Complement system and suicidal behavior

补体系统与自杀行为

• 批准号: 9892445
• 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/9892445
• 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; Military Personnel; Modeling; Mus; Myeloid Cells; Pathway interactions; Peripheral; 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; accomplished suicide; adaptive immune response; arm; brain behavior; brain tissue; complement pathway; complement system; cytokine; depressive symptoms; design; experimental study; knockout gene; 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， 美国从1999年到2017年增长了33%。美国退伍军人有增加的风险 与一般人群相比，自杀率很高，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病 disorder.退伍军人的自杀意念通常与创伤后精神障碍（PTSD）或 抑郁症，往往共存的条件。此外，作为诱发抑郁症的一个根本因素， 慢性压力与自杀想法和行为有关。此外，有外伤史或 是导致创伤后应激障碍的一个非常重要的危险因素。在临床前模型中， 显示诱导行为模式的变化，可用于衡量自杀行为的各个方面， 例如冲动、攻击性和抑郁样行为。最近的证据表明，炎症， 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，迫切需要进行研究，以确定 免疫系统的自杀行为，以确定新的治疗目标。补体系统 是先天免疫的一部分，但也调节适应性免疫反应的许多方面。 补体可通过经典途径、凝集素途径或补体成分3的旁路途径激活 (C3)作为激活途径的汇聚点。我们最近的研究表明，C3在 慢性应激诱导的小鼠抑郁样行为。然而，尚不清楚慢性压力是否- 诱导的补体激活介导自杀行为。我们假设经典途径介导 应激诱导的补体激活导致自杀行为。为了支持这一点，我们的出版物和 初步研究发现，（1）C3和C1 qa（经典途径的关键组分）在 抑郁自杀者的前额叶皮层（PFC）; 2）暴露于慢性应激条件下， 小鼠PFC中C1 qa和C3蛋白水平增加;和（3）通过基因敲除（C3 KO）抑制C3 显著改善慢性应激诱导的攻击性和抑郁样行为， 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PTSD诊断）受试者; 2）研究补体经典途径是否对 应激诱导自杀行为;和3）确定是否中央补体系统介导应激- 诱发自杀行为。鉴于免疫途径在自杀行为中的重要作用， 调节机制可能为开发自杀行为的新疗法提供途径。