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比 一般公众的心理障碍，包括焦虑和抑郁的发展，以及 创伤后应激障碍这些精神障碍的发生伴随着高共患病率， 最近的伊拉克和阿富汗战争（OEF/OIF）退伍军人的这些条件是高度关注的问题。 对VA的意义虽然有许多治疗选择可用于治疗这些疾病， 条件下，他们是轻微响应经典的抗焦虑和抗抑郁治疗时， 都是创伤后应激反应的结果广泛的研究领域 心理神经免疫学已经表明，这些条件与免疫失调有关， 功能，表现为增加全身炎症和改变细胞和体液免疫;这是 被认为是这些疾病的病理生理学基础的机制。我们以前的研究和 其他文献表明，T细胞对创伤应激反应敏感， 行为反应的小鼠，赋予弹性或敏感性的压力取决于类型的 T细胞与细胞因子环境。我们的初步结果强烈表明，CD 8+细胞毒性T细胞是一个主要的免疫调节因子。 是全身和脑部炎症来源，并促进发展适应不良行为的易感性 对压力的反应。另一方面，我们最近发表的研究表明，CD 4 + T细胞可以改善 对压力的行为反应，也许是通过减少炎症，与该领域其他人的工作一致。 因此，本申请的总体目的是在临床前小鼠模型中测试治疗功效 治疗焦虑和抑郁症的方法是通过减少创伤应激反应引发的炎症过程。 我们建议特异性地操纵CD 4+和CD 8 + T细胞介导的免疫，以减少全身和脑 炎症，并改善行为结果。我们提出三个具体目标： 具体目标1将确定创伤应激改变T细胞功能的机制， CD 4+和CD 8 + T细胞对应激反应的归巢特性，以及它们在应激反应中是否发生改变。 糖皮质激素受体敏感性为了实现这一点，我们将用T细胞重建T细胞缺陷型Rag 2-/-小鼠， 来源于表达绿色荧光蛋白（GFP）的小鼠的细胞亚群，允许跟踪和 识别多种组织中的T细胞-包括大脑。此外，我们将进行转录组 使用RNA测序（RNAseq）分析应激与非应激野生型小鼠的T细胞以识别 创伤应激诱导的T细胞活化途径。具体目标2旨在确定 在应激小鼠中操纵CD 4+和CD 8 + T细胞的行为。该方法将涉及a） 用来自应激野生型小鼠的CD 4+或CD 8 + T细胞在Rag 2-/-小鼠中重建，和B）使用 在应激的野生型小鼠中抗CD 4+或CD 8 + T细胞的中和抗体。治疗后，小鼠将 评估焦虑、行为绝望和惊吓反应，作为情绪行为的衡量标准。具体 目的3研究CD 4+和CD 8 + T细胞对外周和脑炎症的影响。 将在外周组织和脑中评价血浆和组织细胞因子水平;将在外周组织和脑中评价神经炎症。 使用小胶质细胞培养物和流式细胞术进一步评估。最后，为了确定CD 8 + T细胞是否赋予其 通过细胞因子TNF-α和IL-6的作用发挥作用。我们还将在存在的情况下阻断这些细胞因子， 的CD 8 + T细胞，并确定是否有减少神经炎症。 本申请中的研究预计将提供CD 8 + T细胞是主要的免疫调节剂的概念证明。 创伤应激暴露引发的炎症过程的来源，并且有可能改善 通过靶向这些细胞来调节情绪此外，它们可能有助于确定压力的独特机制 诱导的T细胞活化和治疗性干预的新靶点，以治疗应激相关的精神障碍。