Role of microglia in neural infection

小胶质细胞在神经感染中的作用

基本信息

批准号：
10391023
负责人：
Tian Wang
金额：
$ 51.61万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10391023
关键词：
Abbreviations Affect Animal Model B-Cell Activation Biochemical Genetics Biological Assay Brain Cell Death Cell model Cells Collaborations Data Development Disease Outbreaks Embryo Endoplasmic Reticulum Enhancers Equus caballus Fetal Growth Retardation Fetus Flavivirus Goals Growth Human IRF3 gene Immune Immunology Impairment In Vitro Incidence Infection Inflammatory Interferon-beta Knock-out Knockout Mice Lead Light MAP Kinase Gene Mediating Microcephaly Microglia Mitogen-Activated Protein Kinases Molecular Mothers Mus Myelogenous Neuraxis Neurons Neurosciences Newborn Infant Nuclear Outcome Outcome Study Play Polymerase Chain Reaction Prevention Prevention strategy Production Protein-Serine-Threonine Kinases RIPK1 gene Reporting Role Source Syndrome TLR3 gene TLR7 gene TLR8 gene TNF Receptor-Associated Factors TRAF6 gene Testing Time Transcription Factor AP-1 Ubiquitin Vertical Disease Transmission Viral Virus Virus Diseases Yolk Cell Yolk Sac ZIKV infection Zika Virus base brain cell conditional knockout congenital zika syndrome cytokine fetal genetic manipulation human embryonic stem cell in vivo infection rate inhibitor-of-apoptosis protein innovation knock-down nerve stem cell neurogenesis progenitor receptor relating to nervous system response stem stem cell function stem cells teratogenesis treatment strategy ubiquitin-protein ligase viral transmission

项目摘要

ABSTRACT Zika virus (ZIKV) infection is associated with congenital ZIKV syndrome (CZS), including various brain anomalies and microcephaly. Our recent studies suggested that yolk sac (YS)-derived microglia (primary immune cells in the brain) and Peli1 (an E3 ubiquitin ligase) are involved in ZIKV infection and its associated CZS. However, it is unknown whether and how Peli1 contributes to the YS-microglia-mediated spread of ZIKV into brain, whether viral infection affects the normal function of microglia, and how such effects influence neural differentiation. Based on preliminary data, we hypothesize that Peli1 plays a critical role in fetal brain ZIKV infection via promoting YS-microglia-mediated ZIKV dissemination into fetal brain and via altering microglial function to affect neural differentiation. This hypothesis will be tested by two specific aims: 1) to determine how Peli1 promotes ZIKV infection of YS-microglia and virus dissemination from microglia to neural stem cells in fetal brains; and 2) to determine how Peli1 mediates microglial activation and alters neural differentiation after ZIKV infection. This integrative study employs biochemical and genetic manipulations in both in vivo animal models and in vitro mouse and human cell platforms. The outcomes will be evaluated by molecular, cellular, and neuroanatomical analyses. Understanding the molecular mechanisms underlying the role of microglia in ZIKV-related brain infection may lead to identification of new targets for prevention and treatment of ZIKV and other virus-mediated congenital neural infections.

抽象的 Zika病毒（ZIKV）感染与先天性ZIKV综合征（CZ）有关，包括各种大脑异常和小头畸形。我们最近的研究表明，蛋黄囊（Ys）衍生的小胶质细胞（原代免疫细胞中的原发性免疫细胞大脑）和PELI1（E3泛素连接酶）参与ZIKV感染及其相关的CZ。但是，它尚不清楚PELI1是否以及如何促进ZIKV介导的YS-Microglia介导的扩散到大脑病毒感染会影响小胶质细胞的正常功能，以及这种影响如何影响神经分化。根据初步数据，我们假设PELI1通过促进YS-Microglia介导的ZIKV传播到胎儿大脑中，并通过改变小胶质功能以影响神经分化。该假设将通过两个具体目的测试：1）确定PELI1如何促进在胎儿大脑中从小胶质细胞到神经干细胞的YS-微神经和病毒传播的ZIKV感染；和2）确定PELI1如何介导小胶质细胞激活并改变ZIKV感染后的神经分化。这综合研究在体内动物模型和体外都采用生化和遗传操作鼠标和人类细胞平台。结果将通过分子，细胞和神经解剖学评估分析。了解小胶质细胞在ZIKV相关大脑中的作用的分子机制感染可能导致鉴定出用于预防和治疗ZIKV和其他病毒介导的新靶先天性神经感染。