Epigenetic Mechanisms of T Cell Dysregulation in PTSD

PTSD 中 T 细胞失调的表观遗传机制

• 批准号: 9217144
• 负责人: Mitzi Nagarkatti
• 金额: $ 48.38万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-11-15 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217144
• 关键词: Afghanistan; Attention; Autoimmune Diseases; Calcineurin; Cells; Cellular Structures; Cellular biology; Clinical Course of Disease; Code; DNA Methylation; DNA Sequence; Diagnosis; Disease; Domestic Violence; Early Diagnosis; Early treatment; Epigenetic Process; Event; Exhibits; Exposure to; Family member; Freedom; Gene Expression; Genes; Goals; Health; High Prevalence; Hydrocortisone; Immune; Immune response; Immunologics; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-17; Iraq; Lead; Life; Mental disorders; Messenger RNA; Methylation; MicroRNAs; Modification; Neighborhoods; Neurodegenerative Disorders; Nucleic Acid Regulatory Sequences; PPP3CA gene; PPP3CC gene; PPP3R2 gene; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phosphorylation; Play; Population Study; Post-Traumatic Stress Disorders; Prevalence; Protein Dephosphorylation; Protein Isoforms; Protein phosphatase; Proteins; Regulation; Reporting; Role; Serine; Severities; Signal Pathway; Signal Transduction; Symptoms; T cell differentiation; T cell regulation; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Threonine; Transfection; Trauma; Variant; Veterans; War; Woman; base; calcineurin phosphatase; cardiovascular disorder risk; chromatin remodeling; combat; cytokine; disorder control; epigenetic marker; epigenetic regulation; epigenomics; genome-wide; high risk; histone methylation; histone modification; immune function; immunoregulation; inhibitor/antagonist; men; methylation pattern; nuclear factors of activated T-cells; operation; transcription factor; traumatic event; urban area

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.

创伤后应激障碍（PTSD）是一种不良精神病病，发生在 暴露于极大的生活事件。 PTSD患者还会出现多种疾病 具有炎症成分。大多数研究表明有一个 PTSD中的过度炎症状态，这是免疫调节的确切机制 在PTSD期间尚不清楚。最近，我们对 PTSD与更大的炎症和宽阔失调的microRNA相关（miR） 具有调节炎症T细胞反应的众多靶标的轮廓。具体来说，我们指出 在PTSD患者中，许多下调MIR针对核因子的成分 活化的T细胞（NFAT）途径，对于激活，增殖和分化至关重要 T细胞。除NFAT蛋白本身外，丝氨酸 - 硫代蛋白磷酸酶 钙调神经酶亚基A（同工型PPP3CA，PPP2CB和PPP3CC）和B（同工型PPP3R1 发现通过去磷酸化激活NFAT的PPP3R2）被发现用作目标 对于PTSD患者的许多失调MIR。 T细胞调节的状态和 特别是，迄今为止尚未评估PTSD中的NFAT途径。基于我们 初步研究，我们将测试中心假设，即PTSD同伴，至少在 部分，具有改变NFAT信号通路的表观遗传机制的失调 导致促炎性状态。我们将继续进行这些研究暴露于创伤的PTSD 与暴露于创伤的非PTSD对照相比，患者。我们将追求3个具体目标： 目标1：我们将确定miR失调导致改变的机制 NFAT信号通路导致PTSD患者的炎症状态。目标2：我们将 确定PTSD是否触发特定miR和/或靶标的差异DNA甲基化 T细胞中的NFAT信号通路成分导致促炎反应。目标3： 我们将测试组蛋白修饰在miR表达中的作用在NFAT成分中 PTSD患者。 总之，我们的研究将描述信号传导的表观遗传机制 导致NFAT信号传导改变以及随之而来的T细胞失调和 PTSD患者过多的炎症。我们的研究还旨在确定 PTSD将有助于早期诊断和治疗。