Leveraging Established Fetal Primate Models to Expedite ZIKV Investigations

总结/摘要 寨卡病毒（ZIKV）的爆发和胎儿脑畸形的惊人增加突出了ZIKV作为一种紧迫的 公共卫生问题。ZIKV最近符合Shephard的致畸性分类标准，因为ZIKV具有以下特征： 大脑异常本申请解决了ZIKV感染与胎儿发育之间的直接关系。 利用我们建立的胎儿灵长类动物宫内发病模型进行脑发育研究。研究概述 在本申请中，利用了我们先前对神经前体细胞发现和合作研究 与灵长类胎儿大脑中的小胶质细胞有关的功能，以及我们在灵长类发育，成像， 病毒学和免疫学。我们的业绩记录和经验丰富的团队提供了实现以下目标的手段： 这一提议-了解ZIKV致畸机制-以及取得进展所需的步骤 to studies研究focused集中on interventions干预.我们的目标是确定ZIKV如何通过以下方式改变皮质发育： 利用我们团队的基本专业知识和研究经验来解决这一紧迫的公共卫生问题 通过以下具体目的快速有效地关注：（1）定义胎儿ZIKV对胎儿的影响。 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皮质发育异常。 这些研究将为ZIKV致畸作用在灵长类动物模型中的基础提供新的见解， 与人类相比，类似的神经发育特征，并通过有效地利用现有的 胎儿病毒感染的灵长类动物模型。总的来说，这些调查集中在胎儿发育的结果 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破坏性疾病的干预策略的指标 ZIKV感染和先天性疾病的后果。

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.