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）：这个NIAID支持的项目使用非人类灵长类动物模型来研究妊娠期间孕产妇感染对婴儿脑发育和产后行为的不良影响。除了成为妊娠期间发病率和死亡率的潜在原因外，人们对流感暴露后代的长期神经行为后果的潜力也越来越大，即使孕产妇症状似乎是温和的和良性的。 A/Sydney/5/97 [H3N2]在中期和晚期妊娠中受控感染的影响正在大量鼠尾草猴子中。高分辨率磁共振成像（MRI）用于检查一岁的全球和区域大脑发育。通过扩散张量成像（DTI）评估白质完整性。对NOT-OD-10-032响应的这种竞争性修订将通过添加遗传分析来扩展和增强父级奖的目标，重点是羟色胺转移蛋白转移基因链接的多态性区域的变异贡献（5-HTTTLPR）。该通知通过NIH基本行为和社会科学机会网络（OPPNET）宣布了竞争性修订应用程序（RO1，RO3，R15，R21，R21/R33和R37）的可用性资金。这种一次性补充的具体目标是为父母项目中已经进行的研究添加对遗传风险的评估。 5HTTLPR等位基因变异赋予的血清素能功能的个体变化与情绪调节的神经回路有关，并有对不良饲养条件的较大行为影响的风险。尽管已经对人类和其他动物的5-HTTLPR多态性进行了广泛的研究，但重点一直是5-羟色胺在大脑中的作用，在很大程度上忽略了其在周围中同样重要的功能，尤其是与脉管，细胞运输和炎症有关。 5-羟色胺受体和转运蛋白也存在于胎盘中。我们的新研究目的将确定5-HTTLPR中这种功能性多态性和长度变化是否与母体和胎儿脆弱性有关，以及后产后出现的大脑和行为表型。我们将区分妊娠女性中的等位基因变体是独立行动还是与胎儿基因型结合起来，从而产生产前感染的素质和更大的影响。新目标的重点是在5-羟色胺转运蛋白基因的启动子区域中的这种多态性，但是作为补充工作的一部分，我们将为所有研究动物提取和归档DNA，以利用未来遗传分析的独特灵长类动物资源作为基础。在这个关键时刻，对产前流感病毒感染的灵长类研究至关重要，弥合啮齿动物模型中的发现以及对人类对流感暴露妊娠的回顾性分析所引起的关注，这意味着产前侮辱是几种神经发育和精神病学疾病的病因学中的关键事件。 公共卫生相关性：怀孕期间对孕产妇健康的身体和心理挑战可能会对胎儿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，目前对怀孕期间流感病毒感染的孕产妇感染有相当大的关注，尤其是在循环中的多种菌株，包括更具毒性的H1N1。我们提议通过5-羟色胺转运蛋白转运蛋白相关多态性区域（5HTTLPR）的特异性变化来确定母亲和婴儿带来的额外风险，该区域与多种不同环境暴露后的脆弱性和病理增加有关。这项扩展和加强我们的研究目标的应用是为了响应NOT-OD-10-032宣布恢复ACT资金用于竞争性修订应用程序（RO1，RO3，R15，R21，R21，R21/R33和R33和R33），通过NIH基本行为和社交科学机会网络（OPPNET）。