Viral Neurobiology in the Prenatal Brain

摘要 胎儿期的大脑特别容易受到病毒感染。这种感染威胁着四分之一的怀孕， 会导致严重的神经发育障碍不同的病毒导致惊人相似的临床 由于重叠的病毒神经病理学和宿主的共同神经元反应的结果。这样的现实 呼吁制定迫切需要的产前护理标准，以预防或治疗病毒性 导致脑损伤。这需要对相应的神经生物学有更深入的了解。 宿主常见神经病毒应答的关键调节因子是雷帕霉素（mTOR）的机制靶点， 在病毒自噬中起重要作用，影响病毒清除和神经元存活。有不安定的 然而，关于mTOR表达和病毒自噬是否是关键的防御机制， 病毒复制和神经元损伤。PI有新的初步数据将mTOR与 一种新的神经病毒反应基因，氨基己糖苷酶B（HEX B），并提出了新的细胞功能， 基因复合物激活产前病毒自噬以防止脑损伤。打开新的研究窗口 对于治疗性干预，这为拟议的K 08研究奠定了基础，该研究严格测试了 神经发育基因表达影响产前病毒对脑损伤易感性的假说。 追求细胞，小鼠和人类系统的三个综合和协同目标，PI将研究如何 mTOR和HEXB的基因表达影响产前病毒易感性，以及如何改变它以预防 脑损伤首先，使用人源性类器官来研究mTOR和HEXB的表达如何影响病毒感染。 清除、神经元存活和上/下游通路（Aim 1）。与此同时，这种关系在产前 在体内进行评估，以确定其对出生后发育的影响（目标2）。mTOR的镜像等位基因系列， HEXB在这些目标中进行了遗传交叉滴定，这将为研究群体基因组分析提供线索 这些基因/通路的变异影响产前脑损伤易感性的程度（目的3）。 该K 08补助金将使用协同/集成系统的研究与理论和技术培训相结合 由国家儿童医院和NINDS的神经生物学、神经病毒学和基因组学方面经验丰富的导师指导。 个性化定制的职业发展计划独特地定位PI，董事会认证的产前-新生儿 重症监护神经学家，科学家，打开多个新的研究窗口到发展中的人类大脑： (a)加深我们对产前神经病毒学的基本理解， 发育基因（mTOR和HEX B）、调控网络和基本细胞功能;（B）检查 产前病毒自噬的遗传调控作为产前精准医学的基石;以及（c）挖掘 一个强大的神经流行病学研究基础设施（联盟，CDC，NIH），以确定产前 豁免权。最终目的是了解病毒神经生物学和神经元损伤之间的联系 在发育中的大脑中，以优化未来几代儿童的神经心理生活体验。

ABSTRACT The prenatal brain is uniquely susceptible to viral infections. Such infections threaten 1 in 4 pregnancies and can cause severe neurodevelopmental disorders if not fetal demise. Different viruses lead to strikingly similar clinical outcomes due to overlapping viral neuropathology and the host’s common neuronal response. Such a reality calls for the development of urgently needed prenatal standards of care for prevention or treatment of virally induced brain injury. This need requires a much-deeper understanding of the corresponding neurobiology. A key regulator of the host’s common neuroviral response is the mechanistic target of rapamycin (mTOR) through essential roles in viral autophagy, which affect viral clearance and neuronal survival. There is unsettled controversy, however, about whether mTOR expression and viral autophagy are key defenses against, or requisites to, viral replication and neuronal injury. The PI has new preliminary data connecting mTOR with a novel neuroviral response gene, Hexosaminidase B (HEXB), and suggesting new cellular functions for this genetic complex in activating prenatal viral autophagy to prevent brain injury. Opening new research windows for therapeutic intervention, this sets the context for the proposed K08 study, which rigorously tests the guiding hypothesis that neurodevelopmental gene expression affects prenatal viral susceptibility toward brain injury. Purusing three integrated and synergistic aims in cellular, mouse, and human systems, the PI will investige how gene expression of mTOR and HEXB affects prenatal viral susceptibility and how it might be altered to prevent brain injury. First, human-derived organoids are used to study how expression of mTOR and HEXB affects viral clearance, neuronal survival, and up/downstream pathways (Aim 1). In parallel, this relationship is prenatally evaluated in vivo to determine its impact on postnatal development (Aim 2). Mirrored allelic series of mTOR and HEXB are genetically cross-titrated in these aims, which will shed light on a population genomic analysis to study the extent to which variants in these genes/pathways affect prenatal susceptibility to brain injury (Aim 3). This K08 grant combines research using synergistic/integrated systems with theoretical and technical training by seasoned mentors in neurobiology, neurovirology, and genomics at Children’s National Hospital and NINDS. The individually tailored career development plan uniquely positions the PI, a board-certified prenatal-neonatal critical care neurologist-scientist, to open multiple new research windows into the developing human brain by: (a) deepening our fundamental understanding of prenatal neurovirology and the crticial role of neuro- developmental genes (mTOR & HEXB), regulatory networks, and essential cellular functions; (b) examining genetic regulation of prenatal viral autophagy as a cornerstone for prenatal precision medicine; and (c) tapping into a robust neuroepidemiology research infrastructure (Consortium, CDC, NIH) to identify prenatal susceptibilities. The ultimate goal is to understand the connection between viral neurobiology and neuronal injury in the developing brain to optimize the neuropsychological life experience of future generations of children.