Maternal Flu Infection and Brain Development in Primates

母体流感感染与灵长类动物的大脑发育

• 批准号: 8038679
• 负责人: CHRISTOPHER L COE
• 金额: $ 8.27万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038679
• 关键词: Maternal; Flu; Infection; Brain; Development

DESCRIPTION (provided by applicant): This NIAID-supported project uses a nonhuman primate model to investigate the adverse effects of maternal infection with influenza virus during pregnancy on infant brain development and behavior postpartum. In addition to being a potential cause of morbidity and mortality during gestation, concern has grown about the potential for long-term neurobehavioral consequences in flu-exposed offspring, even when maternal symptoms are seemingly mild and benign. The effects of controlled infections with A/Sydney/5/97 [H3N2] in mid- and late- pregnancy are being examined prospectively in a large cohort of rhesus monkeys. High resolution Magnetic Resonance Imaging (MRI) is employed to examine global and regional brain development at one year of age. White matter integrity is evaluated with Diffusion Tensor Imaging (DTI). This competitive revision in response to NOT-OD-10-032 will expand and strengthen the aims of the parent award through the addition of a genetic analysis, with a focus on the contribution of variation in the serotonin-transporter gene-linked polymorphic region (5-HTTLPR). The notice announced the Availability of Recovery Act Funds for Competitive Revision Applications (RO1, RO3, R15, R21, R21/R33 and R37) through the NIH Basic Behavioral and Social Science Opportunity Network (OppNet). The specific goal of this one-time supplement is to add an assessment of genetic risk to the research already being conducted in the parent project. Individual variation in serotonergic function conferred by 5HTTLPR allelic variation has been associated with the neural circuitry underlying emotion regulation and a risk for larger behavioral effects of adverse rearing conditions. While there has been extensive research on the 5-HTTLPR polymorphism in humans and other animals already, the focus has been primarily on the role of serotonin in the brain, largely ignoring its equally important functions in the periphery, especially related to the vasculature, cell trafficking, and inflammation. Serotonin receptors and transporter proteins are also present in the placenta. Our new research aim will establish whether this functional polymorphism and length variation in 5-HTTLPR is associated with maternal and fetal vulnerability, and the brain and behavioral phenotype emergent postnatally. We will distinguish whether allelic variants in the gravid female act independently or in conjunction with the fetal genotype to create a diathesis and greater impact of prenatal infection. The emphasis of the new aim is on this polymorphism in the promoter region of the serotonin transporter gene, but as a part of the supplement effort, we will extract and archive DNA for all study animals, to leverage the unique primate resource as a basis for additional genetic analyses in the future. Primate studies of prenatal influenza virus infection are critical at this juncture to bridge the findings in rodent models and the concerns raised by retrospective analyses of humans from flu-exposed pregnancies, which have implicated prenatal insults as critical events in the etiology of several neurodevelopmental and psychiatric disorders. PUBLIC HEALTH RELEVANCE: Physical and psychological challenges to maternal wellbeing during pregnancy can adversely affect fetal brain development and increase the likelihood of several neurodevelopmental and psychiatric disorders. In particular, there is currently considerable concern about maternal infection with influenza virus during pregnancy, especially with multiple strains in circulation, including the more virulent H1N1. We are proposing to determine the added risk posed for mothers and infants by specific variation in the serotonin transporter gene-linked polymorphic region (5HTTLPR), which has been associated with increased vulnerability and pathology after a number of different environmental exposures. This application to expand and strengthen our research aims is in response to NOT-OD-10-032 announcing the Availability of Recovery Act Funds for Competitive Revision Applications (RO1, RO3, R15, R21, R21/R33 and R37) through the NIH Basic Behavioral and Social Science Opportunity Network (OppNet).

描述（由申请人提供）：该NIAID支持的项目使用非人灵长类动物模型来研究妊娠期间母体感染流感病毒对婴儿大脑发育和产后行为的不良影响。除了是妊娠期发病和死亡的潜在原因外，人们还越来越关注流感暴露后代长期神经行为后果的可能性，即使母体症状看似温和和良性。目前正在一个大型恒河猴队列中前瞻性地检查A/Sydney/5/97 [H3 N2]在妊娠中期和晚期控制感染的影响。高分辨率磁共振成像（MRI）用于检查一岁时的整体和区域大脑发育。白色物质的完整性通过扩散张量成像（DTI）进行评价。这项针对NOT-OD-10-032的竞争性修订将通过增加遗传分析来扩大和加强母公司奖项的目标，重点是在降钙素转运蛋白基因连锁多态性区域（5-HTTLPR）中变异的贡献。该通知通过NIH基本行为和社会科学机会网络（OppNet）宣布了恢复法案资金用于竞争性修订申请（RO 1，RO 3，R15，R21，R21/R33和R37）的可用性。这一一次性补充的具体目标是在母项目中已经进行的研究中增加对遗传风险的评估。由5 HTTLPR等位基因变异赋予的多巴胺能功能的个体变异与情绪调节的神经回路和不良养育条件的更大行为影响的风险相关。虽然已经对人类和其他动物的5-HTTLPR多态性进行了广泛的研究，但重点主要集中在5-羟色胺在大脑中的作用上，在很大程度上忽略了其在外周中同样重要的功能，特别是与血管，细胞运输和炎症有关的功能。血清素受体和转运蛋白也存在于胎盘中。我们新的研究目标是确定5-HTTLPR的这种功能多态性和长度变异是否与母体和胎儿的脆弱性以及出生后出现的大脑和行为表型相关。我们将区分妊娠女性中的等位基因变异是独立作用还是与胎儿基因型联合作用，以产生产前感染的素质和更大影响。新目标的重点是5-羟色胺转运蛋白基因启动子区域的多态性，但作为补充工作的一部分，我们将提取和存档所有研究动物的DNA，以利用独特的灵长类动物资源作为未来其他遗传分析的基础。产前流感病毒感染的灵长类动物的研究是至关重要的，在这个关头，桥梁的啮齿动物模型的结果和关注所提出的回顾性分析人类从流感暴露的怀孕，其中涉及产前侮辱的病因学的几个神经发育和精神疾病的关键事件。 公共卫生关系：怀孕期间对母亲健康的身体和心理挑战会对胎儿大脑发育产生不利影响，并增加几种神经发育和精神疾病的可能性。特别是，目前人们相当关注孕妇在怀孕期间感染流感病毒，特别是在传播中的多种毒株，包括毒性更强的H1N1。我们建议确定5-羟色胺转运体基因连锁多态性区域（5 HTTLPR）的特定变异对母亲和婴儿造成的额外风险，该区域与许多不同环境暴露后的脆弱性和病理学增加有关。这个应用程序，以扩大和加强我们的研究目标是响应NOT-OD-10-032宣布恢复法案资金的竞争性修订申请（RO 1，RO 3，R15，R21，R21/R33和R37）通过NIH基本行为和社会科学机会网络（OppNet）的可用性。