Early Life Stress: Epigenetic Regulation of Endocrine and Immune Pathways

描述(由申请人提供)：早期生活压力史是抑郁症和焦虑症以及一系列不良健康结果的重要风险因素。神经内分泌和免疫系统的变化是应激神经生物学反应的关键途径，参与了与抑郁和焦虑症相关的应激诱导的变化。最近的研究表明，对这些途径中的基因进行表观遗传修饰可能是童年逆境影响的一个中心机制。基因甲基化是一种稳定的表观遗传修饰形式，它会减少基因转录。糖皮质激素受体(GR)通过负反馈机制调节神经内分泌功能，参与免疫功能的调节，一直是该领域研究的热点。人们对开发疾病风险的外周血液生物标记物非常感兴趣。不正常的 外周血液中的内分泌和炎症功能可以揭示应激相关的免疫、血管和代谢异常，并且有证据表明外周和中枢基因对某些基因的调控是一致的。糖皮质激素和炎症信号通路中的多个基因可能参与了对童年逆境的反应。关于应激暴露对MDD和PTSD患者肾上腺皮质功能的影响的数据在影响的性质和方向方面是混合的。关于童年逆境对成人的长期影响的研究受到回忆和判断偏差、各种虐待类型的混合以及缺乏关于发育时间的数据的限制。此外，关于MDD和PTSD的肾上腺皮质功能的文献的可变性要求更多地了解所涉及的表型和机制的性质。这项建议的目的是研究儿童慢性逆境对内表型的影响，包括糖皮质激素和炎症信号通路中基因的甲基化，神经内分泌和免疫功能的基础和激发指标，糖皮质激素受体敏感性，以及表型包括应对措施和对压力、抑郁和焦虑障碍症状和诊断的行为/情绪反应，以及躯体症状和健康的措施。这些措施将在一个清晰明了的模型中进行测试，以获得关于压力相关障碍的风险机制的具体知识。

DESCRIPTION (provided by applicant): A history of early life stress is an important risk factor for depressive and anxiety disorders and a range of poor health outcomes. Alterations in the neuroendocrine and immune systems, key pathways in the neurobiological response to stress, are involved in the stress-induced changes that are linked to depressive and anxiety disorders. Recent work indicates that epigenetic modifications to genes in these pathways may be a central mechanism of the effects of childhood adversity. Gene methylation is a stable form of epigenetic modification that reduces gene transcription. The glucocorticoid receptor (GR), which regulates neuroendocrine function through a negative feedback mechanism and contributes to the modulation of immune function, has been the topic of most research on this subject. There is great interest in developing peripheral blood biomarkers of risk for disorders. Abnormalities of endocrine and inflammatory function in peripheral blood can shed light on stress-related immune, vascular, and metabolic abnormalities, and there is some evidence of correspondence between peripheral and central gene regulation for some genes. Multiple genes in the glucocorticoid and inflammatory-signaling pathways are likely involved in the response to childhood adversity. Data on effects of stress exposure on adrenocortical function in MDD and PTSD are mixed with respect to the nature and direction of effects. Studies of the long-term consequences of childhood adversity in adults are limited by recall and judgment biases, a mixture of types of maltreatment, and lack of data on developmental timing. In addition, variability in the literature on adrenocortical function in MDD and PTSD necessitates a greater understanding of the nature of phenotypes and mechanisms involved. The goal of this proposal is to study the effects of chronic childhood adversity on endophenotypes including methylation of genes in the glucocorticoid and inflammatory-signaling pathways, basal and provoked measures of neuroendocrine and immune function, and glucocorticoid receptor sensitivity, as well as phenotypes including measures of coping and behavioral/emotional responses to stress, depressive and anxiety disorder symptoms and diagnose, and measures of somatic symptoms and health. These measures will be tested in a clearly articulated model to yield specific knowledge about the mechanisms of risk for stress-related disorders.