Immunopathological basis of PTSD

描述（由申请人提供）：创伤后应激障碍（PTSD）是一种精神疾病，具有与接触休克后可能发生的生物失调相关的严重症状。暴露于创伤导致下丘脑-垂体-肾上腺（HPA）轴的调节，HPA轴在应激反应中起关键作用，应激反应反过来与免疫系统相互作用以维持稳态。迄今为止，超过160万美国男女在伊拉克战争（伊拉克自由行动，OIF）和阿富汗及周边地区战争（持久自由行动，OEF）中服役。在退伍军人事务部（VA）护理的伊拉克和阿富汗退伍军人中，超过35%的人接受了心理健康诊断，最常见的是创伤后应激障碍。由于在伊拉克和阿富汗战争中服役的退伍军人中PTSD的患病率很高，我们的研究集中在解决这些男性和女性免疫功能障碍的病理基础上。在目前的研究中，我们将测试的中心假设，PTSD关联，至少部分，与表观遗传机制，控制适应性免疫反应的Th 1/Th 2/Th 17/Treg细胞的分化失调，从而改变细胞因子谱和促进炎症反应。具体目的是1）证实血清细胞因子谱与PTSD的严重程度，并确定调节Th/T reg细胞分化的转录因子的作用。此外，是否在Th/T细胞的细胞因子的表达是依赖于丝裂原活化蛋白激酶信号通路将被阐明。2)通过进行高通量microRNA阵列来解决表观遗传机制是否在Th/Treg极化中起作用，并确定Th 1、Th 2、Th 17和Treg细胞因子/转录因子基因启动子的低甲基化或高甲基化水平。产生的miRNA数据将用于相关靶基因预测和失调途径的计算机算法。将进行进一步的研究以评估在用分别下调或上调的miRNA的miRNA模拟物或miR-16转染后T细胞中是否发生细胞因子表达的逆转。基于甲基化数据，将使用细胞因子或其转录因子的高甲基化基因启动子的抑制剂尝试去甲基化，以确定这是否会导致Th/Treg表型特征的逆转。总之，这些研究是新颖的，因为它们不仅有助于了解PTSD患者免疫谱的应激诱导的改变，而且还将提供有关表观遗传标记物和特定细胞因子/趋化因子是否可以作为PTSD生物标记物的有用线索。

DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is a psychiatric condition with severe symptoms associated with biological dysregulation that can occur after exposure to shock. Exposure to trauma results in modulation in the hypothalamic-pituitary-adrenal (HPA) axis, which plays a critical role in the stress response that in turn interacts reciprocally with the immune system to maintain homeostasis. To date, over 1.6 million US men and women have served in the wars in Iraq (Operation Iraqi Freedom, OIF) and Afghanistan and surrounding regions (Operation Enduring Freedom, OEF). Over 35% of returned Iraq and Afghanistan veterans in Department of Veterans Affairs (VA) care have received mental health diagnoses, the most prevalent being PTSD. Inasmuch as, there is significant prevalence of PTSD in combat veterans who have served in the Iraq and Afghanistan wars, our studies have focused on addressing the pathological basis of immune dysfunction in these men and women. In the current study, we will test the central hypothesis that PTSD associates, at least in part, with dysregulation in the epigenetic mechanisms that control the differentiation of Th1/Th2/Th17/Treg cells of the adaptive immune response, thereby altering the cytokine profiles and promoting inflammatory response. The specific aims are 1) to corroborate the serum cytokine profile with severity of PTSD and to determine the role of transcription factors that regulate the differentiation of Th/T reg cells. Furthermore, whether the cytokine expression in Th/Tregs is dependent on the mitogen activated protein kinase signaling pathway will be elucidated. 2) to address whether epigenetic mechanisms play a role in Th/Treg polarization by performing high-throughput microRNAs arrays and to determine the level of hypo- or hypermethylation of Th1, Th2, Th17 and Treg cytokine/transcription factor gene promoters. The miRNA data generated will be used in silico algorithms for related target gene prediction and pathways that are dysregulated. Further studies will be performed to assess whether reversal of the cytokine expression occurs in the T cells following transfection with miRNA mimics or antagomirs of miRNAs that are downregulated or upregulated respectively. Based on the methylation data, demethylation will be attempted using inhibitors for hypermethylated gene promoters of cytokines or their transcription factors to determine whether this would lead to reversal of the Th/Treg phenotypic characteristics. Together, these studies are novel in that they will not only help understand stress-induced alterations in immune profiles in PTSD patients but will also provide useful clues on whether epigenetic markers and specific cytokines/chemokines can serve as bio-markers of PTSD.