Early neural predictors and neuropathogenesis of sensorimotor neurodevelopmental deficits in macaque infants exposed to Zika virus in utero

子宫内暴露于寨卡病毒的猕猴婴儿感觉运动神经发育缺陷的早期神经预测因子和神经发病机制

• 批准号: 10031105
• 负责人: Karla Kaye Ausderau
• 金额: $ 78.98万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10031105
• 关键词: Affect; Age; Age-Months; American; Auditory; Behavior assessment; Birth; Brain; Brain Pathology; Brain imaging; Brain region; Cell Nucleus; Cerebral Palsy; Child; Childhood; Clinical Research; Clinical Trials; Cohort Studies; Congenital Abnormality; Controlled Study; Data; Development; Disease; Early Intervention; Early identification; Electrophysiology (science); Enrollment; Epidemic; Exposure to; Fetus; Funding; Future; Grant; Hearing; Heterogeneity; Histopathology; Human; Individual Differences; Infant; Infection Control; Intervention; Investigation; Life; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Modeling; Motor; Multiple Birth Offspring; Neurodevelopmental Deficit; Neuropathogenesis; Outcome; Pathogenesis; Pathway interactions; Phenotype; Pregnant Women; Primates; Research; Retina; Risk; Sensory; Structure; Symptoms; Testing; Time; United States National Institutes of Health; Virus; Vision; Visual; Wisconsin; ZIKV infection; Zika Virus; base; behavioral outcome; brain abnormalities; brain stem auditory evoked potentials; cohort; congenital zika syndrome; design; early childhood; functional outcomes; hearing impairment; in utero; individual variation; infancy; longitudinal design; motor disorder; neonate; neurodevelopment; neurogenesis; neuropathology; prenatal; prenatal exposure; relating to nervous system; unborn child

PROJECT SUMMARY Prenatal exposure to the Zika virus (ZIKV) poses a threat to the fetus, putting the neonate at risk for significant birth defects (termed congenital Zika syndrome) and neurodevelopmental deficits developing during early child- hood. There are currently no predictors to indicate which children will develop deficits and the neuropathologies underlying these deficits is not defined. It is critical to predict which infants will later develop deficits to max- imize long-term sensorimotor development and functional outcomes. Furthermore, understanding underlying neuropathogenesis is necessary to develop targeted interventions. The purpose of this grant is to define the long-term neurodevelopmental outcomes of ZIKV by rapidly obtaining data from highly controlled studies of rhesus macaques. Specifically, we will: Aim 1: Characterize sensorimotor neurodevelopmental outcomes in macaques with prenatal ZIKV expo- sure. Behavioral assessments focused on sensorimotor development may highlight the distinct developmental trajectories and increased deficits with age in ZIKV-exposed rhesus macaques. Because macaques develop more quickly than humans, sensorimotor neurodevelopmental differences that occur by year 3 may predict future impacts in children born with prenatal ZIKV exposure. Aim 2: Identify early neural predictors of sensorimotor neurodevelopmental deficits in ZIKV-exposed infant macaques with quantitative MRI, hearing and visual studies. We will describe differences between ZIKV-exposed and mock-infection control infants and identify individual differences within ZIKV-exposed in- fants to determine the full spectrum of brain abnormalities. Aim 3: Define neuropathology underlying sensorimotor neurodevelopmental deficits with quantitative brain histopathology. Using cellular quantification and organization of brain nuclei, we aim to identify the neu- ropathogenesis of congenital Zika syndrome to better create appropriate, targeted interventions for children. This study utilizes a large cohort of ZIKV-exposed infant macaques that have been born in other NIH-funded studies and capitalizes on our collaborative team of experts in neuropathology, neurodevelopment and neu- roradiology.

项目摘要 产前暴露于寨卡病毒（ZIKV）对胎儿构成威胁，使新生儿面临着重要的风险 早期儿童期间出生缺陷（称为先天性寨卡综合症）和神经发育缺陷 - 兜帽。目前尚无预测指示哪些儿童会出现缺陷和神经病理学 这些缺陷的基础未定义。至关重要的是，预测哪些婴儿后来会发展出最大的缺陷 模仿长期的感觉运动发展和功能结果。此外，理解潜在的 神经病发生对于制定靶向干预措施是必要的。这笔赠款的目的是定义 ZIKV的长期神经发育结果，通过从高度控制的研究中迅速获得数据 恒河猕猴。 具体来说，我们将： AIM 1：表征具有产前ZIKV Expo-猕猴中的感觉运动神经发育结果 当然。集中于感觉运动发展的行为评估可能会突出不同的发展 在暴露于ZIKV的恒河猕猴中，轨迹和随着年龄的增长而增加。因为猕猴会发展 比人类更快，到3年级发生的感觉运动神经发育差异可能会预测 未来的ZIKV暴露儿童的未来影响。 目标2：确定ZIKV暴露的感觉运动神经发育缺陷的早期神经预测因子 婴儿猕猴具有定量MRI，听力和视觉研究。我们将描述 暴露和模拟感染控制婴儿，并确定暴露于ZIKV的个人差异 伪造以确定脑部异常的全部范围。 AIM 3：定义神经病理学潜在的感觉运动神经发育缺陷 大脑组织病理学。使用脑核的细胞定量和组织，我们旨在确定NEU- 先天性寨卡综合症的综合发生，以更好地为儿童创建适当的有针对性的干预措施。 这项研究利用了大量ZIKV暴露的婴儿猕猴，这些猕猴已出生于其他NIH资助 研究并利用我们的神经病理学，神经发育和神经专家的合作团队 Roradiology。