Validation of Immune Dysfunction in Model of Social Stress: Implications for Major Depression Disorder in Veterans

社会压力模型中免疫功能障碍的验证：对退伍军人重度抑郁症的影响

• 批准号: 10293590
• 负责人: Giulio Maria Pasinetti
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10293590
• 关键词: Affect; Affinity Chromatography; Afghanistan; Anhedonia; Animals; Antidepressive Agents; Anxiety; Area; Arterial Fatty Streak; Astrocytes; Automobile Driving; Award; Bacterial Artificial Chromosomes; Behavior; Behavioral; Bioinformatics; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; Cardiovascular Diseases; Cells; Chronic; Chronic stress; Clinical Research; Coupled; Cytometry; Data; Development; Disease remission; Endothelial Cells; Endothelium; Epithelial; Exposure to; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Health; Human; Immune; Immune System Diseases; Immune signaling; Immunologics; Impairment; Individual Differences; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Interleukin-6; Iraq; Knowledge; Lead; Link; Major Depressive Disorder; Measures; Mediating; Mental Depression; Messenger RNA; Modeling; Monitor; Mood Disorders; Moods; Morbidity - disease rate; Mus; Nucleus Accumbens; Pathogenesis; Pathology; Patients; Pattern; Peripheral; Pharmacological Treatment; Phenotype; Physical Function; Play; Post-Traumatic Stress Disorders; Predisposition; Prevalence; Proteins; Psychological Models; Psychological Stress; Publications; Recruitment Activity; Reporting; Ribosomes; Role; Rupture; Series; Signal Transduction; Stress; Structure; Surface Antigens; Symptoms; Testing; Therapeutic; Tight Junctions; Translating; Tumor-infiltrating immune cells; Validation; Veterans; Withdrawal; Work; anxiety-like behavior; base; behavioral phenotyping; blood-brain barrier permeabilization; brain parenchyma; brain tissue; cardiovascular risk factor; cytokine; depression model; innovation; interest; monocyte; mortality; neural circuit; neurovascular; neurovascular injury; novel; novel therapeutic intervention; pre-clinical; preclinical study; prevent; psychologic; recruit; resilience; response; severe mental illness; social; social defeat; social stress; symptomatology; transcriptome sequencing; transcriptomics; validation studies

Project Summary/Abstract At least 30% of Afghanistan and Iraq veterans are affected by Major Depressive Disorder (MDD) and 20% are affected by post-traumatic stress disorder (PTSD) and other stress-related mood disorders. Currently existing pharmacological treatments elicit temporary remission in <50% of patients; thus, there is an urgent need for novel therapeutic approaches to target MDD and psychological stress-related mood disorders. The prevalence of MDD is two- to threefold higher in patients with cardiovascular disease and MDD is associated with 80% increased risk of cardiovascular morbidity and mortality. Clinical studies report higher levels of circulating pro- inflammatory cytokines in patients with MDD and has been replicated in preclinical animal studies of depression. Individual differences in the modulation of cytokine release (most notably IL-6) are associated with susceptibility vs. resilience to chronic social stress in mice. Chronic inflammation and increases in circulatory pro-inflammatory cytokines associated with stress-induced depression is linked with atherosclerotic plaque formation, progression, and rupture, likely contributing to the pathogenesis of cardiovascular disease. Indeed, immune modulatory approaches to neutralize inflammatory cytokines in the periphery produce antidepressant- like behavioral effects following Chronic Social Defeat Stress (CSDS) in mice as well as in humans with depression and chronic inflammation. The concept of resilience, the ability to maintain normal psychological and physical functioning to avoid serious mental illness has topic of significant interest in Veterans during and post-deployment after exposure to psychological stress.Recently, CSDS-associated depression has been linked to impairment of the blood brain barrier (BBB), a series of protective layers including endothelial cells and astrocytes that plays a critical role in maintaining vascular impermeability between the periphery and brain parenchyma. The proposed validation studies implicate that impairment of the BBB may be causally associated with stress-induced mood disorders. In particular, we will validate and expand our understanding how stress influences the region-dependent impairment of the BBB in stress-induced mood disorders, as previously reported by our collaborators Scott Russo, Anne Schaefer, and Miriam Merad in their publication “Social stress induces neurovascular pathology promoting depression”. Using a well-characterized CSDS model of psychological stress in mice that recapitulates many of the symptoms of MDD including social withdrawal, anhedonia, and anxiety, we will explore through novel technological approaches how chronic psychological stress impairs the BBB. In particular, we will utilize a novel endothelial-specific Translating Ribosome Affinity Purification (TRAP) mouse to explore stress-induced transcriptional patterns in multiple mood-related brain regions to determine transcriptomic patterns to psychological stress. To further explore how psychological stress impairs the BBB, we will utilize an innovative mass cytometry (CyTOF) to determine the immune cell profiles in the periphery and brain tissue of susceptible vs. resilient mice and understand how psychological stress mobilizes the innate immune system and causes infiltration of cytokines into the brain. In summary, the proposal in this Merit Review Award for Validation Studies is of importance to Veteran Health. This VA Merit Review Award is to validate recent findings by our collaborators showing that psychological stress in a model of depression impairs BBB permeability and expand our knowledge into how stress induces region-specific endothelial gene expression changes, leading to vascular damage and depression-linked chronic inflammation. The findings of our studies will provide evidence for preclinical studies for novel therapeutic approaches for treating stress-related MDD for Veterans.

项目摘要/摘要 至少30％ 受创伤后应激障碍（PTSD）和其他与压力有关的情绪障碍的影响。现有 <50％的患者会导致药理治疗引起暂时缓解；因此，迫切需要 靶向MDD和与心理压力有关的情绪障碍的新型热方法。流行率 心血管疾病患者的MDD的MDD高两到三倍，MDD与80％有关 心血管发病率和死亡率的风险增加。临床研究报告了较高水平的循环促进 MDD患者的炎性细胞因子，已在临床前动物研究中复制 沮丧。细胞因子释放调节的个体差异（最著名的IL-6）与 易感性与对小鼠慢性社会压力的韧性。慢性感染和循环增加 与压力引起的抑郁症相关的促炎性细胞因子与动脉粥样硬化斑块有关 形成，进展和破裂，可能导致心血管疾病的发病机理。的确， 免疫调节方法中和外周中炎性细胞因子产生抗抑郁药 就像在慢性社交失败压力（CSD）以及人类中的行为效应一样 抑郁和慢性炎症。韧性的概念，保持正常心理的能力 和避免严重精神疾病的身体功能对在和 暴露于心理压力后的部署后，与CSDS相关的抑郁症一直是 与血脑屏障（BBB）的损伤相关，这是一系列受保护的层，包括内皮细胞 和星形胶质细胞在维持周围和大脑之间的血管不渗透方面起着至关重要的作用 paranchyma。提出的验证研究暗示BBB的损害可能是因果 与压力引起的情绪障碍有关。特别是，我们将验证和扩展我们的理解 压力如何影响BBB在压力引起的情绪障碍中的区域依赖性损害， 以前是由我们的合作者Scott Russo，Anne Schaefer和Miriam Merad在其出版物中报道的 “社会压力诱导神经血管病理学促进抑郁症”。使用良好的CSD 小鼠的心理压力模型，概括了MDD的许多症状，包括社会 戒断，狂热和焦虑，我们将通过新颖的技术方法进行探索 心理压力会损害BBB。特别是，我们将利用一种新颖的内皮特异性翻译 核糖体亲和力纯化（TRAP）小鼠以探索多个应力诱导的转录模式 与情绪相关的大脑区域，确定了心理压力的转录组模式。进一步探索如何 心理压力会损害BBB，我们将利用创新的质量细胞仪（Cytof）来确定 易感与弹性小鼠的外围和脑组织中的免疫细胞谱图，并了解如何 心理压力动员了先天免疫系统，并导致细胞因子浸润到大脑中。 总而言之，该验证研究的优异审查奖中的提案对退伍军人健康至关重要。 该VA功绩评论奖是旨在验证我们的合作者的最新发现，表明心理 抑郁模型中的压力会损害BBB的渗透性，并将我们的知识扩展到压力如何引起 区域特异性的内皮基因表达变化，导致血管损伤和抑郁链接 慢性炎症。我们的研究结果将为新颖的临床前研究提供证据 治疗与退伍军人应力相关的MDD的治疗方法。