Inflammation & glucocorticoid signaling in early life stress and major depression

描述（由申请人提供）：重度抑郁症（MD）与增加的基线炎症反应相关，这被认为是导致MD与某些医学合并症相关的原因。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降低有关，初步证据表明糖皮质激素敏感性降低。本研究的长期目标是进一步研究皮质醇释放改变和GR功能（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的影响。这项工作的主要假设是，在休息条件下和应激后，MD和ELS患者的过度炎症是糖皮质激素对炎症反应抑制不足的结果；这一过程由ELS（皮质醇分泌减少）和MD （GR功能降低）的独立贡献所调节。为了验证这一假设，我们提出了以下具体目标：目的1)测量基线和应激诱导的炎症反应激活在男性MD患者和健康对照（n=17 /组），目的2)将炎症反应激活与基线和应激诱导的皮质醇激活以及GR功能相关联，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。男性将从正在进行的Emory Conte中心项目中招募，该项目旨在研究ELS对神经生物学和行为的影响。对于检查应激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）。应激前、应激中、应激后的炎症指标包括炎症信号通路激活（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（在TSST之前获得的血液样本上进行）将使用脂多糖和大霉素来激活NF-地塞米松来激活GR信号通路。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，探索相关炎症和GR信号通路之间的蛋白-蛋白相互作用。根据这些实验的结果，未来的研究将集中在女性受试者的类似样本上。该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是导致重度抑郁症的重要因素。这项资助的目的是了解有创伤性早期生活经历（如性虐待）的男性与没有这种经历的男性在重度抑郁症的潜在病理生理学上的差异。这样的理解可能有助于根据社会心理和生物学表型为重度抑郁症患者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.