Transgenerational Effects of Early Stress

早期压力的跨代影响

• 批准号: 8768204
• 负责人: Erin Loraine Kinnally
• 金额: $ 23.16万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768204
• 关键词: Adrenal Glands; Affect; Animal Model; Archives; Behavior assessment; Blood; California; Cell Count; Child; Child Development; Child health care; Chronic; DNA Methylation; Data; Depressed mood; Development; Disease; Early-life trauma; Endocrine system; Environmental Risk Factor; Epigenetic Process; Exhibits; Family; Fathers; Female; Generations; Genes; Genetic; Genetic Techniques; Genome; Health; Human; Hydrocortisone; Hypothalamic structure; Immune; Immune system; Immunity; Individual; Infant; Infant Development; Inflammation; Inflammatory; Inherited; Interleukin-1; Interleukin-6; Intervention; Laboratories; Life; Life Stress; Link; Long-Term Effects; Longevity; Macaca; Macaca mulatta; Maternal Deprivation; Mental Health; Methylation; Modeling; Mothers; Nervous system structure; Nucleic Acid Regulatory Sequences; Nurseries; Outcome; Output; Pathway interactions; Pattern; Personal Satisfaction; Physiological; Pituitary Gland; Plasma; Play; Population; Primates; Process; Proteins; Psyche structure; Quality of life; Quantitative Genetics; Randomized; Regulation; Reporting; Research; Risk; Role; Running; Sampling; Social Environment; Stress; TNF gene; Tissues; biobehavior; biological adaptation to stress; cytokine; design; disorder risk; early experience; experience; improved; intergenerational; male; next generation; offspring; pediatric trauma; physical conditioning; postnatal; programs; promoter; public health relevance; response; social; social separation; trait

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.

描述（由申请人提供）：早期压力的影响可能持续一生，影响整个生命周期的身体、心理和社会福祉。早期应激的影响可能不仅限于受影响的一代：早期应激的跨代影响已在各个物种中得到报道。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庭中遗传。使用动物模型来理解这些跨代过程至关重要，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方面最具可转化性的动物模型之一。我们最近观察到父亲（而非母亲）的早期母性剥夺压力或保育（NR）经历对幼年恒河猴的免疫力和生理应激反应的影响。由于父亲在猕猴产后发育中发挥的作用很小，这一发现表明遗传因素可能发挥了作用。多年来，人们一直认为基因组的后天变化不可能遗传给后代，因为我们不知道基因可以因压力而发生变化。我们现在知道，早期应激后多个组织会发生表观遗传可塑性，并且有一些证据表明这些变化可能是遗传的。拟议的研究将使用大量存档数据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。我们将首先利用加州国家灵长类动物研究中心 (CNPRC) 提供的标准化生物行为评估计划从 3000 只幼年恒河猴中采集的存档样本，首先探讨早期 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，我们将评估在暴露于 NR 的雄性的后代和父孙中是否观察到类似的变化。最后，我们将研究 NR 相关的表观遗传模式是否可以通过父系遗传。 DNA甲基化是最稳定的表观遗传标记之一，因此我们将在本研究中将启动子甲基化模式作为早期应激跨代效应的潜在机制。这个应用的意义在于我们将使用高度转化的动物模型来探索 与压力相关的后天健康结果如何代代相传，这可能会揭示新的干预途径，以改善高危儿童及其家庭的健康和生活质量。