Peripheral and central nervous system inflammation associated with military sexual trauma and PTSD

军中性创伤(MST)不幸地在退伍军人中很常见，特别是在女性中，并有生命- 对身心健康的长期影响。包括性侵犯和性骚扰在内的MST， 与创伤后应激障碍(PTSD)和共同疾病密切相关，包括， 抑郁、焦虑、药物使用、肥胖和饮食失调、慢性疼痛和自身免疫力。而其他人 精神疾病，包括抑郁和焦虑，与炎症有关，创伤后应激障碍是独一无二的 与自身免疫性疾病患病率增加50%有关(例如类风湿性关节炎、甲状腺炎和 炎症性肠病)。暴露于MST会进一步增加患自身免疫疾病的风险 混乱程度超过两倍。尽管外周炎症增加是创伤后应激障碍的特征，但它是 尚不清楚外周炎症是否反映了中枢神经系统免疫信号的中断 (CNS)。此外，对创伤后应激障碍发生的免疫失调进行表型鉴定几乎是唯一的 发生于横断面数据收集。然而，如果没有追踪免疫的纵向研究 结合症状的生物标志物，免疫生物标志物是否具有临床指导作用尚不清楚 治疗。此外，虽然流行病学数据支持创伤障碍，特别是MST，可能会 自身免疫性疾病的共同危险因素，MST是否对免疫有独特的影响尚不清楚 发信号。填补这些空白对于了解免疫失调是否以及如何导致 MST退伍军人的症状“状态”，以告知其作为靶向治疗的潜在机制的可行性。 这项建议将通过量化循环中的炎性细胞因子来解决这些知识差距 患有MST相关创伤后应激障碍(+MST/+PTSD)的退伍军人，并比较没有创伤后应激障碍或 MST。除了检测循环中的血浆细胞因子，我们还将检测细胞因子和miRNA。 分离自和星形胶质细胞衍生的外切体(ADE)，它是携带RNA和 从中枢神经系统到血液的蛋白质货物。测量源自CNS的外体种群的生物标志物- 组织来源可以非侵入性地评估神经炎症并比较外周和中枢炎症 与创伤后应激障碍症状有关。我们假设基线外周(血浆)和中枢(外周)水平 与女性退伍军人相比，患有+MST/+创伤后应激障碍的女性退伍军人的炎症标志物将发生变化 没有MST或创伤后应激障碍。基于现有的关于创伤后应激障碍的心理神经免疫学相关性的文献，我们将 用多重技术定量血浆和胞外体中的IL-1β、IL-2、IL-6、干扰素γ和肿瘤坏死因子α 数组。我们还将对外体货物中的免疫调节miRNA进行量化。在+MST/+PTSD组中，我们 还将在3个月和6个月的随访中收集血浆样本，以确定炎性生物标志物是否 与症状随时间的轨迹相关联。一种高度稳定的标记，不跟踪症状 会表明它是风险的标志。相反，如果标记物随着症状严重程度的变化而变化，那么它 可能是驱动症状变化的机制的标志。我们假设免疫标记物特征会 与症状随时间变化的轨迹相对应。 MST的生物学后果对退伍军人来说是一个重大的健康负担，特别是 MST和自身免疫率已经较高的女性。理解MST与MST之间的机制联系 外周和中枢性炎症将有助于我们理解免疫紊乱是 诊断、预后和潜在的治疗目标。以申请人研究免疫的经验为基础 信号和免疫对创伤后应激障碍风险的贡献，拟议的培训计划将提供必要的技能 独立设计和实施生物标记物指导的新方法，以改善患者的生活 神经精神疾病。完成拟议的研究将进一步支持退伍军人事务部 为妇女和心理健康领域的退伍军人护理开发精准医疗工具。

Military sexual trauma (MST) is unfortunately common in Veterans, particularly in women, and has life- long consequences for physical and mental health. MST, which includes both sexual assault and harassment, is strongly associated with post-traumatic stress disorder (PTSD) and co-morbid conditions including, depression, anxiety, substance use, obesity and eating disorders, chronic pain, and autoimmunity. While other psychiatric conditions, including depression and anxiety, are associated with inflammation, PTSD is uniquely associated with a >50% increase in autoimmune disorder prevalence (e.g., rheumatoid arthritis, thyroiditis, and inflammatory bowel disease). Exposure to MST further increases the risk of developing an autoimmune disorder by over two-fold. Although increased peripheral inflammation is well characterized in PTSD, it is unclear if peripheral inflammation reflects a disruption in immune signaling in the central nervous system (CNS). Moreover, phenotyping the immune dysregulation that occurs with PTSD has almost exclusively occurred through cross-sectional data collection. However, without longitudinal studies that track immune biomarkers in conjunction with symptoms, it is unknown if immune biomarkers have clinical utility in guiding treatment. Furthermore, while epidemiological data support that trauma disorders, particularly MST, may have shared risk factors with autoimmune disorders, it is unknown if MST confers unique effects on immune signaling. Filling these gaps is critical to understanding if and how immune dysregulation contributes to symptom "state" in Veterans with MST to inform its viability as a potential mechanism for targeted treatment. This proposal will address these knowledge gaps by quantifying circulating inflammatory cytokines in Veterans with MST-related PTSD (+MST/+PTSD) and comparing cytokine levels to Veterans without PTSD or MST. In addition to examining circulating plasma cytokines, we will also measure cytokines and miRNA isolated from and astrocyte-derived exosomes (ADEs), which are extracellular vesicles that carry RNA and protein cargo to the blood from the CNS. Measuring biomarkers from exosome populations derived from CNS- tissue sources can non-invasively assess neuroinflammation and compare peripheral vs. central inflammation links to PTSD symptoms. We hypothesize that levels of baseline peripheral (plasma) and central (exosome) inflammatory markers will be altered in female Veterans with +MST/+PTSD compared to female Veterans without MST or PTSD. Based on the existing literature of psychoneuroimmunologic correlates of PTSD, we will quantify IL-1β, IL-2, IL-6, IFNγ, and TNFα cytokines from both plasma and exosome cargo using multiplex arrays. We will also quantify immune regulatory miRNA from exosome cargo. In the +MST/+PTSD group, we will also collect plasma samples at 3- and 6-month follow-up visits to determine if inflammatory biomarkers are associated with symptom trajectory across time. A highly stable marker that does not track with symptoms would suggest it is a marker of risk. In contrast, if a marker changes alongside symptom severity over time, it may be a marker of mechanisms driving symptom change. We hypothesize that immune marker profiles will correspond with symptom trajectory over time. The biological consequences of MST represent a significant health burden for Veterans, especially women with already higher MST and autoimmunity rates. Understanding the mechanistic link between MST and peripheral and central inflammation will inform our understanding of immune disruption as a biomarker for diagnosis, prognosis, and potential treatment targets. Building on the applicant's experience studying immune signaling and immune contributions to PTSD risk, the proposed training plan will provide the necessary skills to independently design and implement novel biomarker-guided approaches to improve patients' lives with neuropsychiatric illness. Completing the proposed research will further support the VA mission towards developing precision medicine tools for Veteran care in Women's and mental health.