Immunopathological basis of PTSD

PTSD的免疫病理学基础

• 批准号: 8662798
• 负责人: Prakash S Nagarkatti
• 金额: $ 34.15万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 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/8662798
• 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; epigenetic marker; epigenomics; high risk; hypothalamic-pituitary-adrenal axis; immune function; immunoregulation; inhibitor/antagonist; insight; meetings; men; novel; operation; prognostic; promoter; response; transcription factor

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.

描述（由申请人提供）：创伤后应激障碍（PTSD）是一种精神疾病，具有与生物失调相关的严重症状，可在暴露于休克后发生。暴露于创伤导致下丘脑-垂体-肾上腺（HPA）轴的调节，该轴在应激反应中起关键作用，反过来与免疫系统相互作用以维持体内平衡。迄今为止，有160多万美国男女参加了伊拉克战争（“伊拉克自由行动”）和阿富汗及周边地区的战争（“持久自由行动”）。在退伍军人事务部（VA）治疗的伊拉克和阿富汗退伍军人中，超过35%的人被诊断出精神健康问题，其中最普遍的是PTSD。由于在伊拉克和阿富汗战争中服役的退伍军人中有显著的PTSD患病率，我们的研究集中在解决这些男性和女性免疫功能障碍的病理基础上。在目前的研究中，我们将检验一个中心假设，即PTSD至少在一定程度上与控制适应性免疫反应中Th1/Th2/Th17/Treg细胞分化的表观遗传机制失调有关，从而改变细胞因子谱并促进炎症反应。具体目的是：1)证实血清细胞因子谱与创伤后应激障碍严重程度的关系，并确定转录因子在调节Th/T regg细胞分化中的作用。此外，细胞因子在Th/Tregs中的表达是否依赖于有丝分裂原激活的蛋白激酶信号通路将被阐明。2)通过高通量microrna阵列研究表观遗传机制是否在Th/Treg极化中发挥作用，并确定Th1、Th2、Th17和Treg细胞因子/转录因子基因启动子的低甲基化或高甲基化水平。生成的miRNA数据将用于计算机算法，用于相关靶基因预测和失调通路。将进行进一步的研究，以评估分别转染下调或上调的miRNA模拟物或拮抗剂后，T细胞中细胞因子的表达是否发生逆转。基于甲基化数据，将尝试使用细胞因子的高甲基化基因启动子或其转录因子抑制剂进行去甲基化，以确定这是否会导致Th/Treg表型特征的逆转。总之，这些研究的新颖之处在于，它们不仅有助于理解应激诱导的创伤后应激障碍患者免疫谱的改变，而且还将为表观遗传标记和特定细胞因子/趋化因子是否可以作为创伤后应激障碍的生物标记提供有用的线索。