Inflammation & glucocorticoid signaling in early life stress and major depression

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，据信这有助于MD与某些医学合并症的联系。MD还常伴有下丘脑-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，早期生活应激(ELS)增加的男性MD患者表现出更高的应激诱导的炎症反应，这与血浆皮质醇对应激反应的降低以及糖皮质激素敏感性降低的初步证据有关。这项拟议研究的长期目标是进一步研究皮质醇释放和GR功能改变(糖皮质激素敏感性降低)对MD患者过度炎症的贡献，并评估ELS的贡献。这项拟议工作的基本假设是，患有MD和ELS的男性在休息条件下和应激后的过度炎症是糖皮质激素对炎症反应抑制不足的结果；这一过程受到ELS(皮质醇分泌减少)和MD(GR功能减少)独立贡献的调节。为了验证这一假设，提出了以下具体目标：目的1)测量男性MD患者和有或没有ELS的健康对照组(每组17人)的基础和应激诱导的炎症反应的激活，目的2)将炎症反应的激活与基线和应激诱导的皮质醇激活以及GR功能相关联，以及目的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。男性将从埃默里·孔蒂中心正在进行的一个项目中招募，该项目旨在研究ELS对神经生物学和行为的影响。对于检测压力诱导的免疫和神经内分泌激活的研究，将使用Trier社会压力测试(TSST)。应激前、应激期间和应激后的炎症措施包括炎症信号通路激活(如核因子和MAPK)和血浆炎症标记物，包括急性时相反应物和促炎细胞因子。神经内分泌措施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(在TSST前获得的血液样本上进行)将使用脂多糖和山奈素来激活核因子-地塞米松以激活GR信号通路。相关炎症和GR信号通路之间的蛋白质-蛋白质相互作用将通过免疫沉淀和相关神经内分泌和炎症转录因子的DNA结合特性来探索。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。这一应用将有助于确定内分泌-免疫界面的分子靶点，并可能为MD和ELS的病理生理学及其与内科疾病的关系提供新的见解。过度的炎症和异常的内分泌功能正在成为严重抑郁症的重要因素。这笔赠款的目的是了解有创伤早期生活经历(例如性虐待)的男性与没有这种病史的男性在严重抑郁的潜在病理生理学方面的差异。这样的理解可能有助于根据心理社会和生物学表型为患有严重抑郁症的个体制定个性化的治疗策略。

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.