Role of Agno Protein in JC Virus Life Cycle

Agno 蛋白在 JC 病毒生命周期中的作用

• 批准号: 6496176
• 负责人: MAHMUT SAFAK
• 金额: $ 30.97万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6496176
• 关键词: AIDS /HIV neuropathy; Polyomavirus hominis 2; central nervous system; clinical research; gene deletion mutation; gene expression; genetic mapping; genetic regulation; genetic transcription; human tissue; nervous system disorder; neural degeneration; oligodendroglia; phosphorylation; point mutation; progressive multifocal leukoencephalopathy; protein protein interaction; protein structure function; transcription factor; transfection; virus antigen; virus protein; virus replication

DESCRIPTION (provided by applicant): Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) resulting from the lytic infection of oligodendrocytes by the human polyomavirus, JC virus (PML was once considered a rare complication of middle-aged and elderly patients with lymphoprolifera diseases. In recent years, however, increasingly high incidence of PML in AIDS patients than those wit immunosuppressive disorders led us to believe that PML may also be regarded as a AIDS-associated disease. Lytic phase of JCV appears to be highly complex and remains elusive. A growing body of experimental evidence suggests that the regulation of JC viral gene expression and replication is not mediated solely by the presence absence of a particular transcription factor in a given cell. Rather delicate interactions among transcription or interactions between host and viral regulatory proteins appear to be important determining factors in respect. In support of this hypothesis, we have recently presented evidence of specific functional interactions between a cellular factor, YB-1, and JCV T-antigen and showed that both proteins play important roles in J expression. In addition, our most recent published and unpublished data indicate that JCV late Agno protein, antigen, also appears to have regulatory roles in both viral gene expression and DNA replication through interaction with viral and cellular proteins, notably with T-antigen and YB-1. Hence, here we propose investigate the molecular mechanisms involved in regulation of JCV by the functional interplay between T-antigen, Agno and YB-1. By employing molecular biology, genetics and virological approaches, we will i) perform thorough molecular virological studies to determine the role of Agno in regulation of JCV gene transcription and replication by examining its physical and functional interaction with T-antigen and YB- 1; ii) investigate the function importance of Agno viral lytic cycle by means of both ectopic expression of Agno early in infection mutational analysis and; iii) characterize the potential phosphorylation sites of Agno protein and investigate the role in JCV life cycle. The results from such comprehensive studies will provide valuable information underlying mechanisms involved in both JCV gene regulation and replication; and thereby the progression of JCV-induced CNS disease.

描述（由申请人提供）：进行性多灶性白质脑病 (PML) 是一种中枢神经系统 (CNS) 脱髓鞘疾病 人多瘤病毒 JC 对少突胶质细胞的裂解性感染 病毒（PML曾被认为是中老年人罕见的并发症 患有淋巴细胞增生性疾病的患者。然而近年来，越来越多 艾滋病患者 PML 发生率高于免疫抑制患者 疾病使我们相信 PML 也可能被视为与艾滋病相关的一种疾病。 疾病。 JCV 的裂解期似乎高度复杂且难以捉摸。一个 越来越多的实验证据表明，JC 病毒的调节 基因表达和复制不仅仅由存在或缺失介导 给定细胞中的特定转录因子。比较精致 转录之间的相互作用或宿主与病毒之间的相互作用 调节蛋白似乎是这方面的重要决定因素。在 为了支持这一假设，我们最近提出了具体的证据 细胞因子 YB-1 和 JCV T 抗原之间的功能相互作用 表明这两种蛋白在 J 表达中发挥重要作用。此外， 我们最新发表和未发表的数据表明，JCV 晚期 Agno 蛋白质、抗原似乎也对病毒基因具有调节作用 通过与病毒和细胞相互作用进行表达和 DNA 复制 蛋白质，特别是 T 抗原和 YB-1。因此，我们在这里建议调查 功能性调节 JCV 的分子机制 T 抗原、Agno 和 YB-1 之间的相互作用。通过运用分子生物学， 遗传学和病毒学方法，我们将 i) 进行彻底的分子生物学 病毒学研究以确定 Agno 在 JCV 基因调节中的作用 通过检查其物理和功能来转录和复制 与T-抗原和YB-1相互作用； ii) 研究功能重要性 通过早期 Agno 的异位表达来控制 Agno 病毒裂解周期 感染突变分析； iii) 描述潜力 Agno 蛋白磷酸化位点并研究其在 JCV 生命中的作用 循环。此类综合研究的结果将提供有价值的信息 JCV 基因调控和相关机制的信息 复制；从而导致 JCV 诱导的 CNS 疾病的进展。