Targeting the inflammatory response to treat post-traumatic anxiety and depression.

针对炎症反应来治疗创伤后焦虑和抑郁。

• 批准号: 10350545
• 负责人: Todd D Gould
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350545
• 关键词: Acute; Affect; Afghanistan; Anti-Anxiety Agents; Anti-Inflammatory Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biological Markers; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Cellular Immunity; Cellular Stress; Clinical; Data; Depressive disorder; Development; Diagnosis; Disease; Elements; Emotional; Emotional Stress; Encephalitis; Event; Exposure to; Flow Cytometry; Functional disorder; General Population; Glucocorticoid Receptor; Goals; Green Fluorescent Proteins; Homing; Humoral Immunities; Immune; Immune Targeting; Immune response; Immune system; Immunomodulators; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Intervention; Iraq; Knowledge; Lead; Literature; Measures; Mediating; Memory; Mental Depression; Mental disorders; Microglia; Mus; Nervous System Physiology; Neuraxis; Organ; Pathology; Patients; Peripheral; Physiological; Plasma; Post-Traumatic Stress Disorders; Predisposition; Prevalence; Process; Property; Psychological Stress; Psychoneuroimmunology; Publishing; Research; Risk; Side; Site; Soldier; Source; Stress; T cell therapy; T-Cell Activation; T-Cell Activation Pathway; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; Transgenic Organisms; Travel; Treatment Efficacy; Validation; Veterans; War; Wild Type Mouse; Work; base; behavior influence; behavioral outcome; behavioral response; biological adaptation to stress; cell type; comorbidity; cytokine; cytotoxic CD8 T cells; depressive symptoms; design; effective therapy; emotion dysregulation; emotion regulation; emotional behavior; experience; glucocorticoid receptor alpha; immune function; improved; innovation; mouse model; neurochemistry; neuroinflammation; neutralizing antibody; new therapeutic target; novel; novel strategies; novel therapeutic intervention; patient subsets; pre-clinical; preclinical study; predictive modeling; prevent; programs; protective effect; psychologic; psychological trauma; receptor sensitivity; reconstitution; resilience; response; symptomatic improvement; systemic inflammatory response; therapeutic evaluation; transcriptome; transcriptome sequencing; traumatic event; traumatic stress; treatment of anxiety disorders; treatment strategy

The stress of deployment and exposure to traumatic events puts soldiers at a greater risk than the general public for the development of psychological disorders, including anxiety and depression, as well as post-traumatic stress disorder. These mental disorders occur with high comorbidity, and the prevalence of these conditions in Veterans of the recent Iraq and Afghanistan wars (OEF/OIF) is a concern of high significance for the VA. While a number of therapeutic options are available for the treatment of these conditions, they are marginally responsive to classical anxiolytic and antidepressant treatment when they develop as a consequence of traumatic stress exposure. Extensive research in the field of psychoneuroimmunology has indicated that these conditions are associated with dysregulated immune function, manifested as increased systemic inflammation and altered cellular and humoral immunity; which is believed to be a mechanism underlying the pathophysiology of these disorders. Our previous studies and others in the literature have shown that T cells are responsive to traumatic stress exposure and can influence behavioral responses of mice, conferring either resilience or susceptibility to stress depending upon the type of T cell and the cytokine milieu. Our preliminary results strongly indicate that CD8+ cytotoxic T cells are a major source of systemic and brain inflammation and promote susceptibility to develop maladaptive behavioral responses to stress. On the other side, our recently published study indicates that CD4+ T cells improve behavioral responses to stress, perhaps by reducing inflammation, in line with the work of others in the field. Thus, the overall objective of this application is to test, in a pre-clinical mouse model, the therapeutic efficacy of treating anxiety and depression by reducing inflammatory processes triggered by traumatic stress exposure. We propose to specifically manipulate CD4+ and CD8+ T cell mediated immunity to reduce systemic and brain inflammation, and improve behavioral outcomes. We propose 3 specific aims: Specific Aim 1 will identify mechanisms by which traumatic stress alters T cell functions by examining homing properties of CD4+ and CD8+ T cells in response to stress, and whether they develop alterations in glucocorticoid receptor sensitivity. To accomplish this we will reconstitute T cell deficient Rag2-/- mice with T cell subsets derived from green fluorescent protein (GFP) expressing mice, allowing for the tracking and identification of T cells in multiple tissues- including the brain. Additionally, we will conduct transcriptome analysis of T cells of stressed vs non-stressed wild type mice using RNA-sequencing (RNAseq) to identify pathways of T cell activation induced by traumatic stress. Specific Aim 2 is designed to determine the effects on behavior of manipulating CD4+ and CD8+ T cells in stressed mice. The approach will involve a) reconstitution in Rag2-/- mice with CD4+ or CD8+ T cells from stressed wild type mice, and b) the use of neutralizing antibodies against CD4+ or CD8+ T cells in stressed wild type mice. Following treatment, mice will be assessed for anxiety, behavioral despair, and startle reactivity as measures of emotional behavior. Specific Aim 3 will study the effects of manipulating CD4+ and CD8+ T cells on peripheral and brain inflammation. Plasma and tissue cytokine levels will be evaluated in peripheral tissue and brain; neuroinflammation will be further assessed using microglial cultures and flow cytometry. Finally, to determine if CD8+ T cells confer their effects through the actions of the cytokines TNF-α and IL-6. We will also block these cytokines in the presence of CD8+ T cells and determine if there is a reduction in neuroinflammation. The studies in this application are expected to provide proof of concept that CD8+ T cells are the main source of inflammatory processes triggered by traumatic stress exposure and it is possible to improve emotional regulation by targeting these cells. Furthermore, they may help identify unique mechanisms of stress induced T cell activation and novel targets of therapeutic intervention to treat stress related mental disorders.

部署和暴露于创伤事件的压力使士兵面临的风险大于 公众开发心理疾病，包括动画和抑郁症以及 创伤后应激障碍。这些精神障碍的合并症很高，流行率 这些条件在最近的伊拉克和阿富汗战争（OEF/OIF）的退伍军人中是高度关注的 VA的意义。尽管有许多治疗选择可用于治疗 条件，当他们对经典的抗焦虑和抗抑郁药的治疗略有响应 由于外伤性压力暴露而发展。在该领域的广泛研究 Psychoneuromumumumumumumanology表明这些疾病与免疫失调有关 功能，表现为增加的全身注射以及细胞和体液免疫的改变；就是 被认为是这些疾病病理生理学的基础机制。我们以前的研究和 文献中的其他人表明，T细胞对创伤性压力暴露有反应，并且会影响 小鼠的行为反应，会议的韧性或对压力的敏感性，具体取决于 T细胞和细胞因子环境。我们的初步结果强烈表明CD8+细胞毒性T细胞是主要的 系统性和大脑感染的来源，并促进发展适应不良行为的敏感性 对压力的反应。另一方面，我们最近发表的研究表明CD4+ T细胞有所改善 行为对压力的反应，也许是通过减少炎症与该领域其他人的工作相一致的。 这是该应用的总体目的是在临床前鼠标模型中测试治疗效率 通过减少创伤性压力触发的炎症过程来治疗焦虑和抑郁。 我们建议专门操纵CD4+和CD8+ T细胞介导的免疫启动，以降低全身和脑 炎症并改善行为结果。我们提出了3个具体目标： 特定目标1将通过检查创伤应力改变T细胞功能的机制 CD4+和CD8+ T细胞的归巢特性响应压力，以及它们是否在 糖皮质激素受体敏感性。为此，我们将用T构建T细胞缺陷rag2 - / - 鼠标 源自表达小鼠的绿色荧光蛋白（GFP）的细胞子集，允许跟踪和 在包括大脑在内的多次T细胞鉴定。此外，我们将进行转录组 使用RNA测序（RNASEQ）鉴定应力与无压力野生型小鼠的T细胞的分析以鉴定 创伤应力诱导的T细胞活化的途径。特定目标2旨在确定效果 关于应力小鼠操纵CD4+和CD8+ T细胞的行为。该方法将涉及a） 用CD4+或CD8+ T细胞从应力的野生型小鼠中重新构成rag2 - / - 小鼠，b）使用 在应力野生型小鼠中中和针对CD4+或CD8+ T细胞的抗体。治疗后，小鼠将 评估动画，行为绝望和惊吓反应性，作为情绪行为的衡量。具体的 AIM 3将研究操纵CD4+和CD8+ T细胞对周围和脑注射的影响。 血浆和组织细胞因子水平将在外周组织和大脑中进行评估。神经炎症将是 使用小胶质细胞培养和流式细胞仪进一步评估。最后，确定CD8+ T细胞是否会汇总 通过细胞因子TNF-α和IL-6的作用作用。我们还将在存在的情况下阻止这些细胞因子 CD8+ T细胞的大量，并确定神经炎症是否减少。 预计该应用中的研究将提供概念证明CD8+ T细胞是主要的 受创伤性压力暴露触发的炎症过程的来源，可以改善 通过靶向这些细胞来调节情绪调节。此外，它们可能有助于确定压力的独特机制 诱导T细胞激活和治疗干预的新靶标，以治疗与压力相关的精神疾病。