Epigenetic Modifications in the Nonhuman Primate Model of Maternal Immune Activation

流行病学研究表明，孕妇在怀孕期间感染艾滋病毒是造成艾滋病风险的一个关键因素。 神经发育障碍（NDD），包括精神分裂症（SZ）和自闭症谱系障碍（ASD）。 转化的动物模型表明，母体免疫激活（MIA）对胎儿的免疫功能有负面影响。 神经发育，并导致在以后的生活中出现异常行为。来自啮齿动物的新证据 MIA模型表明，产前免疫激发不仅在暴露的哺乳动物中诱导NDD样表型， 这表明，MIA的风险可能是指数大于 以前理解。虽然表观基因机制可以解释终身和跨代 与母体感染相关的影响，从临床前的表观遗传学结果转化存在局限性， 啮齿动物MIA模型到人类。我们的研究计划已经将MIA模型从啮齿动物扩展到非人类 灵长类动物，表明恒河猴出生的MIA治疗的母鼠表现出改变的行为，免疫 功能和神经发育。在这里，我们建议利用目前的加州大学戴维斯分校康特中心资助 MIA暴露的非人灵长类动物队列首次评估了MIA对灵长类动物的影响。 表观基因组这一群体也提供了一个前所未有的机会，探索潜在的跨代 在啮齿动物模型中描述的MIA对与人类关系更密切的物种的影响。我们建议研究 MIA暴露和对照雄性中的免疫细胞和生殖系表观基因组， 从青春期到成年早期我们将确定这些变化是否能解释不良的神经行为 在暴露的一代发展，也赋予跨代遗传的MIA效应的风险。 来自临床和临床前研究的证据表明，表观遗传和跨代遗传 在拟议的研究中探索的机制可能与一些独立于当前的NDD有关。 诊断分类因此，拟议的研究可能会提供深入了解的分子机制， 将产前免疫挑战与持久的大脑和行为异常联系起来，这些异常与许多 与产前环境损伤有关的人类大脑疾病。

Maternal infection during pregnancy has emerged from epidemiological research as a key factor in the risk for neurodevelopmental disorders (NDD), including schizophrenia (SZ) and autism spectrum disorder (ASD). Translational animal models demonstrate that maternal immune activation (MIA) negatively affects fetal neurodevelopment and leads to the emergence of aberrant behavior later in life. Emerging evidence from rodent MIA models suggests that prenatal immune challenge induces NDD-like phenotypes not only in exposed individuals but also their descendants, suggesting that the risks of MIA may be exponentially greater than previously understood. Although epigenomic mechanisms could explain both lifetime and transgenerational effects associated with maternal infection, there are limitations in translating epigenetic findings from preclinical rodent MIA models to humans. Our research program has extended the MIA model from rodents to nonhuman primates, demonstrating that rhesus monkeys born the MIA-treated dams exhibit alterations in behavior, immune function, and neural development. Here we propose to leverage the current UC Davis Conte Center funded cohort of MIA exposed nonhuman primates to evaluate, for the first time, the effects of MIA on the primate’s epigenome. This cohort also provides an unprecedented opportunity to explore the potential transgenerational effects of MIA described in rodent models in a species more closely related to humans. We propose to examine the immune cell and germ-line epigenome in MIA-exposed and CONTROL males as they mature from adolescence into early adulthood. We will determine if these changes explain adverse neurobehavioral development in the exposed generation and also confer risk for transgenerational inheritance of MIA effects. Converging evidence from clinical and preclinical studies suggests that the epigenetic and transgenerational mechanisms explored in the proposed studies may be relevant to a number of NDDs independent of current diagnostic classifications. Thus the proposed studies may provide insight into the molecular mechanisms that link prenatal immune challenge to long-lasting brain and behavior abnormalities that are relevant to a number of human brain disorders associated with prenatal environmental insults.