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：
Andrew Atwell Oberst
金额：
$ 44.13万
依托单位：
UNIVERSITY OF WASHINGTON
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

来源：
https://reporter.nih.gov/project-details/10089217
关键词：
Address Adult Affect Animals Apoptosis Attention Biochemical Brain Injuries Cell Death Cells Cessation of life Cytomegalovirus DNA Viruses Dangerousness Data Defect Demyelinating Diseases Development Diagnosis Evolution Flavivirus Genetic Transcription Growth Health Host Defense Human Image Immune Immune response Impairment In Vitro Infection Inflammatory Influenza A virus Knockout Mice Lead Ligands Mass Spectrum Analysis Mediating Methods Modeling Motor Mus Nature Neuraxis Neuroglia Neurologic Neurons Organism Paralysed Pathology Pathway interactions Peripheral Phosphotransferases Physiological Population Production Protein Kinase RIPK1 gene Receptor Activation Research Role Signal Pathway Signal Transduction Simplexvirus Symptoms System Testing Tissues Transgenic Mice Transgenic Organisms Tropism Viral Virus Virus Diseases West Nile viral infection West Nile virus Wild Type Mouse Work ZIKV infection Zika Virus base cell suicide cell type chemokine experimental study global health imaging approach knockout animal mouse model nerve damage neuroinflammation neuropathology novel pathogen pathogenic virus prevent programs receptor expression receptor function recruit response small molecule trafficking

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.

坏死性是一种程序性细胞死亡的一种形式，通过激活受体相互作用而执行蛋白激酶（RIPK），RIPK1和RIPK3。虽然这种细胞死亡通路一直是强烈的主题研究，重要的生理环境仍然难以捉摸。我们发现老鼠缺乏 RIPK3非常容易受到神经活动西尼罗河病毒（WNV）的感染。 RIPK3 敲除动物无法控制中枢神经系统（CNS）内的病毒生长，因为它们在该组织中募集免疫细胞的募集中表现出严重的缺陷。值得注意的是，RIPK3缺陷小鼠也无法控制Zika病毒（ZIKV）感染，并显示神经系统障碍和上升瘫痪感染这种病原体。令人惊讶的是，RIPK3在这种情况下的保护作用是完全的独立于其在诱导程序性细胞死亡中的作用；相反，RIPK3是正常产生需要的 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。考虑到这些意外初步数据，该应用的中心假设是病毒诱导的RIPK3激活中枢神经系统不会触发细胞死亡，而是激活炎症转录程序用于神经炎症，免疫细胞募集和宿主保护。该应用程序将调查此事通过关注三个目标来假设。首先，我们将努力了解RIPK3如何在中枢神经系统中参与为了促进宿主保护，使用该组织中RIPK3的条件缺失和转基因表达结合最先进的成像方法。接下来，我们将使用生化方法和新型鼠标了解RIPK3的下游目标的模型，这些目标负责协调神经炎症。最后，我们将调查RIPK3在宿主保护免受ZIKV感染中的作用，以及研究在ZIKV感染的RIPK3基因敲除小鼠中观察到的运动功能的意外缺陷。这项工作将共同定义一个新的信号途径对全球健康构成重大威胁的病毒病原体。