们可以检查后代神经发育程序的机制，我们发现， 父亲的压力显着改变后代HPA应激轴的调节和重编程下丘脑。 从机制上讲，我们在应激雄性的成熟精子中鉴定了9种特异性miRNA， 后代表型。此外，我们能够完全概括后代表型， 将这9种miRNA显微注射到受精卵中。使用单细胞扩增技术，我们 确定了这些miRNAs的一个新的作用，以显着影响受精后胚胎发育，提供 大量证据表明，精子miRNA是可编程的环境，并能够传递这一点。 信息允许父系指导胚胎发育。因此，我们的建议将利用我们的鼠标 父亲压力模型来检查：1）压力改变父亲生殖细胞miRNA的机制， 影响神经发育并产生后代表型，2）遗传的跨代传递 由父亲压力和精子miRNAs编程的第二代压力失调，以及3） 通过增加血脑屏障促进父源性应激表型的后代脑内机制 渗透性和抑制性组蛋白表观遗传编程。