The study of virus-induced brain disorders by a model system using neural stem cells

使用神经干细胞的模型系统研究病毒引起的脑部疾病

• 批准号: 13670210
• 负责人: KOSUGI Isao
• 金额: $ 2.18万
• 依托单位: Hamamatsu University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670210/
• 关键词: neural stem cells; virus; cytomegalovirus; brain disorders; virus vector; gene transduction; サイトメガロウイルス

Cytomegalovirus (CMV) is the most frequent infectious cause of development disorders of the brain in humans. Infection of the neural stem/progenitor cells (NSPCs) seems to be primarily responsible for the generation of the brain abnormalities. Previously, we reported that NSPCs prepared from fetal mouse brains were permissive for murine CMV (MCMV) infection, and that the virus infection suppressed their growth and migration, and inhibited their differentiation, especially neuronal differentiation (Lab Invest 2000). However, it needs to be elucidated how viral genes cause the disorder of NSPCs during MCMV infection. In this study we tried to establish a model system for investigating the effects of MCMV genes on the growth and differentiation of NSPCs. An immediate early 1 (ie1) gene was transduced into NSPCs via a retrovirus vector. The transduction of ie1 suppressed the growth of NSPCs. When NSPCs were induced to differentiate, in the ie1-transduced NSPCs the expression of microtubules-associated protein 5 (MAP5), an early neuronal marker, was decreased as compared with control. These data suggest that MCMV IE1 protein disrupts the ability of self-renewal and multi-potency which are the principal functions of NSPCs. The transduction of viral genes into NSPCs might provide a model system for clarifying the pathogenesis of the brain abnormalities in congenital CMV infection in humans.

巨细胞病毒（CMV）是人类大脑发育障碍的最常见的感染性原因。神经干/祖细胞（NSPCs）的感染似乎是脑异常产生的主要原因。先前，我们报道了从胎鼠脑制备的NSPCs允许鼠CMV（MCMV）感染，并且病毒感染抑制它们的生长和迁移，并抑制它们的分化，特别是神经元分化（Lab Invest 2000）。然而，病毒基因如何导致MCMV感染时NSPCs的紊乱还需要进一步阐明。本研究试图建立一个研究MCMV基因对NSPCs生长和分化影响的模型系统。通过逆转录病毒载体将立即早期1（ie 1）基因转导到NSPCs中。ie 1的转导抑制NSPCs的生长。当NSPCs被诱导分化时，与对照组相比，在ie 1转导的NSPCs中，微管相关蛋白5（MAP 5）的表达降低，这是一种早期神经元标记物。这些数据表明MCMV IE 1蛋白破坏了NSPCs的自我更新和多能性能力，而这些能力是NSPCs的主要功能。将病毒基因转导入NSPCs可能为阐明人类先天性CMV感染脑异常的发病机制提供一个模型系统。

项目成果

Kawasaki H, Kosugi I, Arai Y, Tsutsui Y: "The amount of immature glial cells in organotypic brain slices determines the susceptibility to murine cytomegalovirus infection"Laboratory Investigation. 82(10). 1347-1358 (2002)

Kawasaki H、Kosugi I、Arai Y、Ttsutsui Y：“器官型脑切片中未成熟胶质细胞的数量决定了对鼠巨细胞病毒感染的易感性”实验室研究。

Li R-Y, et al.: "Activation of murine cytoznegalovirus immediate-early promoter in cerebral ventricular zone and glial progenitor cells in transgenic mice"Glia. 35. 41-52 (2001)

Li R-Y 等人：“转基因小鼠脑室区和神经胶质祖细胞中鼠类细胞负病毒立即早期启动子的激活”

Tsutsui Y, Kawasaki H, Kosugi I: "Reactivation of latent cytomegalovirus infection in mouse brain cells detected after transfer to brain slice cultures"Journal of Virology. 76(14). 7247-7254 (2002)

Tsutsui Y、Kawasaki H、Kosugi I：“转移至脑切片培养物后检测到的小鼠脑细胞中潜伏巨细胞病毒感染的重新激活”病毒学杂志。

Kosugi I, Kawasaki H, Arai Y, Tsutsui Y: "Innate Immune Reponses to Cytomegalovirus Infection in the Developing Mouse Brain and Their Evasion by Virus-Infected Neurons"American Journal of Pathology. 161(3). 919-928 (2002)

Kosugi I、Kawasaki H、Arai Y、Ttsutsui Y：“发育中小鼠大脑中巨细胞病毒感染的先天免疫反应及其通过病毒感染的神经元的逃避”美国病理学杂志。

Nakamura M, Zhou XZ, Kishi S, Kosugi I, Tsutsui Y, Lu KP: "A specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle"Current Biology. 11(19). 1512-1516 (2001)

Nakamura M、Zhou XZ、Kishi S、Kosugi I、Ttsutsui Y、Lu KP：“端粒蛋白 Pin2/TRF1 与有丝分裂纺锤体之间的特异性相互作用”当前生物学。