Immunopathological basis of PTSD

PTSD的免疫病理学基础

基本信息

批准号：
8167365
负责人：
Prakash S Nagarkatti
金额：
$ 34.52万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8167365
关键词：
Address Afghanistan Algorithms Anti-Inflammatory Agents Anti-inflammatory Attention Biological Biological Assay Biological Markers CD4 Positive T Lymphocytes Caring Cells Characteristics Chemicals Clinical Communities Computer Simulation DNA Methylation DNA Structure Data Development Diagnosis Diagnostic Early Diagnosis Early treatment Epigenetic Process Event Exhibits Exposure to Freedom Functional disorder Gene Expression Gene Targeting Genes Genetic Health Personnel Healthcare Helper-Inducer T-Lymphocyte Histone Deacetylation Homeostasis Hydrocortisone Hypermethylation Immune Immune System Diseases Immune response Immune system In Vitro Incidence Individual Inflammatory Inflammatory Response Intervention Iraq Lead Life Mental Health Mental disorders Methods Methylation MicroRNAs Mitogen-Activated Protein Kinases Modification Pathway interactions Patients Peripheral Play Post-Traumatic Stress Disorders Prevalence Prevention therapy Regulation Regulatory T-Lymphocyte Reporting Research Role Serum Severities Severity of illness Shock Signal Pathway Stress Symptoms System T-Lymphocyte Testing Th1/Th2 Differentiation Pathway Transcription factor genes Transfection Trauma Variant Veterans War Woman base biological adaptation to stress chemokine chromatin remodeling combat cytokine demethylation epigenomics high risk hypothalamic-pituitary-adrenal axis immune function immunoregulation inhibitor/antagonist insight meetings men novel operation prognostic promoter response transcription factor

项目摘要

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.

描述（由申请人提供）：创伤后应激障碍（PTSD）是一种精神病病，具有与生物失调有关的严重症状，可能在暴露于冲击后发生。暴露于创伤会导致下丘脑 - 垂体 - 肾上腺（HPA）轴的调节，该轴在应力反应中起着至关重要的作用，而应力反应又与免疫系统相互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的战争（伊拉克自由行动，OIF行动）和阿富汗及周边地区（持久自由行动，OEF）。超过35％的退伍军人事务部（VA）护理中返回的伊拉克和阿富汗退伍军人接受了心理健康诊断，最普遍的是PTSD。随着在伊拉克和阿富汗战争中服役的战斗退伍军人中，PTSD的严重患病率很大，我们的研究重点是解决这些男人和女性免疫功能障碍的病理基础。在当前的研究中，我们将检验以下中心假设：PTSD伴侣至少部分地与表观遗传机制失调，这些机制控制了适应性免疫反应的Th1/Th2/Th17/Treg细胞的分化，从而改变了细胞因子特征并改变了炎症反应。具体目的是1）证实血清细胞因子特征与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，TH/Treg中的细胞因子表达是否取决于有丝分裂原激活的蛋白激酶信号传导途径。 2）解决表观遗传机制是否通过执行高通量microRNA阵列并确定TH1，TH2，TH17，TH17和Treg细胞因子/转录因子基因启动子的低甲基化水平是否在TH/Treg极化中起作用。产生的miRNA数据将用于用于相关目标基因预测和失调途径的硅算法中。将进行进一步的研究，以评估用miRNA模拟物或Antagomirs分别下调或上调的miRNA模拟物或Antagomirs后，在T细胞中发生了细胞因子表达的逆转。基于甲基化数据，将尝试使用用于细胞因子的高甲基化基因启动子或其转录因子的抑制剂尝试脱甲基化，以确定这是否会导致TH/Treg表型特征的逆转。这些研究在一起是新颖的，因为它们不仅将有助于了解PTSD患者的应激诱导的免疫特征改变，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）是一种精神病病，具有与生物失调有关的严重症状，可能在暴露于冲击后发生。我们的研究旨在确定这些患者和基本机制诱导的免疫学改变，以制定预防和治疗的策略。