The Role of the RIP Kinases in Coordinating Neuroinflammation and Host Defense

RIP 激酶在协调神经炎症和宿主防御中的作用

基本信息

  • 批准号:
    10089217
  • 负责人:
  • 金额:
    $ 44.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-02-01 至 2023-01-31
  • 项目状态:
    已结题

项目摘要

Necroptosis is a form of programmed cell death that is executed by activation of the Receptor Interacting Protein Kinases (RIPKs), RIPK1 and RIPK3. While this cell death pathway has been the subject of intense study, physiological settings in which it is important have remained elusive. We have found that mice lacking RIPK3 are highly susceptible to infection by the neuroinvasive flavivirus West Nile virus (WNV). RIPK3 knockout animals are unable to control viral growth within the central nervous system (CNS), because they display a profound defect in the recruitment of immune cells into this tissue. Notably, RIPK3-deficient mice also fail to control Zika virus (ZIKV) infection, and display neurological impairments and ascending paralysis upon infection with this pathogen. Surprisingly, the protective role of RIPK3 in this setting is wholly independent of its role in inducing programmed cell death; rather, RIPK3 is required for normal production of inflammatory chemokines and immune cell trafficking in the WNV-infected CNS. Given these unexpected preliminary data, the central hypothesis of this application is that virus-induced RIPK3 activation within the CNS does not trigger cell death, but rather activates an inflammatory transcription program is required for neuroinflammation, immune cell recruitment, and host protection. This application will investigate this hypothesis by focusing on three Aims. First, we will work to understand how RIPK3 is engaged within the CNS to promote host protection, using conditional deletion and transgenic expression of RIPK3 within this tissue in combination with cutting-edge imaging approaches. Next, we will use biochemical methods and novel mouse models to understand the downstream targets of RIPK3 that are responsible for the coordination of neuroinflammation. Finally, we will investigate the role of RIPK3 in host protection against ZIKV infection, and investigate the unexpected defects in motor function observed in ZIKV-infected RIPK3 knockout mice. Together, this work will define a novel signaling pathway responsible for host defense against neuroinvasive viral pathogens that represent a significant threat to global health.
坏死性凋亡是程序性细胞死亡的一种形式,其通过激活受体相互作用蛋白来执行。 蛋白激酶(RIPK),RIPK 1和RIPK 3。虽然这种细胞死亡途径一直是激烈的主题, 研究中,生理环境中,它是重要的仍然难以捉摸。我们发现老鼠缺乏 RIPK 3对神经侵入性黄病毒西尼罗河病毒(WNV)的感染高度敏感。RIPK3 基因敲除动物不能控制中枢神经系统(CNS)内的病毒生长,因为它们 在免疫细胞进入这个组织的过程中表现出严重的缺陷。值得注意的是,RIPK 3缺陷小鼠 也无法控制寨卡病毒(ZIKV)感染,并显示神经损伤和上行性瘫痪 感染了这种病原体。令人惊讶的是,RIPK 3在这种情况下的保护作用完全是 独立于其在诱导程序性细胞死亡中的作用;相反,RIPK 3是正常生产细胞所必需的。 WNV感染的中枢神经系统中的炎症趋化因子和免疫细胞运输。鉴于这些意想不到的 根据初步数据,本申请的中心假设是,病毒诱导的RIPK 3在细胞内的激活是通过细胞内的细胞凋亡来实现的。 CNS不会触发细胞死亡,而是激活炎症转录程序是必需的。 用于神经炎症、免疫细胞募集和宿主保护。本应用程序将对此进行调查 假设,重点是三个目标。首先,我们将努力了解RIPK 3是如何参与CNS的 为了促进宿主保护,在该组织中使用RIPK 3的条件性缺失和转基因表达, 结合先进的成像方法。接下来,我们将使用生物化学方法和新型小鼠 模型,以了解RIPK 3的下游目标,负责协调 神经炎症最后,我们将研究RIPK 3在宿主保护免受ZIKV感染中的作用,并 研究在ZIKV感染的RIPK 3敲除小鼠中观察到的运动功能的意外缺陷。 总之,这项工作将确定一个新的信号通路负责宿主防御神经侵入性 病毒病原体对全球健康构成重大威胁。

项目成果

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Andrew Atwell Oberst其他文献

Andrew Atwell Oberst的其他文献

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{{ truncateString('Andrew Atwell Oberst', 18)}}的其他基金

"Survivor" neurons drive persistent inflammation following West Nile virus infection
西尼罗河病毒感染后,“幸存者”神经元驱动持续炎症
  • 批准号:
    10731043
  • 财政年份:
    2023
  • 资助金额:
    $ 44.13万
  • 项目类别:
Activation of inflammatory programmed cell death by SARS-CoV-2
SARS-CoV-2 激活炎症性程序性细胞死亡
  • 批准号:
    10615162
  • 财政年份:
    2022
  • 资助金额:
    $ 44.13万
  • 项目类别:
Activation of inflammatory programmed cell death by SARS-CoV-2
SARS-CoV-2 激活炎症性程序性细胞死亡
  • 批准号:
    10450286
  • 财政年份:
    2022
  • 资助金额:
    $ 44.13万
  • 项目类别:
ZBP1 activation
ZBP1激活
  • 批准号:
    10549766
  • 财政年份:
    2021
  • 资助金额:
    $ 44.13万
  • 项目类别:
Training in Cellular & Molecular Biology
蜂窝培训
  • 批准号:
    10427115
  • 财政年份:
    2021
  • 资助金额:
    $ 44.13万
  • 项目类别:
Training in Cellular & Molecular Biology
蜂窝培训
  • 批准号:
    10654830
  • 财政年份:
    2021
  • 资助金额:
    $ 44.13万
  • 项目类别:
ZBP1 activation
ZBP1激活
  • 批准号:
    10208144
  • 财政年份:
    2021
  • 资助金额:
    $ 44.13万
  • 项目类别:
Immune activation by necroptotic cell death
坏死性细胞死亡激活免疫
  • 批准号:
    10318967
  • 财政年份:
    2019
  • 资助金额:
    $ 44.13万
  • 项目类别:
Immune activation by necroptotic cell death
坏死性细胞死亡激活免疫
  • 批准号:
    10544990
  • 财政年份:
    2019
  • 资助金额:
    $ 44.13万
  • 项目类别:
The Role of the RIP Kinases in Coordinating Neuroinflammation and Host Defense
RIP 激酶在协调神经炎症和宿主防御中的作用
  • 批准号:
    10326792
  • 财政年份:
    2018
  • 资助金额:
    $ 44.13万
  • 项目类别:

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