Viral Neurobiology in the Prenatal Brain

产前大脑中的病毒神经生物学

• 批准号: 10448161
• 负责人: Youssef A Kousa
• 金额: $ 18.13万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448161
• 关键词: Affect; Alleles; Animals; Autophagocytosis; Award; Biological Models; Brain; Brain Injuries; Candidate Disease Gene; Caring; Cell Survival; Cell physiology; Centers for Disease Control and Prevention (U.S.); Cerebral Palsy; Cerebrum; Child; Childhood; Clinical; Clinical Data; Code; Complex; Country; Critical Care; Data; Development; Development Plans; Developmental Delay Disorders; Dizygotic Twins; Epilepsy; FRAP1 gene; Foundations; Future Generations; Gene Expression; Genes; Genetic; Genomics; Goals; Grant; Health; Hospitals; Human; Image; Individual; Infant; Infection; International; Internships; Lead; Life; Life Experience; Light; Lysosomes; Mentors; Modeling; Mothers; Motor; Motor Cortex; Mus; National Institute of Neurological Disorders and Stroke; Neonatal; Neurobiology; Neurodevelopmental Disability; Neurodevelopmental Disorder; Neuroepidemiology; Neurologist; Neuronal Injury; Neurons; Neuropsychology; Neurovirology; Organoids; Outcome; PI3K/AKT; Pathway interactions; Population; Positioning Attribute; Precision therapeutics; Predisposition; Pregnancy; Prevention; Prevention strategy; Proteins; Regulation; Research; Research Infrastructure; Research Personnel; Risk; Role; Scientist; Seasons; Secure; Series; Study Subject; System; Testing; Therapeutic Intervention; Training; United States National Institutes of Health; Variant; Viral; Viral Load result; Virus; Virus Diseases; Virus Replication; Western Blotting; Work; ZIKA; beta-n-acetylhexosaminidase; career development; clinical phenotype; clinical sequencing; disability; exome sequencing; follow-up; humanized mouse; in vivo; infant infection; knock-down; loss of function; loss of function mutation; member; nerve stem cell; neurodevelopment; neuronal survival; neuropathology; novel; overexpression; pandemic disease; postnatal; postnatal development; precision medicine; prenatal; prevent; public-private partnership; response; severe injury; single-cell RNA sequencing; targeted treatment; transcriptome sequencing

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.

抽象的 产前大脑独特地容易受到病毒感染的影响。这种感染威胁着四分之一的怀孕，可以 如果不是胎儿死亡，会导致严重的神经发育障碍。不同的病毒导致非常相似的临床 由于重叠的病毒神经病理学和宿主的常见神经反应而产生的结果。这样的现实 呼吁制定迫切需要的产前护理标准，以预防或实际治疗 诱发脑损伤。这需要对相应的神经生物学有一个更少的了解。 宿主常见神经病毒反应的关键调节剂是雷帕霉素（MTOR）的机械目标 在病毒自噬中的重要作用，会影响病毒清除和神经元存活。有未解决的问题 然而，关于mTOR表达和病毒自噬是否是针对或 必要是病毒复制和神经元损伤。 PI具有新的初步数据，将MTOR连接到 新型神经病毒反应基因，己糖胺酶B（HEXB），并为此提出了新的细胞功能 激活产前病毒自噬以防止脑损伤的遗传复合物。打开新的研究窗口 对于治疗干预，这为拟议的K08研究设定了背景，该研究严格测试了指导 假设神经发育基因表达会影响产前病毒易感性对脑损伤。 PI在细胞，小鼠和人类系统中纯化三个综合和协同的目标，PI将研究如何研究 MTOR和HEXB的基因表达会影响产前病毒易感性，以及如何改变它 脑损伤。首先，人类衍生的类器官用于研究MTOR和HEXB的表达如何影响病毒 清除，神经元存活和上/下游途径（AIM 1）。同时，这种关系是产前的 在体内评估以确定其对产后发展的影响（AIM 2）。镜像Allic系列MTOR和 在这些目的中，HEXB在遗传上进行了跨约二刺激，这将阐明人群基因组分析以研究 这些基因/途径中的变体在多大程度上影响产前对脑损伤的敏感性（AIM 3）。 该K08赠款组合研究使用协同/集成系统和理论和技术培训 由儿童国家医院和Ninds的神经生物学，神经病毒学和基因组学经验丰富的导师。 单独量身定制的职业发展计划独特地定位了PI，这是一个经过董事会认证的产前纳塔尔 重症监护神经科医生科学家，通过以下方式向发展中的人类大脑打开多个新的研究窗口 （a）加深我们对产前神经病毒学和神经神经病毒学的基本理解 发育基因（MTOR和HEXB），调节网络和必需的细胞功能； （b）考试 产前病毒自噬作为产前精确药物的基石的遗传调节； （c）窃听 进入强大的神经性ePidemiology研究基础设施（财团，CDC，NIH），以识别产前 敏感性。最终目标是了解病毒神经生物学与神经元损伤之间的联系 在发展中的大脑中，以优化子孙后代的神经心理生活经验。