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

不幸的是，军事性创伤（MST）在退伍军人中很常见，特别是在女性中，并且具有生命- 对身心健康的长期影响。MST包括性侵犯和性骚扰， 与创伤后应激障碍（PTSD）和共病状况密切相关， 抑郁、焦虑、物质使用、肥胖和饮食失调、慢性疼痛和自身免疫。而其他 精神疾病，包括抑郁和焦虑，与炎症有关，PTSD是唯一的 与自身免疫性疾病患病率增加>50%相关（例如，类风湿性关节炎，甲状腺炎， 炎症性肠病）。暴露于MST进一步增加了发生自身免疫性疾病的风险。 超过两倍的紊乱。尽管外周炎症增加在PTSD中具有很好的特征， 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，PTSD患者的免疫失调表型几乎完全由 通过横向数据收集。然而，没有追踪免疫的纵向研究， 尽管免疫生物标志物与症状结合使用，但尚不清楚免疫生物标志物是否具有指导治疗的临床实用性。 治疗此外，虽然流行病学数据支持创伤性疾病，特别是MST， 与自身免疫性疾病共享的风险因素，尚不清楚MST是否对免疫系统有独特的影响。 发信号。填补这些空白对于理解免疫失调是否以及如何有助于 症状“状态”的退伍军人与MST告知其可行性作为一个潜在的机制，有针对性的治疗。 这项提案将通过量化循环中的炎症细胞因子来解决这些知识缺口。 患有MST相关PTSD（+MST/+PTSD）的退伍军人，并将细胞因子水平与没有PTSD的退伍军人进行比较， MST。除了检测循环血浆细胞因子外，我们还将检测细胞因子和miRNA。 分离自星形胶质细胞来源的外泌体（ADE），其是携带RNA的胞外囊泡， 从中枢神经系统输送到血液中。测量源自CNS的外来体群体的生物标志物- 组织来源可以非侵入性地评估神经炎症， 与PTSD症状的联系我们假设基线外周（血浆）和中枢（外泌体）水平 与女性退伍军人相比，患有+MST/+PTSD的女性退伍军人的炎症标志物将发生改变 没有MST或PTSD基于现有的PTSD的心理神经免疫学相关文献，我们将 使用多重PCR技术定量来自血浆和外泌体货物的IL-1β、IL-2、IL-6、IFNγ和TNFα细胞因子， 阵我们还将定量来自外泌体货物的免疫调节miRNA。在+MST/+PTSD组中，我们 还将在3个月和6个月随访时收集血浆样本，以确定炎症生物标志物是否 与症状的时间轨迹相关。一种高度稳定的标记物，不随症状而变化 表明这是一种风险标志。相反，如果一个标志物随着症状严重程度的变化而变化， 可能是驱动症状变化的机制的标志。我们假设免疫标志物图谱将 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， MST和自身免疫率已经较高的女性。理解MST与 外周和中枢炎症将使我们了解免疫破坏作为生物标志物， 诊断、预后和潜在治疗靶点。根据申请人学习免疫学的经验， 信号和免疫对PTSD风险的贡献，拟议的培训计划将提供必要的技能， 独立设计和实施新的生物标志物引导的方法，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VA的使命， 为退伍军人妇女和心理健康护理开发精确的医疗工具。

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.