Quantitative neuroanatomical analyses of Zika-exposed macaque brains

项目摘要/摘要 虽然胎儿ZIKV感染的破坏性神经后果(例如小头畸形)是显而易见的，但神经 创造这些结果的机制尚不清楚。来自人类细胞系和小鼠的研究积累 提示ZIKV感染神经前体细胞的能力可能是一种机制，但这些 在整个有机体和灵长类动物(包括人类)的大脑中，过程影响神经解剖学是未知的。 这项拟议的工作是理解ZIKV如何通过以下方式扰乱大脑结构和功能的第一步 对感染或暴露于非人类灵长类动物的大脑进行全脑神经解剖学分析 敬ZIKV。我们利用已经存在的由NIH资助的资源--大脑和其他生物 暴露于ZIKV或感染ZIKV的恒河猴样本，这是正在进行的确定 恒河猴作为人寨卡病毒感染模型及寨卡病毒疫苗试验。我们将量化 神经元、神经胶质细胞和分裂细胞的数量、密度和细胞大小 在胎儿发育的不同时期暴露或感染ZIKV的猕猴皮质下区域 成人期。拟议工作的总体目标是发展对如何安排时间的理解 寨卡病毒感染与寨卡病毒发展和继发临床表现的关系 症状(发烧、体重减轻)和病毒血症(感染程度、活跃感染时间)会影响中断 正常的中枢神经系统神经解剖学。

Project Summary/Abstract While the devastating neural consequences (e.g., microcephaly) of fetal ZIKV infection are clear, the neural mechanisms that create those outcomes are not clear. Accumulating research from human cell lines and mice suggest that ZIKV's ability to infect neural progenitors may be one mechanism, but the extent to which these processes impact neuroanatomy in whole organisms and in primate (including human) brains are unknown. The proposed work takes the first step in understanding how ZIKV disrupts brain structure and function by performing whole-brain neuroanatomical analyses on brains from nonhuman primates infected with or exposed to ZIKV. We capitalize upon an already existing NIH-funded resource – the brains and other biological samples from rhesus macaques exposed to or infected with ZIKV as part of ongoing work establishing the rhesus macaque as a model for human ZIKV infection and testing vaccines for ZIKV. We will quantify the number, density, and cell size of neurons, glia, and dividing cells in a number of representative cortical and subcortical areas in macaques exposed to or infected with ZIKV at various times of fetal development or in adulthood. The overarching goal of the proposed work is to develop an understanding of how the timing of ZIKV infection relative to development and subsequent manifestation of ZIKV both in terms of clinical symptoms (fever, weight loss) and viremia (magnitude of infection, time of active infection) influence disruption of normal central nervous system neuroanatomy.