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

• 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
• 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

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危险因素。神经内分泌和免疫系统的改变是对压力的神经生物学反应的关键途径，涉及与抑郁症和焦虑症相关的压力引起的变化。最近的研究表明，这些途径中基因的表观遗传修饰可能是童年逆境影响的核心机制。基因甲基化是表观遗传修饰的一种稳定形式，可减少基因转录。糖皮质激素受体（GR）通过负反馈机制调节神经内分泌功能，并有助于调节免疫功能，一直是该主题大多数研究的主题。人们对开发疾病风险的外周血生物标志物非常感兴趣。异常情况 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枢基因调控之间存在对应关系。糖皮质激素和炎症信号通路中的多个基因可能参与对童年逆境的反应。关于压力暴露对 MDD 和 PTSD 肾上腺皮质功能影响的数据在影响的性质和方向方面是混杂的。对成人童年逆境的长期后果的研究受到记忆和判断偏差、虐待类型的混合以及发育时间数据缺乏的限制。此外，关于 MDD 和 PTSD 中肾上腺皮质功能的文献存在差异，因此需要更好地了解所涉及的表型和机制的性质。该提案的目的是研究慢性童年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测量、糖皮质激素受体敏感性，以及表型，包括对压力、抑郁和焦虑症症状的应对和行为/情绪反应的测量和 诊断以及躯体症状和健康的测量。这些措施将在一个清晰明确的模型中进行测试，以获得有关压力相关疾病风险机制的具体知识。