Transgenerational Effects of Early Stress

描述（由申请人提供）：早期压力的影响可以持续一生，影响整个生命周期的身体，精神和社会福祉。早期压力的影响可能并不局限于受影响的一代：据报道，跨物种的早期压力的跨代影响。这意味着，在社会和个人层面上，早期压力对健康的长期影响可能比以前所理解的更难缓解。确定压力跨代影响的机制可能有助于我们理解为什么一些与压力相关的特征和疾病会在家族中遗传。使用动物模型来理解这些跨代过程是至关重要的，因为早期生活压力可以在实验室环境中随机化和标准化。此外，恒河猴是研究压力跨代影响的理想选择，因为它们是人类健康和发展的最可翻译的动物模型之一。我们最近观察了父亲的影响，而不是母亲的早期母亲剥夺压力，或育儿（NR）的经验，对婴儿恒河猴免疫和生理应激反应。由于父亲在猕猴出生后的发育中所起的作用很小，这一发现表明遗传因素可能起作用。多年来，人们一直认为获得的基因组变化不可能遗传给后代，因为我们不知道基因会因压力而改变。我们现在知道，表观遗传可塑性发生在早期应激后的多个组织中，有一些证据表明这些变化可能是遗传的。这项拟议的研究将使用大量存档数据样本来检验表观遗传因素是否在灵长类动物NR应激的跨代健康影响中发挥作用。在加州国家灵长类动物研究中心（CNPRC）的标准化生物行为评估项目中收集了3000只幼年猕猴的存档样本，我们将首先探索早期NR应激是否会在表观遗传上加剧炎症和生理应激反应。接下来，我们将评估是否在核暴露雄性的后代和父系后代中观察到类似的变化。最后，我们将研究nrr相关的表观遗传模式是否可通过父系遗传。DNA甲基化是最稳定的表观遗传标记之一，因此在本研究中，我们将启动子甲基化模式作为早期应激跨代效应的潜在机制。这一应用的意义在于我们将使用高度可转化的动物模型进行探索

DESCRIPTION (provided by applicant): The effects of early stress can last a lifetime, affecting physical, mental, and social well-being across the lifespan. The effects of early stress may not be limited to the affected generation: trans-generational effects of early stress have been reported across species. This means that, at both the societal and individual level, the long-term health effects of early stress may be harder to alleviate than was previously understood. Identifying the mechanisms of the transgenerational effects of stress may help us understand why some stress-related traits and diseases run in families. The use of animal models to understand these transgenerational processes is critical because early life stress can be randomized and standardized in a laboratory setting. Additionally, rhesus macaques are ideal for examining the transgenerational effects of stress, as they are one of our most translatable animal models of human health and development. We have recently observed effects of fathers', but not mothers', experience of early maternal deprivation stress, or nursery rearing (NR), on infant rhesus macaque immunity and physiological stress response. Since fathers play little role in macaque postnatal development, this finding suggests that heritable factors may play a role. For many years, it would have been thought impossible that acquired changes to the genome could be passed on to offspring, because we did not know that genes could be changed in response to stress. We now know that epigenetic plasticity occurs in multiple tissues following early stress, and there is some evidence that these changes might be inherited. The proposed study will use a large sample of archived data to examine whether epigenetic factors play a role in the transgenerational health effects of NR stress in primates. Using archived samples collected from 3000 infant rhesus macaques during a standardized BioBehavioral Assessment Program available only at the California National Primate Research Center (CNPRC), we will first explore whether early NR stress epigenetically exacerbates inflammation and physiological stress response. Next, we will assess whether similar changes are observed in offspring and paternal grand-offspring of NR-exposed males. Finally, we will investigate whether NR-related epigenetic patterns are heritable via the paternal line. DNA methylation is one of the most stable epigenetic marks, so we will target promoter methylation patterns as a potential mechanism for the transgenerational effects of early stress in this study. The significance of this application is that we will use a highly translational animal model to explore how acquired stress-related health outcomes can be transmitted across generations, which may reveal new avenues for intervention to improve the health and quality of life of at-risk children and their families.