Maternal Flu Infection and Brain Development in Primates

描述（由申请人提供）：本项目由niaid资助，采用非人类灵长类动物模型研究妊娠期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。除了作为妊娠期发病和死亡的潜在原因外，人们越来越关注暴露于流感的后代长期神经行为后果的可能性，即使母亲的症状看似轻微和良性。A/Sydney/5/97 [H3N2]控制感染对妊娠中后期的影响正在一大批恒河猴中进行前瞻性研究。高分辨率磁共振成像（MRI）用于检查一岁时大脑的整体和区域发育。用弥散张量成像（DTI）评估白质完整性。这一针对no - od -10-032的竞争性修订将通过增加基因分析来扩大和加强亲本奖的目标，重点关注5-羟色胺转运体基因相关多态性区域（5-HTTLPR）变异的贡献。该通知宣布通过NIH基础行为和社会科学机会网络（OppNet）为竞争性修订申请（RO1, RO3, R15, R21， R21/R33和R37）提供恢复法案资金。这一一次性补充的具体目标是在母体项目中已经进行的研究中增加一项遗传风险评估。5HTTLPR等位基因变异导致的血清素能功能的个体差异与情绪调节背后的神经回路有关，也与不良养育条件对更大行为影响的风险有关。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，很大程度上忽略了它在外周神经系统中同样重要的功能，特别是与脉管系统、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。我们的新研究目标是确定5-HTTLPR的这种功能多态性和长度变异是否与母体和胎儿易感性以及出生后出现的大脑和行为表型有关。我们将区分妊娠女性的等位基因变异是否独立或与胎儿基因型共同作用，以创造一种素质和更大的产前感染影响。新目标的重点是5 -羟色胺转运基因启动子区域的多态性，但作为补充工作的一部分，我们将提取并存档所有研究动物的DNA，以利用独特的灵长类资源作为未来额外遗传分析的基础。灵长类动物产前流感病毒感染的研究在这个关键时刻至关重要，可以将啮齿动物模型的发现与流感暴露孕妇的回顾性分析所引起的关注联系起来，这些分析表明产前侮辱是几种神经发育和精神疾病病因学中的关键事件。

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).