Zika virus infection of neural stem cells to model pathogen-induced microcephaly

寨卡病毒感染神经干细胞来模拟病原体诱导的小头畸形

• 批准号: 9266693
• 负责人: Stacy Michelle Horner
• 金额: $ 19.88万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266693
• 关键词: Address; Apoptosis; Behavior; Biological Assay; Biology; Brain; Brain Injuries; Cell Cycle; Cell Survival; Cell division; Cells; Cellular Assay; Centers for Disease Control and Prevention (U.S.); Cytomegalovirus; Data; Development; Diagnostic; Embryo; Epidemic; Flavivirus; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Growth; Hand; Health; Human; Image; Immunofluorescence Immunologic; Infection; Intellectual functioning disability; Knowledge; Life; Link; Messenger RNA; Methods; Methylation; Microcephaly; Mitosis; Modeling; Modification; Molecular; Molecular Profiling; Mus; Nervous system structure; Neurodevelopmental Disorder; Neuroglia; Neurons; Outcome; Pathogenesis; Phenotype; Population; Pregnancy; Production; Public Health; RNA; RNA Viruses; Satellite Viruses; Severities; Silver; Staging; Testing; Therapeutic; Transcript; Virus; Virus Activation; Virus Diseases; Virus Receptors; Zika Virus; brain size; cell type; fetal; mRNA Expression; mouse model; nerve stem cell; nervous system disorder; neuropathology; novel; pathogen; prevent; prospective; stem cell differentiation; stem cell division; transcriptome; viral RNA; virology

Zika virus (ZIKV) is an RNA virus of the flavivirus genus that is causing an emerging global epidemic. ZIKV infection has been strongly associated with neurological disorders, including congenital microcephaly, in which brain size is severely reduced. Moreover the CDC has recently concluded that ZIKV causes microcephaly. The severity of ZIKV-associated microcephaly is suggestive of an early insult to brain development. In human microcephalic brains, ZIKV RNA has been detected in neurons and prospective glia. In mouse models of ZIKV infection, virus has also been detected in these same populations. ZIKV has also been shown to infect neural stem cells impacting their growth and survival. During early stages of fetal brain development, neural stem cells produce neurons and shift to glia production as development proceeds. Neural stem cell dysfunction is thought to be an underlying cause for genetic forms of microcephaly. Altogether this suggests a potential mechanism to explain why ZIKV infects both neurons and glia. In this proposal we will test the hypothesis that ZIKV infection targets embryonic neural stem cells, altering their cellular behavior and transcriptome. Using a novel set of assays developed in our labs, we will pursue two aims. First, we will determine how ZIKV impacts neural stem cells including production of new viable progeny. Second we will define the host mRNAs dynamically regulated by ZIKV infection in neural stem cells. Upon completion, these aims will elucidate a fundamental understanding of ZIKV biology, particularly within the developing nervous system, essential information for beginning to control the ZIKV epidemic.

寨卡病毒（ZIKV）是一种黄病毒属的RNA病毒，正在引起一种新兴的全球流行病。ZIKV感染与神经系统疾病密切相关，包括先天性小头畸形，其中大脑尺寸严重缩小。此外，CDC最近得出结论，ZIKV导致小头畸形。ZIKV相关的小头畸形的严重程度提示对大脑发育的早期损害。在人类小头脑中，已经在神经元和预期神经胶质中检测到ZIKV RNA。在ZIKV感染的小鼠模型中，也在这些相同的群体中检测到病毒。ZIKV也被证明感染神经干细胞，影响它们的生长和存活。在胎儿大脑发育的早期阶段，神经干细胞产生神经元，并随着发育的进行而转变为神经胶质细胞。神经干细胞功能障碍被认为是遗传性小头畸形的潜在原因。总而言之，这表明了一种解释ZIKV感染神经元和神经胶质的潜在机制。在这项提案中，我们将测试ZIKV感染靶向胚胎神经干细胞，改变其细胞行为和转录组的假设。使用我们实验室开发的一套新的检测方法，我们将追求两个目标。首先，我们将确定ZIKV如何影响神经干细胞，包括产生新的有活力的后代。其次，我们将定义在神经干细胞中由ZIKV感染动态调节的宿主mRNA。完成后，这些目标将阐明对ZIKV生物学的基本理解，特别是在发育中的神经系统中，这是开始控制ZIKV流行病的重要信息。