Leveraging Established Fetal Primate Models to Expedite ZIKV Investigations

利用已建立的胎儿灵长类动物模型加快 ZIKV 研究

基本信息

批准号：
9543066
负责人：
Peter A Barry
金额：
$ 10.04万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9543066
关键词：
Address Apoptotic Architecture Biodistribution Brain Cell physiology Cells Cerebral cortex Classification Clinical Cortical Malformation Cytomegalovirus Data Development Disease Disease Outbreaks Ensure Fetal Development Fetal Growth Fetus Frequencies Genes Glial Cell Proliferation Goals Human Image Immunology Infection Inflammation Intervention Intraventricular Investigation Latin America Link Macaca mulatta Mediating Microglia Modeling Monitor Monkeys Neuroglia Neurons Newborn Infant Outcome Pathogenesis Pathogenicity Pathology Population Pregnancy Primates Protocols documentation Public Health Radial Reporting Research Resources Role Safety Teratogens Testing Tissues Ultrasonography Viral Virus Virus Diseases Zika Virus brain malformation congenital infection cytokine cytotoxic experience fetal immune activation in utero insight intraperitoneal model development nerve stem cell neural precursor cell neurodevelopment nonhuman primate novel therapeutic intervention novel vaccines primate development viral transmission virology

项目摘要

SUMMARY / ABSTRACT The outbreak of Zika virus (ZIKV) and the alarming rise in fetal brain malformations highlight ZIKV as an urgent public health concern. ZIKV has recently met Shephard's criteria for teratogenic classification because of the brain anomalies reported. This application addresses the direct relationship between ZIKV infection and fetal brain development using our established fetal primate model of intrauterine pathogenesis. The studies outlined in this application leverage our prior discoveries and collaborative investigations on neural precursor cell function in relation to microglia in the fetal primate brain, and our expertise in primate development, imaging, virology, and immunology. Our track record and experienced team provides the means to pursue the goals of this proposal—understanding the mechanism(s) of ZIKV teratogenesis—and the steps necessary to progress to studies focused on interventions. Our goal is to determine how ZIKV alters cortical development by capitalizing on our team's essential expertise and research experiences to address this urgent public health concern rapidly and effectively through the following Specific Aims: (1) Define the impact of fetal ZIKV on neural precursor cells and cortical development, and (2) Determine the impact of fetal ZIKV infection on fetal and maternal inflammation and assess if inflammation is predictive of abnormalities in cortical development. These studies will provide new insights into the underpinnings of ZIKV teratogenesis in a primate model with similar neurodevelopmental features when compared to humans, and by efficiently leveraging an existing primate model of fetal viral infection. Overall, these investigations focus on fetal developmental outcomes associated with direct ZIKV infection and will provide the necessary mechanistic understanding and outcome metrics to assess intervention strategies that protect the fetus and newborn from the devastating consequences of ZIKV infection and congenital disease.

摘要/摘要寨卡病毒 (ZIKV) 的爆发和胎儿脑畸形的惊人增加凸显了 ZIKV 的紧迫性由于寨卡病毒 (ZIKV) 引起的公共卫生问题，最近符合谢泼德 (Shephard) 的致畸分类标准。该应用程序解决了 ZIKV 感染与胎儿之间的直接关系。使用我们建立的胎儿灵长类动物子宫内发病机制模型来研究大脑发育。在此应用中，利用我们之前对神经前体细胞的发现和合作研究与胎儿灵长类动物大脑中小胶质细胞相关的功能，以及我们在灵长类动物发育、成像、我们的记录和经验丰富的团队提供了实现病毒学和免疫学目标的方法。该提案——了解 ZIKV 致畸机制——以及取得进展所需的步骤我们的目标是确定 ZIKV 如何通过干预来改变皮质发育。利用我们团队的重要专业知识和研究经验来解决这一紧迫的公共卫生问题通过以下具体目标快速有效地关注： (1) 明确胎儿寨卡病毒对神经前体细胞和皮质发育，以及（2）确定胎儿ZIKV感染对胎儿的影响和母体炎症，并评估炎症是否预示着皮质发育异常。这些研究将为灵长类动物模型中 ZIKV 致畸的基础提供新的见解与人类相比，并通过有效利用现有的神经发育特征，总体而言，这些研究重点是胎儿发育结果。与直接 ZIKV 感染相关，并将提供必要的机制理解和结果评估保护胎儿和新生儿免受毁灭性灾难的干预策略的指标 ZIKV 感染和先天性疾病的后果。