Effects of Stress and Obesity on Longitudinal Epigenetic Programming

项目摘要。社会压力不断改变与精神障碍有关的生理标志物， 下丘脑-垂体-肾上腺（HPA）轴失调以及促炎性增加， 抗炎细胞因子减少。类似的变化也可以在致肥饮食中观察到 和肥胖症。重要的是，社会压力和肥胖饮食的共同发生， 发育是精神和代谢紊乱的潜在危险因素。研究中的一个关键问题 这些疾病及其相互作用涉及长- 术语生物编程。特别是，哪些分子变化转化为功能性后果 与精神健康和新陈代谢相关的问题仍然是难以捉摸的。先前的证据表明， 通过表观遗传修饰嵌入可能会将环境暴露转化为不利的发育 健康成果。然而，目前尚不清楚的是，表观遗传变化是如何在发育过程中出现的，以及 它们影响疾病的发展轨迹。人类的横断面表观遗传学研究无法解开 这些复杂的环境因素和表观遗传适应的因果影响。我们建议利用 作为非人灵长类动物受资助的纵向产后发育研究的一部分采集的样本 (NHP)社会压力和肥胖的模型，以检查压力和饮食引起的 从出生到青春期的DNA甲基化（DNAm）的全基因组修饰。动态表观遗传 变化将与相关功能结局相关，包括神经内分泌、炎症和行为 表型我们的目标是研究DNA的形成和功能的模式，以应对社会压力 和致肥胖饮食暴露，并研究其对功能性 与精神和代谢健康相关的结果。我们的核心假设是， 社会压力和致肥饮食影响外周DNAm谱， 预测与压力和代谢相关的生理标志物。我们将用两个例子来验证我们的假设。 具体目的：1）确定和比较暴露于以下物质的NHP中HPA轴基因的纵向DNAm谱： 社会压力、致肥饮食和匹配对照。DNAm的变化是否预示着生理性 压力、炎症和代谢轨迹的标志物？2)确定和比较全基因组DNA 暴露于社会压力、致肥胖饮食和匹配对照的NHP的特征。更广泛的是什么 分子途径和网络的变化，以应对社会压力和肥胖的饮食摄入？我们 建议的意义在于，这些纵向的，对有害环境的控制研究， 发育过程中的因素在人类中是不可行的。我们的NHP模型提供了直接转化的方法 具有产生人类精神和代谢轨迹的预测标记的独特可能性。

Project Summary. Social stress consistently alters physiological markers related to mental disorders including hypothalamus-pituitary-adrenal (HPA) axis dysregulation as well as an increase in proinflammatory, and a decrease in anti-inflammatory cytokines. Similar changes can be observed in response to obesogenic diets and in obesity. Importantly, the co-occurrence of social stress and the consumption of obesogenic diets during development are potent risk factors for both mental and metabolic disorders. A key question in the study of these disorders and their interaction concerns the temporal sequences and molecular mechanisms of long- term biological programming. In particular, which molecular changes translate into functional consequences relevant to mental health and metabolism often remains elusive. Prior evidence suggests that biological embedding via epigenetic modifications may translate environmental exposure into unfavorable developmental health outcomes. What is unclear, however, is how epigenetic changes emerge during development and how they influence disease trajectories. Cross-sectional epigenetic studies in humans are unable to disentangle the causal effects of these complex environmental factors and epigenetic adaptations. We propose to leverage samples collected as part of a funded longitudinal, postnatal developmental study in a non-human primate (NHP) model of social stress and obesity to examine the chronology and dynamics of stress- and diet-induced genome-wide modification of DNA methylation (DNAm) from birth to adolescence. The dynamic epigenetic changes will be related to relevant functional outcomes including neuroendocrine, inflammatory and behavioral phenotypes. Our goal is to examine the formation and function of DNAm patterns in response to social stress and obesogenic diet exposure in NHPs and to investigate their additive and distinct effect on functional outcomes relevant for mental and metabolic health. Our central hypotheses are that developmental exposure to social stress and an obesogenic diet in rhesus monkeys affect peripheral DNAm profiles that are in turn predictive of physiological markers related to stress and metabolism. We will test our hypotheses with two specific aims: 1) Determine and compare longitudinal DNAm profiles of HPA axis genes in NHPs exposed to social stress, an obesogenic diet and matched controls. Are DNAm changes predictive of physiological markers of stress, inflammation and metabolic trajectories? 2) Determine and compare genome-wide DNAm profiles in NHPs exposed to social stress, an obesogenic diet and matched controls. What are the broader molecular pathways and networks that change in response to social stress and obesogenic diet intake? Our proposal's significance lays in the fact that these longitudinal, controlled studies on detrimental environmental factors during development are not feasible in humans. Our NHP model offers a direct translational approach with the unique possibility to generate predictive markers for mental and metabolic trajectories in humans.