Chronic stress, complement immune system and behavior
Chronic stress, complement immune system and behavior
批准号:
10396335
负责人:
Anilkumar Pillai
金额:
$18.7万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-09-23 至 2022-06-30
中文摘要
慢性压力是多种精神疾病发展的重要危险因素,
现有的治疗方法是不够的。慢性压力也会引起炎症升高,
然而,人类和动物模型中的炎症反应,
行为异常的原因还不太清楚我们假设慢性压力引起的行为
外周干扰素-α(IFN-α)介导的小胶质细胞活化和补体-
在涉及认知、情绪和社会行为的大脑区域中的依赖性突触损失。最近的研究
这表明补体依赖性途径和介导突触消除的小胶质细胞
在一些疾病状况中,包括精神障碍,发育被不适当地激活。
补体成分3(C3)是所有补体激活途径的枢纽,C3及其受体,
C3 aR 1介导各种疾病状况的小鼠模型中的突触丧失。我们最近的研究发现,C3
在慢性不可预测的应激(CUS)后,小鼠的前额叶皮层(PFC)中的表达增加,
抑郁症自杀者的研究此外,C3 aR 1缺陷改善了小鼠的抑郁样表型
暴露于CUS。此外,最近的研究表明,外周IFN-α在小胶质细胞介导的
炎性疾病条件下的突触损失。据报道,血液中IFN-α表达增加
长期IFN-α治疗经常引发各种神经精神疾病,
症状我们的初步研究发现,IFN-α mRNA水平在脾脏中显著增加,但在
暴露于CUS的小鼠的mPFC。此外,用抗IFN-α受体(IFNAR)抗体治疗小鼠,
压力引起的社交缺陷和抑郁样行为。这些意见提出了重要的问题。
因为C3 aR 1在小胶质细胞和单核细胞/巨噬细胞(Mo/MFs)中表达,所以不知道C3 aR 1是否在小胶质细胞和单核细胞/巨噬细胞中表达。
小胶质细胞或Mo/MFs中的C3 aR 1对于慢性应激诱导的突触丧失和行为效应至关重要。
虽然抗IFNAR治疗具有保护作用,但外周IFN-α是否激活IFN-α受体尚不清楚。
小胶质细胞和补体系统促进突触丢失和行为改变,
应力条件在这个探索性的应用程序中,我们将在以下两个具体的
目标。使用条件突变小鼠,Aim 1将检验小胶质细胞C3 aR 1介导慢性炎症的假设。
压力引起的突触丧失和行为异常。使用抗IFNAR抗体和IFNAR 1 −/−嵌合体
目的2将检验在慢性应激下增加的I型IFN信号传导促进小胶质细胞增殖的假设。
激活、补体激活、突触丢失和行为异常。如果成功,我们的项目将
在理解外周炎症和应激诱导的炎症之间的联系途径方面取得了新的进展,
行为异常,从而允许开发新的治疗策略,包括
基于补体的抑制剂或抗体策略在压力相关的心理健康障碍。
英文摘要
Chronic stress is an important risk factor for the development of multiple psychiatric disorders for which
existing therapies are inadequate. Chronic stress can also provoke elevated inflammation and exaggerated
inflammatory responses in both humans and animal models, however, the mechanisms that link inflammation
to behavioral abnormalities are not well understood. We hypothesize that chronic stress-induced behavioral
changes result from peripheral interferon alpha (IFN-α)-mediated microglia activation and complement-
dependent synaptic loss in brain regions involved in cognition, mood and social behavior. Recent studies
indicate that the complement-dependent pathway and microglia that mediate synapse elimination in
development are inappropriately activated in some disease conditions including psychiatric disorders.
Complement component 3 (C3) is the hub of all complement activation pathways, and C3 and its receptor,
C3aR1 mediate synapse loss in mouse models of various disease conditions. Our recent study found that C3
expression is increased in the prefrontal cortex (PFC) of mice following chronic unpredictable stress (CUS) and
in depressed suicide subjects. Also, C3aR1 deficiency improved the depression-like phenotype in mice
exposed to CUS. Further, recent studies indicate an important role of peripheral IFN-α in microglia-mediated
synaptic loss in inflammatory disease conditions. Increased IFN-α expression has been reported in the blood
of depressed subjects, and long-term IFN-α treatment frequently triggers a variety of neuropsychiatric
symptoms. Our preliminary studies found a significant increase in IFN-α mRNA levels in the spleen, but not in
mPFC of mice exposed to CUS. Also, treatment of mice with anti-IFN-α receptor (IFNAR) antibody attenuated
stress-induced social deficits and depressive-like behavior. These observations raise important questions.
Because C3aR1 is expressed in microglia and monocytes/macrophages (Mo/MFs), it is not known whether
C3aR1 in microglia or Mo/MFs is critical for chronic stress-induced effects on synapse loss and behavior.
Although treatment with anti-IFNAR was protective, it is not known whether peripheral IFN-α activates
microglia and the complement system to promote synaptic loss and behavioral changes observed in chronic
stress conditions. In this exploratory application, we will address these questions in the following two specific
aims. Using conditional mutant mice, Aim 1 will test the hypothesis that microglial C3aR1 mediates chronic
stress-induced synapse loss and behavioral abnormalities. Using anti-IFNAR antibody and IFNAR1−/− chimera
mice, Aim 2 will test the hypothesis that increased type I IFN signaling under chronic stress promotes microglia
activation, complement activation, synaptic loss and behavioral abnormalities. If successful, our project will
create new developments in understanding the pathways linking peripheral inflammation and stress-induced
behavioral abnormalities, and thereby allow the development of novel strategies for treatment, including
complement-based inhibitors or antibody strategies in stress-related mental health disorders.
期刊论文(9)
专著(0)
科研奖励(0)
会议论文
登录
查看更多内容
DOI:
10.1038/s41380-023-02189-7
发表时间:
2023-09
期刊:
MOLECULAR PSYCHIATRY
影响因子:
11
作者:
[Tripathi, Ashutosh, Bartosh, Alona, Whitehead, Carl, Pillai, Anilkumar]
通讯作者:
Pillai, Anilkumar
DOI:
10.1038/s41380-021-01065-6
发表时间:
2021-07
期刊:
Molecular psychiatry
影响因子:
11
作者:
[Tripathi A, Whitehead C, Surrao K, Pillai A, Madeshiya A, Li Y, Khodadadi H, Ahmed AO, Turecki G, Baban B, Pillai A]
通讯作者:
Pillai A
DOI:
10.1016/j.mito.2021.08.016
发表时间:
2021-11
期刊:
Mitochondrion
影响因子:
4.4
作者:
[Tripathi A, Scaini G, Barichello T, Quevedo J, Pillai A]
通讯作者:
Pillai A
DOI:
10.1038/s41398-022-01794-4
发表时间:
2022-02-01
期刊:
Translational psychiatry
影响因子:
6.8
作者:
[Madeshiya AK, Whitehead C, Tripathi A, Pillai A]
通讯作者:
Pillai A
DOI:
10.1007/s40473-020-00207-4
发表时间:
2020-09
期刊:
Current behavioral neuroscience reports
影响因子:
1.7
作者:
[Feng T, Tripathi A, Pillai A]
通讯作者:
Pillai A
Mitochondrial DNA, chronic stress, and inflammation
-
批准号:10664066
-
项目类别:
-
资助金额:$44.57万
-
财政年份:2022
-
负责人:Anilkumar Pillai
-
依托单位:
Complement system and suicidal behavior
-
批准号:10553166
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Anilkumar Pillai
-
依托单位:
Complement system and suicidal behavior
-
批准号:10078543
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Anilkumar Pillai
-
依托单位:
Complement system and suicidal behavior
-
批准号:10438527
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Anilkumar Pillai
-
依托单位:
Complement system and suicidal behavior
-
批准号:9892445
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Anilkumar Pillai
-
依托单位:
Complement Component, Neuroinflammation and Depression
-
批准号:10462803
-
项目类别:
-
资助金额:$38.7万
-
财政年份:2019
-
负责人:Anilkumar Pillai
-
依托单位:
Complement Component, Neuroinflammation and Depression
-
批准号:10670822
-
项目类别:
-
资助金额:$38.42万
-
财政年份:2019
-
负责人:Anilkumar Pillai
-
依托单位:
Complement component, neuroinflammation and depression
-
批准号:9914544
-
项目类别:
-
资助金额:$38.71万
-
财政年份:2019
-
负责人:Anilkumar Pillai
-
依托单位:
Chronic stress, complement immune system and behavior
-
批准号:9905204
-
项目类别:
-
资助金额:$19.09万
-
财政年份:2019
-
负责人:Anilkumar Pillai
-
依托单位:
Complement component, neuroinflammation and depression
-
批准号:10021717
-
项目类别:
-
资助金额:$38.21万
-
财政年份:2019
-
负责人:Anilkumar Pillai
-
依托单位:
Chronic stress, complement immune system and behavior
-
批准号:10021726
-
项目类别:
-
资助金额:$4.64万
-
财政年份:2019
-
负责人:Anilkumar Pillai
-
依托单位:
Complement Component, Neuroinflammation and Depression
-
批准号:10402977
-
项目类别:
-
资助金额:$39.54万
-
财政年份:2019
-
负责人:Anilkumar Pillai
-
依托单位:
Regulation of TrkB signaling by 5-HT: role of transglutaminase 2
-
批准号:8399992
-
项目类别:
-
资助金额:$28.5万
-
财政年份:2012
-
负责人:Anilkumar Pillai
-
依托单位:
Regulation of TrkB signaling by 5-HT: role of transglutaminase 2
-
批准号:8703795
-
项目类别:
-
资助金额:$29.5万
-
财政年份:2012
-
负责人:Anilkumar Pillai
-
依托单位:
Regulation of TrkB signaling by 5-HT: role of transglutaminase 2
-
批准号:8890227
-
项目类别:
-
资助金额:$30.0万
-
财政年份:2012
-
负责人:Anilkumar Pillai
-
依托单位:
Regulation of TrkB signaling by 5-HT: role of transglutaminase 2
-
批准号:8516115
-
项目类别:
-
资助金额:$27.74万
-
财政年份:2012
-
负责人:Anilkumar Pillai
-
依托单位:
Regulation of TrkB signaling by 5-HT: role of transglutaminase 2
-
批准号:9119128
-
项目类别:
-
资助金额:$30.0万
-
财政年份:2012
-
负责人:Anilkumar Pillai
-
依托单位:
BDNF/TrkB: a possible therapeutic target for schizophrenia
-
批准号:8005040
-
项目类别:
-
资助金额:$7.35万
-
财政年份:2010
-
负责人:Anilkumar Pillai
-
依托单位:
Glucocorticoid-induced TrkB receptor regulation by ubiquitination
-
批准号:8089576
-
项目类别:
-
资助金额:$18.07万
-
财政年份:2010
-
负责人:Anilkumar Pillai
-
依托单位:
BDNF/TrkB: a possible therapeutic target for schizophrenia
-
批准号:7790032
-
项目类别:
-
资助金额:$7.35万
-
财政年份:2010
-
负责人:Anilkumar Pillai
-
依托单位:
国内基金
海外基金
登录
查看更多内容
Tmem30a通过ER Stress/NF-κB信号通路调节肠上皮细胞屏障功能稳态介导炎症性肠病的研究
-
批准号:82300629
-
项目类别:青年科学基金项目
-
资助金额:30万元
-
批准年份:2023
-
负责人:彭坤
-
依托单位:
生理/病理应激差异化调控肝再生的“蓝斑—中缝”神经环路机制
-
批准号:82371517
-
项目类别:面上项目
-
资助金额:49.00万元
-
批准年份:2023
-
负责人:杨立群
-
依托单位:
槲皮素控释系统调控Mettl3/Per1修复氧化应激损伤促牙周炎骨再生及机制研究
-
批准号:82370921
-
项目类别:面上项目
-
资助金额:48.00万元
-
批准年份:2023
-
负责人:徐袁瑾
-
依托单位:
Sestrin2抑制内质网应激对早产儿视网膜病变的调控作用及其机制研究
-
批准号:82371070
-
项目类别:面上项目
-
资助金额:49.00万元
-
批准年份:2023
-
负责人:赵培泉
-
依托单位:
组蛋白乙酰化修饰ATG13激活自噬在牵张应力介导骨缝Gli1+干细胞成骨中的机制研究
-
批准号:82370988
-
项目类别:面上项目
-
资助金额:48.00万元
-
批准年份:2023
-
负责人:经典
-
依托单位:
二甲双胍抗肥胖新机制:调节小胶质细胞ER stress-EVs缓解下丘脑炎症
-
批准号:--
-
项目类别:青年科学基金项目
-
资助金额:30万元
-
批准年份:2022
-
负责人:李璇
-
依托单位:
肿瘤相关巨噬细胞通过Stress Granule 形成调控炎症小体促进舌鳞癌转移的机制研究
-
批准号:
-
项目类别:省市级项目
-
资助金额:10.0万元
-
批准年份:2021
-
负责人:王友元
-
依托单位:
雄性线虫特异分泌蛋白F56D2.8调节衰老与寿命的机制研究
-
批准号:32100604
-
项目类别:青年科学基金项目(C类)
-
资助金额:30.0万元
-
批准年份:2021
-
负责人:龚健科
-
依托单位:
炎症相关因子 RKIP 通过活化 ER stress 相关的IRE1α/XBP1 信号轴调控肝脏疾病的机制研究
-
批准号:LY22H030007
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2021
-
负责人:赵杰
-
依托单位:
ACSL4/ER stress/GPX4通路在溃疡性结肠炎中对Ferroptosis的调控机制研究
-
批准号:82100558
-
项目类别:青年科学基金项目(C类)
-
资助金额:30.0万元
-
批准年份:2021
-
负责人:徐敏仪
-
依托单位: