Effects of Stress and Obesity on Longitudinal Epigenetic Programming

压力和肥胖对纵向表观遗传编程的影响

基本信息

批准号：
9901599
负责人：
Kelly F Ethun
金额：
$ 16.47万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901599
关键词：
Address Adolescence Adolescent Adrenal Glands Affect Age Animals Anti-Inflammatory Agents Biological Biology Birth Brain Child Childhood Chronic Chronic stress Chronology Complex Consumption Controlled Study Cross-Sectional Studies DNA Methylation DNA Modification Process Data Development Diet Disease Dyslipidemias Environmental Exposure Environmental Risk Factor Epigenetic Process Exposure to Female Functional disorder Funding Genes Genomics Glucocorticoid Receptor Goals Health Human Hydrocortisone Hypermethylation Hypothalamic structure Inflammation Inflammatory Insulin Resistance Intake Interleukin-6 Knowledge Lead Leptin Lipids Macaca mulatta Measures Mediating Mental Health Mental disorders Metabolic Metabolic Diseases Metabolic syndrome Metabolism Mission Modeling Modification Molecular Molecular Chaperones Myelin NR3C1 gene National Institute of Child Health and Human Development Nature Neurosecretory Systems Obesity Outcome Parents Pathway interactions Peripheral Phenotype Physiological Physiology Pituitary Gland Pituitary-Adrenal System Prevention therapy Psyche structure Public Health Regulation Research Resistance Risk Factors Risk Marker Role Sampling Severities Signal Transduction Stress Synaptic Transmission Synaptic plasticity Testing Translating United States National Institutes of Health Weight Gain adipokines behavioral phenotyping biological systems brain volume cytokine epigenetic regulation functional outcomes genome-wide glycemic control human data immunoregulation innovation insight lipid metabolism metabolic phenotype methylation pattern neurodevelopment nonhuman primate obesogenic phenotypic data postnatal predictive marker response social social stress stress disorder stressor translational approach

项目摘要

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.

项目摘要。社会压力始终改变与精神障碍有关的生理标志物下丘脑 - 垂体 - 肾上腺（HPA）轴功能障碍以及促炎的增加和A 减少抗炎细胞因子。响应肥胖饮食可以观察到类似的变化和肥胖。重要的是，社会压力的同时出现以及在发展是精神和代谢疾病的有效风险因素。研究的关键问题这些疾病及其相互作用涉及长期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心理健康和新陈代谢相关，通常仍然难以捉摸。先前的证据表明生物学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展健康结果。然而，尚不清楚的是表观遗传学在发育过程中如何出现它们会影响疾病轨迹。人类的横断面表观遗传学研究无法解散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类灵长类动物的纵向，产后发展研究的一部分收集的样品（NHP）社会压力和肥胖的模型，以检查压力和饮食诱导的年代学和动力学从出生到青春期，DNA甲基化（DNAM）的全基因组修饰。动态表观遗传学变化将与相关功能结果有关，包括神经内分泌，炎症和行为表型。我们的目标是检查响应社会压力的DNA模式的形成和功能 NHP中的肥胖性饮食暴露，并研究其对功能的添加剂和明显的影响与精神和代谢健康有关的结果。我们的核心假设是发展曝光恒河猴的社会压力和肥胖饮食会影响外围DNAM概况预测与压力和代谢有关的生理标志物。我们将用两个检验我们的假设具体目的：1）确定和比较暴露于NHP的HPA轴基因的纵向DNAM谱。社会压力，肥胖饮食和匹配的对照。 DNAM的变化可以预测生理吗压力，炎症和代谢轨迹的标记？ 2）确定并比较全基因组DNAM NHP中的特征暴露于社会压力，肥胖饮食和匹配的对照中。更广泛的是什么响应于社会压力和肥胖饮食摄入的分子途径和网络？我们的提案的意义在这一事实中是关于有害环境的这些纵向，受控的研究在人类中，发展过程中的因素是不可行的。我们的NHP模型提供了直接的翻译方法具有为人类精神和代谢轨迹产生预测标记的独特可能性。