Molecular Neuro-pathogenesis of Congenital Cytomegalovirus Infection

先天性巨细胞病毒感染的分子神经发病机制

• 批准号: 9980766
• 负责人: Qiyi Tang
• 金额: $ 37.75万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-07 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980766
• 关键词: Achievement; Address; Affect; Area; Behavior; Biological Assay; Brain; Cell Culture Techniques; Cell Differentiation process; Cell Lineage; Cells; Cerebral Palsy; Congenital Disorders; Crossbreeding; Cytomegalovirus; Cytomegalovirus Infections; Data; Defect; Development; Disease; Down Syndrome; Electroporation; Embryo; Embryonic Development; Epigenetic Process; Fetal Alcohol Syndrome; Gene Activation; Gene Delivery; Genetic Transcription; Goals; Health; Human; Immediate-Early Proteins; In Vitro; Incidence; Infant; Infection; Intellectual functioning disability; Mediating; Medical; Microcephaly; Modeling; Molecular; Molecular Virology; Mus; Mutant Strains Mice; Neural Tube Defects; Neurocognitive; Neurodevelopmental Disorder; Neurologic; Neuropathogenesis; Neurosciences; Newborn Infant; Notch Signaling Pathway; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Positioning Attribute; Process; Proteins; Publications; Regimen; Research; Research Personnel; Retinitis; Role; Seizures; Sensorineural Hearing Loss; Signal Transduction; Signaling Protein; System; Technology; Testing; Therapeutic; Transcriptional Activation; Transgenic Mice; United States; Vaccines; Viral; Wild Type Mouse; brain abnormalities; career; clinically relevant; congenital cytomegalovirus; differential expression; disability; embryo/fetus; experimental study; in utero; innovation; molecular pathology; mouse model; neonate; nerve stem cell; neurocognitive disorder; neurogenesis; notch protein; novel strategies; parent grant; postnatal; pre-clinical; programs; relating to nervous system; stem; stem cell proliferation; stem cells; stemness; virology

PROJECT SUMMARY/ABSTRACT Human cytomegalovirus (HCMV) infection is the leading infectious cause of congenital disorders in newborns. Congenital HCMV infection causes permanent neurological and neurocognitive disabilities and results in significant health problems worldwide. Our preliminary findings reveal that Notch pathway is affected by HCMV infection and probably via interaction with CMV-encoded protein, IE1. Therefore, we propose to explore the molecular pathogenic mechanism via Notch pathway underlying abnormal brain development caused by congenital CMV infection. This proposed approach is fundamentally different from previous studies because we apply our unique technologies to explore the mechanisms that CMV employs to interfere with the brain development of embryos. We will apply the in vitro HCMV infection system, in utero electroporation system for mouse CMV (MCMV) gene delivery, conditional transgenic mouse model, and intraplacental MCMV infection system. Our long-term goal is to reveal the mechanisms underlying CMV-induced congenital neurodevelopmental disorders and develop potential anti-CMV therapeutics. We hypothesize that the coordinative interaction between CMV and Notch signaling is the key to causing developmental defects of infected neural progenitor cells (NPCs) in embryos, resulting in permanent neurological and intellectual disabilities. The hypothesis is supported by our preliminary data and publications from in vitro and in vivo experiments that HCMV infection affects Notch signaling, that Notch signaling is involved in CMV-caused defects of NPC proliferation, that IE1 is essential and sufficient to inhibit NPC proliferation, and that IE1 interacts with proteins of Notch signaling pathway. We will test our hypothesis via the following Specific Aims: Aim 1. To examine molecular mechanisms for how HCMV IE1 causes defects of human NSC/NPC proliferation and differentiation in cell culture; and Aim 2. To examine how the CMV IE1 causes different stages of neurogenic defect using an IE1-inducible transgenic mouse model and a clinically- relevant intraplacental MCMV infection mouse model. We believe that the present proposal is innovative in several points: First, this is one of the first studies that uses an inducible transgenic mouse model introducing a specific CMV protein, IE1, to address molecular mechanisms underlying congenital CMV infection. Second, we study the congenital CMV infection pathology from molecular levels to behavior levels. Lastly, investigators with different professional backgrounds (virology and neuroscience) are working together to address an important question with high medical impact. Positive impacts will include qualitative advances in understanding molecular virology and CMV pathobiology in particular, and that understanding the mechanisms CMV uses to cause neural defects may thus drive development of new, selective anti-CMV therapeutic strategies.

项目摘要/摘要人类巨细胞病毒（HCMV）感染是主要的感染原因 新生儿的先天性疾病。先天性HCMV感染引起永久神经系统和 神经认知障碍并导致全球重大健康问题。我们的初步发现揭示了 该Notch途径受HCMV感染的影响，并且可能是通过与CMV编码蛋白IE1相互作用的。 因此，我们建议通过底层的缺口途径探索分子致病机制 先天性CMV感染引起的脑发育异常。这种提出的方​​法从根本上是 与以前的研究不同，因为我们运用我们独特的技术来探索 CMV采用干扰胚胎的大脑发育。我们将应用体外HCMV感染 系统，在用于小鼠CMV（MCMV）基因递送的子宫电穿孔系统中 模型和腔内MCMV感染系统。我们的长期目标是揭示基本机制 CMV引起的先天性神经发育障碍并发展潜在的抗CMV治疗剂。我们 假设CMV和Notch信号之间的协调相互作用是引起引起的关键 胚胎中感染神经祖细胞（NPC）的发育缺陷，导致永久性 神经和智力残疾。该假设得到了我们的初步数据和出版物的支持 从体外和体内实验HCMV感染会影响Notch信号传导，Notch信号是 参与CMV引起的NPC增殖缺陷，IE1是必不可少的，足以抑制NPC 增殖，并且IE1与Notch信号通路的蛋白质相互作用。我们将通过 以下特定目的：目标1。检查HCMV IE1的分子机制如何导致缺陷 人类NSC/NPC增殖和细胞培养中的分化；和目标2。检查CMV IE1如何 使用IE1诱导的转基因小鼠模型和临床 - 相关的内部MCMV感染小鼠模型。我们认为，目前的提议是创新的 几点：首先，这是使用诱导的转基因小鼠模型引入A的最早研究之一 特定的CMV蛋白IE1解决了先天性CMV感染的分子机制。第二，我们 研究先天性CMV感染病理学从分子水平到行为水平。最后，调查人员 具有不同的专业背景（病毒学和神经科学）正在共同解决 具有高医疗影响的重要问题。积极的影响将包括定性进步 特别是了解分子病毒学和CMV病理生物学，并且了解机制 CMV用来引起神经缺陷可能会推动新的，选择性抗CMV治疗的发展 策略。