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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：
10549739
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/10549739
关键词：
Abbreviations Affect Animal Model B-Cell Activation Biochemical Biological Assay Brain Cell Death Cell model Cells Central Nervous System Collaborations Data Development Disease Outbreaks Embryo Embryonic Development 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 Light MAP Kinase Gene Mediating Microcephaly Microglia Mitogen-Activated Protein Kinases Molecular Mothers Mus Myelogenous Neuroanatomy Neurons Neurosciences Newborn Infant Nuclear Outcome Outcome Study Play Polymerase Chain Reaction Prevention Prevention strategy Production Productivity 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 Transmission Viral Virus Virus Diseases Yolk Sac ZIKV infection Zika Virus brain cell conditional knockout congenital zika syndrome cytokine fetal genetic manipulation glial activation human embryonic stem cell in vivo infection rate inhibitor-of-apoptosis protein innovation knock-down nerve stem cell neural neurogenesis novel therapeutic intervention progenitor receptor response stem cell function teratogenesis transmission process ubiquitin-protein ligase

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.

抽象的寨卡病毒 (ZIKV) 感染与先天性 ZIKV 综合征 (CZS) 相关，包括各种脑部异常和小头畸形。我们最近的研究表明，卵黄囊 (YS) 衍生的小胶质细胞（初级免疫细胞）大脑）和 Peli1（一种 E3 泛素连接酶）参与 ZIKV 感染及其相关的 CZS。然而，它目前尚不清楚 Peli1 是否以及如何促进 YS-小胶质细胞介导的 ZIKV 传播到大脑中，是否病毒感染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 通过以下方式在胎儿脑 ZIKV 感染中发挥关键作用：促进 YS 小胶质细胞介导的 ZIKV 传播到胎儿大脑中，并通过改变小胶质细胞功能来影响神经分化。该假设将通过两个具体目标进行检验：1）确定 Peli1 如何促进 YS-小胶质细胞的 ZIKV 感染以及病毒从小胶质细胞传播到胎儿大脑中的神经干细胞；和 2) 确定 Peli1 在 ZIKV 感染后如何介导小胶质细胞激活并改变神经分化。这综合研究在体内和体外动物模型中采用生化和遗传操作小鼠和人类细胞平台。结果将通过分子、细胞和神经解剖学进行评估分析。了解小胶质细胞在 ZIKV 相关大脑中作用的分子机制感染可能导致确定预防和治疗 ZIKV 和其他病毒介导的新靶点先天性神经感染。