Complement system and suicidal behavior

补体系统和自杀行为

• 批准号: 10438527
• 负责人: Anilkumar Pillai
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438527
• 关键词: Address; Animal Model; Antidepressive Agents; Area; Attenuated; Autopsy; Behavior; Behavioral Paradigm; Bone Marrow; Brain; Cessation of life; Chimera organism; Chronic; Chronic stress; Classical Complement Pathway; Complement; Complement 3; Complement Activation; Complement Factor H; Complement Inactivators; Confounding Factors (Epidemiology); Data; Depressed mood; Diagnosis; Disease; Exposure to; Feeling suicidal; Functional disorder; General Population; Goals; Human; Immune; Immune system; Immunity; Impulsivity; Individual; Infiltration; Inflammation; Inflammatory; Learned Helplessness; Lectin; Measures; Mediating; Mental Depression; Mental disorders; Messenger RNA; Microglia; Modeling; Mus; Myeloid Cells; Pathway interactions; Peripheral; Persons; Pharmaceutical Preparations; Pre-Clinical Model; Prefrontal Cortex; Proteins; Publishing; Recording of previous events; Regulation; Reporting; Risk Factors; Role; Stress; Substance of Abuse; Suicide; Therapeutic; Therapeutic Agents; United States; Veterans; War; adaptive immune response; arm; brain behavior; brain tissue; complement pathway; complement system; completed suicide; cytokine; depressive symptoms; design; experimental study; knockout gene; military veteran; monocyte; mouse model; new therapeutic target; novel; novel therapeutics; prevent; recruit; suicidal behavior; suicidal risk; suicide brain; suicide rate; trauma exposure

Approximately 800,000 people die from suicide each year and the recent data show that the suicide rate in the United States has increased 33% from 1999 to 2017. United States military veterans have an increased risk of suicide compared with the general population, and approximately 18 to 22 veterans die from suicide each day. It has been reported that up to 90% of individuals who complete suicide have an underlying psychiatric disorder. Suicidal ideation in war veterans is often associated with post-traumatic disorder (PTSD) or depression, conditions that often coexist. In addition, as a fundamental factor in the provocation of depression, chronic stress is associated with suicidal thoughts and behaviors. Also, a history of prior exposure to trauma or to chronic stress is an extremely potent risk factor for PTSD. In preclinical models, chronic stress has been shown to induce changes in behavioral paradigms that can be used to measure aspects of suicidal behavior such as impulsive, aggressive, and depressive-like behaviors. Recent evidence indicate that inflammation, as manifested by increased levels of pro‐inflammatory cytokines, contributes to the pathophysiology of suicidality. However, there is a critical need for studies that are designed to determine the role of specific components of the immune system in suicidal behavior in order to identify novel therapeutic targets. The complement system is part of the innate arm of immunity, but also regulates many aspects of the adaptive immune response. Complement can be activated via the classical, lectin or alternative pathway with complement component 3 (C3) as the converging point of the activation pathways. Our recent study showed an important role of C3 in chronic stress-induced depressive-like behavior in mice. However, it is not known whether chronic stress- induced complement activation mediates suicidal behavior. We hypothesize that classical pathway mediates stress-induced complement activation leading to suicidal behavior. In supporting this, our published and preliminary studies found that (1) C3 and C1qa (a key component of classical pathway) are highly expressed in the prefrontal cortex (PFC) of depressed suicide subjects; 2) exposure to chronic stress conditions induces increases in C1qa and C3 protein levels in mouse PFC; and (3) inhibition of C3 by gene knockout (C3 KO) significantly ameliorated chronic stress-induced aggressive and depressive-like behavior, and infiltration of monocytes into mouse PFC. To further understand the role of complement activation in suicidal behavior, we propose the three Specific Aims to 1) determine the role of complement activation pathway in suicide (with depression or PTSD diagnosis) subjects; 2) investigate whether complement classical pathway is critical to stress-induced suicidal behavior; and 3) determine whether central complement system mediates stress- induced suicidal behavior. Given the important role of immune pathways in suicidal behavior, identifying novel regulatory mechanisms may provide avenues to develop newer therapeutics for suicidal behavior.

每年约有80万人死于自杀，最近的数据显示，美国的自杀率 从1999年到2017年，美国增长了33%。美国退伍军人患癌症的风险增加 与一般人口相比，自杀人数最多，每天约有18至22名退伍军人死于自杀。 据报道，高达90%的自杀者有潜在的精神疾病 无序。退伍军人的自杀意念通常与创伤后精神障碍(PTSD)或 抑郁症，通常并存的情况。此外，作为引发抑郁症的一个基本因素， 慢性压力与自杀念头和行为有关。此外，以前接触过创伤或 慢性压力是导致创伤后应激障碍的一个极其重要的风险因素。在临床前模型中，慢性应激一直是 显示导致可用于测量自杀行为方面的行为范例的变化 例如冲动、攻击性和类似抑郁的行为。最近的证据表明，炎症，如 表现为促炎细胞因子水平的增加，有助于自杀的病理生理学。 然而，迫切需要研究旨在确定特定成分的作用 免疫系统在自杀行为中的作用，以确定新的治疗靶点。补充性系统 是先天免疫手臂的一部分，也调节着获得性免疫反应的许多方面。 补体可以通过经典的、凝集素或补体成分3的替代途径被激活 (C3)作为激活途径的聚合点。我们最近的研究表明，补体C3在 慢性应激诱导的小鼠抑郁样行为。然而，目前还不知道慢性压力是否- 诱导的补体激活介导自杀行为。我们假设经典通路通过 应激诱导的补体激活导致自杀行为。为了支持这一点，我们出版的和 初步研究发现：(1)C3和C1qa(经典途径的关键成分)在 抑郁症自杀者的前额叶皮质(PFC)；2)暴露在慢性应激条件下 小鼠PFC中C1qA和C3蛋白水平的增加；以及(3)基因敲除(C3KO)对C3的抑制 显著改善慢性应激诱导的攻击性和抑郁样行为，以及 将单核细胞转化为小鼠PFC。为了进一步了解补体激活在自杀行为中的作用，我们 提出三个具体目标：1)确定补体激活途径在自杀中的作用 抑郁症或创伤后应激障碍诊断)受试者；2)调查补体经典途径是否对 应激诱导的自杀行为；以及3)确定中枢补体系统是否介导应激- 诱发自杀行为。鉴于免疫途径在自杀行为中的重要作用，识别新的 调节机制可能为开发新的自杀行为疗法提供途径。