The Olive Baboon model of Zika Virus induced fetal brain injury

寨卡病毒诱发胎儿脑损伤的橄榄狒狒模型

基本信息

批准号：
9413669
负责人：
DEAN MYERS
金额：
$ 22.2万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9413669
关键词：
Acute Address Aedes Americas Apoptosis Area Autophagocytosis Autopsy Behavioral Biometry Blood Vessels Blood flow Brain Brain Pathology Brain Stem Brazil Calcified Cell Cycle Progression Cell Differentiation process Cells Central Nervous System Diseases Central Nervous System Infections Cerebellar malformation Cerebral cortex Cerebrum Clinical Cognitive Communities Complement Congenital Abnormality Culicidae Data Development Disease Outbreaks Embryo Epidemic Experimental Animal Model Fetal Death Fetal Growth Fetal Growth Retardation Fetal Tissues Fetus First Pregnancy Trimester Flavivirus French Polynesia Genetic Gestational Age Gliosis Goals Human Immune Immunology Impairment In Vitro Infant Infection Infiltration Inflammation Inflammatory Response Injury International Lead Lesion Link Macaca nemestrina Microcephaly Mitotic Modeling Mus Necrosis Neurobiology Neuroglia Neurologic Neurons Oklahoma Oligodendroglia Oligohydramnios Outcome Oxidative Stress Papio Papio anubis Pathologic Pathology Penetration Phenotype Physiology Placenta Placentation Pregnancy Primates Proliferating Radial Reporting Research Resource Sharing Resources Rodent Role Second Pregnancy Trimester Severities Source Structure Study models Telencephalon Third Pregnancy Trimester Time Translations Ultrasonography Umbilical Blood United States National Institutes of Health Ventricular Viremia Virus Diseases World Health Organization Zika Virus base calcification congenital zika syndrome experience fetal fetal brain injury fetal medicine gray matter mouse model myelination nerve stem cell neuroinflammation neuropathology nonhuman primate pregnant public health emergency response subcutaneous subventricular zone white matter white matter damage

项目摘要

Zika virus (ZIKV) is transmitted to humans via the Aedes genus of mosquito. Following massive outbreaks of ZIKV infections in French Polynesia in 2013/14 and subsequently in Brazil in 2015, the World Health Organization (WHO) issued a Public Health Emergency of International Concern (Feb, 2016) based on the link between ZIKV and infants born with a spectrum of neurological insults including microcephaly and CNS lesions. Targeting of the fetal CNS is of major significance and concern due to the devastating outcome of microcephaly and the potential for sub-clinical yet significant impacts on the fetal CNS in the absence of microcephaly that could result in cognitive, behavioral and other CNS disorders. The olive baboon's (Papio anubis) similarity to humans in terms of genetics, brain development, placentation, size and immunology makes the baboon an excellent translational model for studies on ZIKV infection during pregnancy. Our research team has flavivirus experience, including ZIKV, in baboons. We complement this with expertise in neurobiology, maternal-fetal medicine and physiology necessary to accomplish our aims. The Oklahoma Baboon Research Resource provides us access to the needed numbers of timed-pregnant baboons to complete our aims. Our overarching hypothesis is that maternal ZIKV infection at different stages of gestation (first, second or third trimester) will result in different degrees of fetal CNS pathological phenotypes, the most severe arising from early gestation infection. Specific Aim 1- Analyze the fetal brain at 170dG (~term) to determine the effect of prolonged ZIKV infection performed at 50, 90 and 150dG (days gestation). Specific Aim 2: Analyze the fetal brain at 14 d post inoculation at early (50dG), mid (90dG) and late (150dG) gestation. We will also assess the maternal and fetal immune, inflammatory responses, viremia, fetal growth and placental pathology and function (umbilical blood flow) in response to ZIKV to relate timing of ZIKV infection and degree of inflammatory response to fetal outcome. The findings will provide essential data in a relevant non-human primate on the fetal outcome of ZIKV.

寨卡病毒 (ZIKV) 通过伊蚊属传播给人类。继 2013/2014 年法属波利尼西亚和随后的 2015 年巴西大规模爆发寨卡病毒感染后，世界卫生组织 (WHO) 基于寨卡病毒与出生时携带寨卡病毒的婴儿之间的联系，发布了国际关注的突发公共卫生事件（2016 年 2 月）。一系列神经损伤，包括小头畸形和中枢神经系统病变。由于小头畸形的破坏性后果以及在不存在小头畸形的情况下可能对胎儿中枢神经系统产生亚临床但显着的影响（可能导致认知、行为和其他中枢神经系统疾病），因此针对胎儿中枢神经系统具有重要意义和关注。橄榄狒狒 (Papio anubis) 在遗传学、大脑发育、胎盘、体型和免疫学方面与人类相似，这使得狒狒成为研究怀孕期间寨卡病毒感染的绝佳转化模型。我们的研究团队拥有在狒狒身上治疗黄病毒（包括 ZIKV）的经验。我们用神经生物学、母胎医学和生理学方面的专业知识来补充这一点，以实现我们的目标。俄克拉荷马州狒狒研究资源为我们提供了完成我们目标所需数量的定时怀孕狒狒的途径。我们的总体假设是，母亲在妊娠不同阶段（妊娠早期、中期或晚期）感染 ZIKV 会导致胎儿出现不同程度的 CNS 病理表型，其中最严重的是妊娠早期感染。具体目标 1 - 在 170dG（~足月）时分析胎儿大脑，以确定在 50、90 和 150dG（妊娠天数）时进行的长期 ZIKV 感染的影响。具体目标 2：在妊娠早期 (50dG)、中期 (90dG) 和晚期 (150dG) 接种后 14 天分析胎儿大脑。我们还将评估针对 ZIKV 的母体和胎儿免疫、炎症反应、病毒血症、胎儿生长以及胎盘病理学和功能（脐血流量），以将 ZIKV 感染时间和炎症反应程度与胎儿结局联系起来。这些发现将为相关非人类灵长类动物提供 ZIKV 胎儿结局的重要数据。