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.
坏死坏死是一种程序性细胞死亡的形式,是通过受体相互作用的激活来执行的

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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