Effects of Stress and Obesity on Longitudinal Epigenetic Programming

项目摘要。社交压力持续改变与精神障碍相关的生理标记物，包括 下丘脑-垂体-肾上腺(HPA)轴失调以及促炎作用增加，以及 抗炎细胞因子减少。类似的变化也可以观察到对肥胖饮食的反应 还有肥胖症。重要的是，社会压力和肥胖饮食的消费在 发展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 这些紊乱及其相互作用关系到长时间高血压的时间序列和分子机制。 术语生物编程。特别是，哪些分子变化转化为功能后果 与精神健康和新陈代谢相关的问题往往仍然难以捉摸。先前的证据表明，生物学上的 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 健康结果。然而，尚不清楚的是，表观遗传变化是如何在发育过程中出现的，以及如何出现的。 它们会影响疾病的轨迹。人类的横断式表观遗传学研究无法理清 这些复杂环境因素和表观遗传适应的因果效应。我们建议利用 作为一项资助的非人类灵长类纵向出生后发育研究的一部分收集的样本 (NHP)社会压力和肥胖模型，以研究压力和饮食诱导的时间顺序和动态 从出生到青春期的全基因组DNA甲基化修饰(DNaM)。动态表观遗传学 变化将与相关的功能结果相关，包括神经内分泌、炎症和行为 表型。我们的目标是研究dNaM模式的形成和功能，以应对社会压力 和肥胖饮食暴露，并研究它们的添加和对功能的不同影响 与精神和代谢健康相关的结果。我们的中心假设是发育中的暴露 社会压力和肥胖饮食会影响猕猴的外周dNaM谱，进而 预测与压力和新陈代谢有关的生理标志物。我们将用两个例子来检验我们的假设 具体目标：1)测定和比较暴露于HPA轴基因的纵向dNaM谱 社会压力、肥胖饮食和匹配的对照组。DNaM变化可以预测生理性变化吗？ 应激、炎症和代谢轨迹的标记物？2)确定和比较全基因组dNaM 暴露于社会压力、肥胖饮食和匹配对照组的NHP的概况。更广泛的是什么？ 因社会压力和肥胖饮食摄入而改变的分子途径和网络？我们的 该提案的意义在于，这些关于有害环境的纵向、对照研究 发育过程中的因素在人类身上是不可行的。我们的NHP模式提供了直接的翻译方法 具有为人类的精神和新陈代谢轨迹生成预测性标记的独特可能性。

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.