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Investigating astrocytic RIPK3 as a driver of protective neuroinflammation during viral encephalitis

研究星形细胞 RIPK3 作为病毒性脑炎期间保护性神经炎症的驱动因素

基本信息

批准号：
10549809
负责人：
Brian Daniels
金额：
$ 38.27万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549809
关键词：
Apoptosis Astrocytes Biological Blood Vessels Brain Brain region Cell Death Cells Central Nervous System Central Nervous System Diseases Central Nervous System Infections Central Nervous System Viral Diseases Chemotactic Factors Complex Data Disease Elements Encephalitis Flavivirus Gene Expression Genetic Genetic Transcription Immune Immune signaling Impaired cognition Infection Infiltration Inflammation Inflammatory Intervention Kinetics Leukocytes Metabolic Molecular Molecular Biology Molecular Target Necrosis Nerve Degeneration Nervous System Trauma Neuroglia Neuroimmune Output Pathogenicity Pathologic Pathway interactions Process Protein Kinase Interaction Proteomics Publishing RIPK1 gene RIPK3 gene Receptor Activation Role Signal Transduction Signaling Molecule System Testing Time Transcript Viral Viral Encephalitis Viral Load result Viral Physiology Virus Diseases Virus Replication Work ZIKV infection Zika Virus cell type experimental study global health immune function immunopathology in vivo migration mouse genetics neural neuroinflammation neurotoxic neurotropic novel overexpression pathogen programs recruit therapeutic development tool transcriptomics

项目摘要

Abstract Astrocytes are versatile glial cells that regulate diverse processes in the central nervous system (CNS). Roles for astrocytes during disease are complex and include both protective and pathologic functions. Recently, distinct astrocyte activation states have been described, though the molecular mechanisms that govern astrocyte polarization during neurotropic viral infection are not well understood. Here, we propose that receptor-interacting protein kinase-3 (RIPK3) is a previously unappreciated driver of inflammatory astrocyte activation during viral infection of the CNS. While roles for RIPK3 in programmed cell death have been extensively characterized, our published work has described pleiotropic, cell death-independent functions for this pathway in the coordination of protective neuroinflammation during viral encephalitis. In preliminary studies, we now show that RIPK3 signaling in astrocytes is required for survival and virologic control following challenge with Zika virus, an emerging neurotropic pathogen of global concern. Using a combination of novel mouse genetic tools, we will elucidate roles for RIPK3 signaling in astrocytes by 1) Defining profiles of expression, activation, and antiviral function for astrocytic RIPK3; 2) Determining roles for astrocytic RIPK3 signaling in coordinating neuroinflammation; and 3) Defining key substrates and transcriptional outputs of RIPK3 signaling in astrocytes. Together, our studies promise to identify new molecular mechanisms governing protective neuroimmune function during viral encephalitis.

摘要星形胶质细胞是一种功能多样的神经胶质细胞，在中枢神经系统（CNS）中调节多种过程。星形胶质细胞在疾病中的作用是复杂的，包括保护和病理功能。最近，尽管控制星形胶质细胞的分子机制嗜神经性病毒感染期间的极化尚不清楚。在这里，我们提出受体相互作用蛋白激酶-3（RIPK 3）是病毒感染过程中炎性星形胶质细胞活化的一种以前未被认识的驱动因子， CNS感染。虽然RIPK 3在程序性细胞死亡中的作用已被广泛表征，但我们的研究表明，已发表的工作已经描述了该途径在协调中的多效性，细胞死亡独立功能病毒性脑炎时的保护性神经炎症在初步研究中，我们现在表明RIPK 3 星形胶质细胞中的信号传导是寨卡病毒攻击后存活和病毒学控制所必需的，全球关注的嗜神经性病原体使用一系列新颖的小鼠遗传工具，我们将阐明RIPK 3信号传导在星形胶质细胞中的作用，通过1）定义表达，激活和抗病毒 2）确定星形胶质细胞RIPK 3信号转导在协调细胞内信号转导中的作用; 神经炎症;和3）定义星形胶质细胞中RIPK 3信号传导的关键底物和转录输出。总之，我们的研究有望确定新的分子机制，管理保护性神经免疫功能在病毒性脑炎期间。