Viral Neurobiology in the Prenatal Brain

摘要 产前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孕妇，并可能 导致严重的神经发育障碍，如果不是胎儿死亡的话。不同的病毒导致惊人的相似临床 由于重叠的病毒神经病理学和宿主的共同神经元反应所致的结果。这样的现实 呼吁制定急需的产前护理标准，以预防或治疗病毒性肺炎 诱发性脑损伤。这种需要需要对相应的神经生物学有更深入的了解。 宿主常见神经病毒反应的关键调节因子是雷帕霉素(MTOR)的机制靶点，通过 在影响病毒清除和神经元存活的病毒自噬中发挥重要作用。有不稳定的情况 然而，关于mTOR表达和病毒自噬是否是预防或 病毒复制和神经元损伤的必备条件。PI有新的初步数据将mTOR与 新的神经病毒反应基因--己糖氨酸酶B(HEXB)及其新的细胞功能 在激活产前病毒自噬以防止脑损伤方面的遗传复合体。打开新的研究窗口 对于治疗干预，这为拟议的K08研究奠定了背景，该研究严格测试了指导 假设神经发育基因表达会影响出生前病毒对脑损伤的易感性。 为了在细胞、小鼠和人类系统中实现三个整合和协同的目标，PI将研究如何 MTOR和HEXB基因表达对产前病毒易感性的影响以及如何改变它以防止 脑部受伤。首先，使用人类衍生的有机化合物来研究mTOR和HEXB的表达如何影响病毒 清除、神经元存活和上行/下行通路(目标1)。同时，这种关系在婚前就发生了 体内评估，以确定其对出生后发育的影响(目标2)。MTOR和mTOR的镜像等位基因序列 HEXB在这些目的上是基因交叉滴定的，这将为研究种群基因组分析提供线索 这些基因/途径的变异在多大程度上影响对脑损伤的产前易感性(目标3)。 K08奖助金将使用协同/集成系统进行的研究与理论和技术培训相结合 由国立儿童医院和NINDS的神经生物学、神经病毒学和基因组学方面的经验丰富的导师提供。 个人量身定做的职业发展计划独特地定位了PI，一名获得董事会认证的产前新生儿 重症监护神经学家兼科学家，通过以下方式打开对发育中的人脑的多个新的研究窗口： (A)加深我们对产前神经病毒学和神经病毒学的关键作用的基本了解。 发育基因(mTOR和HEXB)、调节网络和基本细胞功能；(B)检查 作为产前精准医学基石的产前病毒自噬的遗传调控；和(C)敲击 进入强大的神经流行病学研究基础设施(Consortium、CDC、NIH)，以识别产前 易感性。最终目标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，以优化后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.