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况， 暴露在极度紧张的生活事件中。创伤后应激障碍患者也会出现各种障碍 有炎症成分虽然大多数研究表明， PTSD中过度的炎症状态，免疫调节的精确机制 创伤后应激障碍是不明确的。最近，我们有一个令人兴奋的观察， PTSD与更严重的炎症和广泛失调的microRNA（miR）相关 具有调节炎性T细胞反应的众多靶点。具体来说，我们注意到 PTSD患者中许多下调的miR靶向核因子的成分， 活化T细胞（NFAT）通路，对活化，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 钙调磷酸酶亚基A（亚型PPP 3 CA、PPP 2 CB和PPP 3 CC）和B（亚型PPP 3 R1 和PPP 3R 2），其通过去磷酸化激活NFAT，被发现作为靶点 在PTSD患者中有许多失调的miR。T细胞调节的状态， 特别是，PTSD中的NFAT通路迄今尚未被评估。基于我们 初步研究，我们将测试中心假设，创伤后应激障碍的关联，至少在 部分，与改变NFAT信号通路的表观遗传机制失调 导致炎症状态我们将继续这些研究创伤暴露的创伤后应激障碍 与创伤暴露的非PTSD对照组相比。我们将追求三个具体目标： 目的1：我们将确定miR失调导致细胞凋亡改变的机制。 NFAT信号通路导致创伤后应激障碍患者出现炎症状态。目标2：我们 确定PTSD是否触发特异性miR和/或靶点的差异DNA甲基化， T细胞中的NFAT信号传导途径组分导致促炎反应。目标3： 我们将测试组蛋白修饰在NFAT组分上miR表达中的作用， 创伤后应激障碍患者 总之，我们的研究将描绘信号转导的表观遗传机制 导致NFAT信号传导改变和随后的T细胞失调的途径， 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志物， 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.