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.

项目概要/摘要 至少 30% 的阿富汗和伊拉克退伍军人患有重度抑郁症 (MDD)，其中 20% 患有抑郁症 受创伤后应激障碍（PTSD）和其他目前存在的压力相关情绪障碍的影响。 药物治疗可使<50%的患者得到暂时缓解，因此迫切需要药物治疗； 针对 MDD 和心理压力相关情绪障碍的新治疗方法。 患有心血管疾病的患者的 MDD 发病率高出两到三倍，并且 MDD 与 80% 的患者相关 临床研究报告循环血前体水平升高。 MDD 患者的炎症细胞因子，并已在临床前动物研究中得到重复 细胞因子释放（最显着的是 IL-6）调节的个体差异与抑郁症有关。 小鼠对慢性社会压力的易感性与恢复能力。 与压力诱发的抑郁症相关的促炎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制。 中和外周炎症细胞因子的免疫调节方法可产生抗抑郁药 例如小鼠和人类在慢性社交挫败压力（CSDS）后的行为影响 抑郁症和慢性炎症的概念，即保持正常心理的能力。 和避免严重精神疾病的身体功能是退伍军人在服役期间和期间非常感兴趣的话题 部署后遭受心理压力后。最近，CSDS 相关抑郁症已被研究 与血脑屏障 (BBB) 受损有关，血脑屏障是一系列保护层，包括内皮细胞 星形胶质细胞在维持外周和大脑之间的血管不通透性方面发挥着关键作用 拟议的验证研究表明 BBB 损伤可能是因果关系。 特别是与压力引起的情绪障碍相关，我们将验证和扩展我们的理解。 在压力引起的情绪障碍中，压力如何影响 BBB 的区域依赖性损伤，如 我们的合作者 Scott Russo、Anne Schaefer 和 Miriam Merad 之前在他们的出版物中报道过 “社会压力会诱发神经血管病理，从而促进抑郁”。 小鼠心理压力模型，概括了 MDD 的许多症状，包括社交症状 退缩、快感缺乏和焦虑，我们将通过新颖的技术方法探索慢性 心理压力会损害血脑屏障，我们将利用一种新型的内皮特异性翻译。 核糖体亲和纯化（TRAP）小鼠探索应激诱导的转录模式 情绪相关的大脑区域以确定心理压力的转录组模式。 心理压力会损害 BBB，我们将利用创新的质谱流式细胞仪 (CyTOF) 来确定 易感小鼠与复原小鼠的外周和脑组织中的免疫细胞概况，并了解如何 心理压力会调动先天免疫系统，导致细胞因子渗入大脑。 总之，本次验证研究优异评审奖中的提案对于退伍军人健康非常重要。 该 VA 优异评审奖旨在验证我们的合作者最近的研究结果，表明心理 抑郁症模型中的压力会损害 BBB 通透性，并扩展我们对压力如何诱发的知识 区域特异性内皮基因表达变化，导致血管损伤和抑郁症相关 我们的研究结果将为新型的临床前研究提供证据。 治疗退伍军人与压力相关的抑郁症的治疗方法。