Maternal Flu Infection and Brain Development in Primates

描述(申请人提供)：这项由NIAID资助的项目使用非人类灵长类动物模型来调查孕妇在怀孕期间感染流感病毒对婴儿大脑发育和产后行为的不利影响。除了是孕期发病率和死亡率的潜在原因外，人们越来越担心接触流感的后代可能会产生长期的神经行为后果，即使母亲的症状看起来很轻微和良性。对妊娠中期和晚期感染A/悉尼/5/97[H3N2]的受控感染的影响正在对一大群恒河猴进行前瞻性研究。高分辨率磁共振成像(MRI)被用来检查一岁时全球和区域大脑的发育。用扩散张量成像(DTI)评价脑白质完整性。这一针对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父母奖的目标，重点是5-羟色胺转运体基因连锁多态区域(5-HTTLPR)的变异的贡献。该通知宣布，通过NIH基本行为和社会科学机会网络(OppNet)，恢复法案资金可用于竞争性修订申请(RO1、R03、R15、R21、R21/R33和R37)。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的基础上增加对遗传风险的评估。由5HTTLPR等位基因变异导致的5-羟色胺能功能的个体差异与情绪调节的神经回路相关，并有可能导致不良养育条件对行为产生更大的影响。虽然5-HTTLPR在人类和其他动物中的多态性已经有了广泛的研究，但人们的注意力主要集中在5-羟色胺在大脑中的作用上，很大程度上忽略了它在外周同样重要的功能，特别是与血管系统、细胞运输和炎症相关的功能。5-羟色胺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的这种功能多态和长度变异是否与母体和胎儿的易感性以及出生后脑部和行为表型的出现有关。我们将区分怀孕女性中的等位基因变异是独立发挥作用，还是与胎儿基因一起产生素质和更大的产前感染影响。新目标的重点是5-羟色胺转运体基因启动子区域的这种多态，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进一步遗传分析的基础。灵长类动物对产前流感病毒感染的研究在这一点上至关重要，以弥合啮齿动物模型的发现和对接触流感怀孕的人类的回顾分析提出的关切，这些分析表明，产前侮辱是几种神经发育和精神疾病的病因学中的关键事件。 公共卫生相关性：孕期母体健康面临的生理和心理挑战可能会对胎儿大脑发育产生不利影响，并增加患上几种神经发育和精神疾病的可能性。特别是，目前对孕妇在怀孕期间感染流感病毒有相当大的关注，特别是在多种毒株正在传播的情况下，包括毒力更强的H1N1。我们建议确定5-羟色胺转运体基因连锁多态区域(5HTTLPR)的特定变异对母亲和婴儿构成的额外风险，该变异与在一些不同的环境暴露后增加的脆弱性和病理学有关。这项扩大和加强我们研究目标的申请是对NOT-OD-10-032宣布通过NIH基本行为和社会科学机会网络(OppNet)为竞争性修订申请(RO1、R03、R15、R21、R21/R33和R37)提供恢复法案资金的回应。

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).