Inflammation & glucocorticoid signaling in early life stress and major depression

炎

• 批准号: 7541711
• 负责人: THADDEUS PACE
• 金额: $ 7.65万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-19 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541711
• 关键词: Acute-Phase Proteins; Anisomycin; Behavior; Binding; Biological; Blood specimen; C-reactive protein; Cardiovascular Diseases; Cell Nucleus; Cells; Characteristics; Companions; Complement Factor B; Corticotropin; Corticotropin-Releasing Hormone; Cytoplasm; DNA Binding; Data; Dexamethasone; Diabetes Mellitus; Disease; Disease Outcome; Elements; Endocrine; Exhibits; Female; Functional disorder; Future; Glucocorticoid Receptor; Glucocorticoids; Goals; Grant; Haptoglobins; Hormones; Hydrocortisone; Immune; Immune response; Immune system; Immunoprecipitation; In Vitro; Indium; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-1 Receptors; Interleukin-6; Interleukins; JUN gene; Life Experience; Life Stress; Lipopolysaccharides; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MAPK14 gene; MAPK8 gene; Major Depressive Disorder; Malignant Neoplasms; Measures; Medical; Mitogen-Activated Protein Kinases; Molecular Target; Morbidity - disease rate; Neurobiology; Neurosecretory Systems; Nuclear; Nuclear Extract; Participant; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Phosphotransferases; Physiological; Plasma; Process; Proteins; Psychosocial Stress; Receptor Activation; Receptor Signaling; Recording of previous events; Recruitment Activity; Relative (related person); Reporting; Research; Rest; Sampling; Severities; Sexual abuse; Signal Pathway; Signal Transduction; Stress; TNF gene; Testing; Transcortin; Trier Social Stress Test; Whole Blood; Work; activating transcription factor; base; biological adaptation to stress; cytokine; depressed; depression; hypothalamic-pituitary-adrenal axis; immune function; in vivo; inflammatory marker; insight; male; men; novel; protein protein interaction; psychosocial; receptor; receptor function; receptor sensitivity; research study; response; stress-activated protein kinase 1; stressor; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Major Depression (MD) has been associated with increased baseline inflammatory responses that are believed to contribute to the association of MD with certain medical co-morbidities. MD is also often accompanied by hypothalamic-pituitary adrenal axis abnormalities, including altered cortisol release and impaired glucocorticoid receptor (GR) function. Interestingly, recent data indicates that male MD patients with increased early life stress (ELS) exhibit increased stress-induced inflammatory responses that are associated with reduced plasma cortisol responses to stress and preliminary evidence of decreased glucocorticoid sensitivity. The long term objectives of the proposed research are to further examine the contribution of altered cortisol release and GR function (reduced glucocorticoid sensitivity) to excessive inflammation in patients with MD, and to evaluate the contribution of ELS. The primary hypothesis of the proposed work is that excessive inflammation under resting conditions and after stress in men with MD and ELS is the result of insufficient glucocorticoid inhibition of inflammatory responses; a process that is modulated by independent contributions from ELS (reduced cortisol secretion) and MD (reduced GR function). To test this hypothesis, the following specific aims are proposed: Aim 1) to measure baseline and stress-induced activation of inflammatory responses in male MD patients and healthy controls with or without ELS (n=17 per group), Aim 2) to correlate activation of inflammatory responses with baseline and stress-induced activation of cortisol as well as GR function, and Aim 3) to measure molecular interactions between inflammatory signaling pathways and GR signaling pathways in vivo and in vitro. Men will be recruited from an ongoing Emory Conte Center project examining the consequences of ELS on neurobiology and behavior. For studies examining stress-induced immune and neuroendocrine activation, the Trier Social Stress Test (TSST) will be employed. Inflammatory measures before, during, and after stress will include inflammatory signaling pathway activation (e.g. NF- and MAPK) and plasma inflammatory markers including acute phase reactants and proinflammatory cytokines. Neuroendocrine measures will include plasma cortisol and assessments of GR function (e.g. GR-DNA-binding and GR nuclear localization). In vitro studies (conducted on blood samples obtained prior to the TSST) will employ lipopolysaccharide and anisomycin to activate NF- dexamethasone to activate GR signaling pathways. Protein-protein interactions between relevant inflammatory and GR signaling pathways will be explored by immunoprecipitation and DNA-binding characteristics of relevant neuroendocrine and inflammatory transcription factors. Informed by the results from these experiments, future studies will focus on a similar sample of female subjects. This application will help to identify molecular targets at the endocrine-immune interface and may provide novel insights into the pathophysiology of MD and ELS and their relationship to medical illnesses. Excessive inflammation and abnormal endocrine function are emerging as important elements in major depression. The goal of this grant is to understand differences in the underlying pathophysiology of major depression in men with traumatic early life experiences (e.g. sexual abuse), compared to men without such a history. Such an understanding may help individualize treatment strategies for individuals with major depression based on both psychosocial and biological phenotypes.

描述（由申请人提供）：重度抑郁症 (MD) 与基线炎症反应增加有关，据信这些炎症反应导致 MD 与某些医学共病的关联。 MD 还经常伴有下丘脑-垂体肾上腺轴异常，包括皮质醇释放改变和糖皮质激素受体 (GR) 功能受损。有趣的是，最近的数据表明，早期生活压力（ELS）增加的男性MD患者表现出压力诱导的炎症反应增加，这与血浆皮质醇对压力的反应减少有关，初步证据表明糖皮质激素敏感性降低。拟议研究的长期目标是进一步检查皮质醇释放和 GR 功能改变（糖皮质激素敏感性降低）对 MD 患者过度炎症的影响，并评估 ELS 的贡献。这项工作的主要假设是，患有 MD 和 ELS 的男性在静息条件下和应激后过度炎症是糖皮质激素对炎症反应抑制不足的结果；一个由 ELS（皮质醇分泌减少）和 MD（GR 功能减少）独立贡献调节的过程。为了检验这一假设，提出了以下具体目标：目标 1) 测量男性 MD 患者和健康对照（每组 n=17）的基线和应激诱导的炎症反应激活（每组 n=17），目标 2) 进行关联基线炎症反应的激活和应激诱导的皮质醇激活以及 GR 功能，目标 3) 测量体内和体外炎症信号通路和 GR 信号通路之间的分子相互作用。埃默里孔特中心正在进行的一项研究 ELS 对神经生物学和行为的影响的项目将从中招募男性。对于检查压力诱导的免疫和神经内分泌激活的研究，将采用特里尔社会压力测试（TSST）。应激之前、期间和之后的炎症指标包括炎症信号通路激活（例如 NF- 和 MAPK）和血浆炎症标志物，包括急性期反应物和促炎细胞因子。神经内分泌测量将包括血浆皮质醇和 GR 功能评估（例如 GR-DNA 结合和 GR 核定位）。体外研究（对 TSST 之前获得的血液样本进行）将使用脂多糖和茴香霉素来激活 NF-地塞米松，从而激活 GR 信号通路。将通过相关神经内分泌和炎症转录因子的免疫沉淀和 DNA 结合特征来探索相关炎症和 GR 信号通路之间的蛋白质-蛋白质相互作用。根据这些实验的结果，未来的研究将集中在类似的女性受试者样本上。该应用将有助于识别内分泌-免疫界面的分子靶标，并可能为 MD 和 ELS 的病理生理学及其与医学疾病的关系提供新的见解。过度炎症和内分泌功能异常正在成为重度抑郁症的重要因素。这笔赠款的目的是了解具有创伤性早期生活经历（例如性虐待）的男性与没有此类历史的男性相比，重度抑郁症的潜在病理生理学差异。这种理解可能有助于根据社会心理和生物表型对重度抑郁症患者制定个性化的治疗策略。