Early Life Stress: Epigenetic Regulation of Endocrine and Immune Pathways

早期生活压力：内分泌和免疫途径的表观遗传调节

基本信息

批准号：
9243128
负责人：
AUDREY TYRKA
金额：
$ 59.95万
依托单位：
BUTLER HOSPITAL (PROVIDENCE, RI)
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-17 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9243128
关键词：
Adult Affect Animals Anxiety Anxiety Disorders Autopsy Behavioral Binding Sites Biological Markers Blood Vessels Caring Cells Child Abuse Childhood Chronic Cytokine Gene DNA Data Depressive disorder Development Dexamethasone Diagnosis Disease Dissociation Dose Emotional Endocrine Epigenetic Process Failure Fatigue Feedback Gene Expression Gene Expression Regulation Genes Genetic Transcription Glucocorticoid Receptor Glucocorticoids Goals Health Hormonal Human Hydrocortisone Immune Immune system In Vitro Individual Inflammation Inflammatory Interpersonal Relations Interview Judgment Knowledge Laboratories Lead Leukocytes Life Stress Light Link Literature Longitudinal Studies Measures Mediating Mental Depression Metabolic Metabolic syndrome Methylation Modeling Modification Mononuclear Nature Neurobiology Neurosecretory Systems Outcome Pain Pathway interactions Peripheral Phenotype Physiological Post-Traumatic Stress Disorders Prevention approach Promoter Regions Psychopathology Psychosocial Stress Receptor Gene Recording of previous events Regulation Reporting Research Risk Risk Factors Rodent Sampling Signal Pathway Signal Transduction Source Standardization Stress Stress Tests Symptoms Syndrome System TNF gene Testing Trauma Trier Social Stress Test Work anxiety symptoms base behavioral response brain tissue coping cytokine demethylation depressive symptoms disorder risk endophenotype epigenetic regulation epigenome immune function immunoregulation in vivo indexing insight interest maltreatment neglect neurobiological mechanism peripheral blood promoter public health relevance receptor expression receptor sensitivity response stress disorder stress related disorder stressor suicide victim transcription factor young adult

项目摘要

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.

描述（由申请人提供）：早期压力的历史是抑郁症和焦虑症以及一系列健康状况不佳的重要危险因素。神经内分泌和免疫系统的改变，神经生物学反应中的关键途径与应激诱导的变化有关，这些变化与抑郁症和焦虑症有关。最近的工作表明，在这些途径中对基因的表观遗传修饰可能是儿童逆境作用的核心机制。基因甲基化是一种稳定的表观遗传修饰形式，可降低基因转录。糖皮质激素受体（GR）通过负反馈机制调节神经内分泌功能并有助于免疫功能的调节，一直是该主题的大多数研究的主题。人们对发展有疾病风险的外围血液生物标志物非常感兴趣。异常外周血中的内分泌和炎症功能可以揭示与压力相关的免疫，血管和代谢异常，并且有一些证据表明某些基因的外周和中心基因调节之间的对应关系。糖皮质激素和炎性信号途径中的多个基因可能参与对儿童逆境的反应。有关效应的性质和方向，混合了压力暴露对MDD和PTSD中肾上腺皮质功能的影响的数据。对成人儿童逆境的长期后果的研究受到召回和判断偏见的限制，虐待类型的混合物以及缺乏关于发育时机的数据。此外，关于MDD和PTSD中肾上腺皮质功能的可变性，需要对涉及的表型和机制的性质有更深入的了解。该建议的目的是研究慢性儿童逆境对糖皮质激素和炎症信号途径的基因的影响，包括神经内分泌和免疫功能的基础和挑衅的措施，以及葡萄皮层受体敏感性，以及对呼吸症状的压力和情绪术语，以及情绪术语/情绪术语，以及情绪化的症状，并挑衅的措施。诊断和躯体症状和健康的措施。这些措施将在一个清晰明确的模型中进行测试，以产生有关与压力相关疾病风险机制的特定知识。