Immunopathological basis of PTSD

描述(申请人提供)：创伤后应激障碍(PTSD)是一种精神状态，其严重症状与生物调节失调有关，可在暴露于休克后发生。暴露在创伤中会导致下丘脑-垂体-肾上腺(HPA)轴的调节，这在应激反应中起着关键作用，而应激反应反过来又与免疫系统相互作用，以维持体内平衡。到目前为止，超过160万名美国男女在伊拉克战争(伊拉克自由行动，OIF)和阿富汗及其周边地区(持久自由行动，OEF)中服役。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，其中最常见的是创伤后应激障碍。鉴于在伊拉克和阿富汗战争中服役的退伍军人中创伤后应激障碍的发病率很高，我们的研究重点是解决这些男性和女性免疫功能障碍的病理基础。在目前的研究中，我们将检验核心假设，即创伤后应激障碍至少部分与表观遗传机制的失调有关，该机制控制获得性免疫反应中Th1/Th2/Th17/Treg细胞的分化，从而改变细胞因子谱并促进炎症反应。其具体目的是：1)证实血清细胞因子谱与创伤后应激障碍的严重程度，并确定转录因子在调节Th/T细胞分化中的作用。此外，Th/Tregs中细胞因子的表达是否依赖于丝裂原活化蛋白激酶信号通路将被阐明。2)通过高通量的microRNAs芯片研究表观遗传机制是否在Th/Treg极化中起作用，并确定Th1、Th2、Th17和Treg细胞因子/转录因子基因启动子的甲基化水平。生成的miRNA数据将用于相关目标基因预测和失调途径的计算机算法。进一步的研究将评估在分别下调或上调的miRNA模拟物或miRNAs的抗组体转染后，T细胞中细胞因子的表达是否发生逆转。根据甲基化数据，将尝试使用细胞因子或其转录因子的超甲基化基因启动子的抑制剂来尝试去甲基化，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应激诱导的PTSD患者免疫特征的变化，而且还将提供关于表观遗传标记和特定细胞因子/趋化因子是否可以作为PTSD的生物标记的有用线索。 公共卫生相关性：创伤后应激障碍(PTSD)是一种精神疾病，其严重症状与生物调节失调有关，可在暴露于休克后发生。我们的研究旨在确定这些患者的免疫学改变及其潜在的机制，以便制定预防和治疗的策略。

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. PUBLIC HEALTH RELEVANCE: Post-traumatic stress disorder (PTSD) is a psychiatric condition with severe symptoms associated with biological dysregulation that can occur after exposure to shock. Our studies are aimed at determining the immunological alterations induced in these patients and the underlying mechanisms so as to develop strategies for its prevention and therapy.