Epigenetic Mechanisms of T Cell Dysregulation in PTSD

创伤后应激障碍(PTSD)是一种不良的精神状态，发生在 暴露在极度紧张的生活事件中。创伤后应激障碍患者还会发展成各种疾病。 带有炎症成分。虽然大多数研究表明， 创伤后应激障碍的过度炎症状态，免疫调节的确切机制 创伤后应激障碍期间的情况尚不清楚。最近，我们做了一个令人兴奋的观察， 创伤后应激障碍与更严重的炎症和广泛失调的microRNA(MiR)相关 介绍了许多调节炎性T细胞反应的靶点。具体来说，我们注意到 创伤后应激障碍患者中大量下调的MIR靶向核因子的成分 活化的T细胞(NFAT)途径，对细胞的激活、增殖和分化至关重要 T细胞。除了NFAT蛋白本身，丝氨酸-苏氨酸蛋白磷酸酶 钙调神经磷酸酶亚单位A(亚型PPP3CA、亚型PPP2CB和亚型PPP3CC)和亚型B(亚型PPP3R1 和PPP3R2)，通过去磷酸化激活NFAT)被发现作为靶标 对于创伤后应激障碍患者的大量调节失调的微血管受体。T细胞调节的状态，以及在 特别是，创伤后应激障碍中的NFAT通路到目前为止还没有得到评估。基于我们的 初步研究，我们将检验创伤后应激障碍与之相关的中心假说，至少在 部分，与改变NFAT信号通路的表观遗传机制的失调有关 导致了一个支持炎症的状态。我们将继续这些研究--创伤后应激障碍 患者与创伤暴露的非创伤后应激障碍对照组进行比较。我们将追求3个具体目标： 目标1：我们将确定miR失调导致的改变的机制 NFAT信号通路导致创伤后应激障碍患者的炎症状态。目标2：我们将 确定创伤后应激障碍是否触发特定miR和/或靶基因的差异DNA甲基化 T细胞中的NFAT信号通路组件可导致促炎反应。目标3： 我们将测试组蛋白修饰在NFAT组件上miRs表达中的作用 创伤后应激障碍患者。 我们的研究将共同描绘潜在的表观遗传机制。 导致NFAT信号变化和由此导致的T细胞失调和 创伤后应激障碍患者的过度炎症。我们的研究还旨在确定表观遗传生物标记物 有助于创伤后应激障碍的早期诊断和治疗。

Post-traumatic stress disorder (PTSD) is an adverse psychiatric condition that occurs after exposure to extremely stressful life events. PTSD patients also develop a variety of disorders with an inflammatory component. While majority of the studies indicate that there is an excessive inflammatory state in PTSD, the precise mechanisms of immunomodulation seen during PTSD are not clear. Recently, we have made an exciting observation that the severity of PTSD is correlated with greater inflammation and a broadly dysregulated microRNA (miR) profile with numerous targets that regulate inflammatory T cell response. Specifically, we noted that numerous downregulated miRs in PTSD patients targeted components of the nuclear factor of activated T cells (NFAT) pathway, crucial for the activation, proliferation and differentiation of T cells. In addition to the NFAT proteins themselves, the serine-threonine protein phosphatase calcineurin subunits A (isoforms PPP3CA, PPP2CB, and PPP3CC) and B (isoforms PPP3R1 and PPP3R2), which activate NFAT through dephosphorylation, were found to serve as targets for numerous dysregulated miRs in PTSD patients. The status of the T cell regulation, and in particular, the NFAT pathway in PTSD has not been evaluated thus far. Based on our preliminary studies, we will test the central hypothesis that PTSD associates, at least in part, with dysregulation in the epigenetic mechanisms that alter NFAT signaling pathway leading to a pro-inflammatory state. We will pursue these studies trauma-exposed PTSD patients when compared to trauma-exposed non-PTSD controls. We will pursue 3 specific aims: Aim 1: We will identify the mechanisms through which miR dysregulation leads to alterations in NFAT signaling pathway leading to an inflammatory state in PTSD patients. Aim 2: We will determine whether PTSD triggers differential DNA methylation of specific miR and/or targets of NFAT signaling pathway components in T cells leading to pro-inflammatory response. Aim 3: We will test the role of histone modifications in the expression of miRs on NFAT components in PTSD patients. Together, our studies will delineate the epigenetic mechanisms underlying signaling pathways that lead to alterations in NFAT signaling and consequent T cell dysregulation and excess inflammation in PTSD patients. Our studies also aim to identify epigenetic biomarkers of PTSD that will help in the early diagnosis and treatment.