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: 6627804
• 负责人: MAHMUT SAFAK
• 金额: $ 28.6万
• 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/6627804
• 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 In addition, our most recent published and unpublished data indicate that JCV late Agno protein, antigen, also appears to have regulatory roles in both viral gene expression and DNA replication through interaction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）：进行性多灶性白细胞病 （PML）是中枢神经系统（CNS）的脱髓鞘疾病，导致 从人类多瘤病毒JC的少突胶质细胞的裂解感染中 病毒（PML曾经被认为是中年和老年人的罕见并发症 患有淋巴结菌病的患者。但是，近年来，越来越多 艾滋病患者的PML发病率高于那些机智的免疫抑制 疾病使我们相信PML也可能被视为艾滋病相关 疾病。 JCV的裂解阶段似乎是高度复杂的，并且仍然难以捉摸。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而介导 给定细胞中特定转录因子的特定。相当细腻 转录或宿主与病毒之间的相互作用之间的相互作用 调节蛋白似乎是重要的决定因素。在 对这一假设的支持，我们最近提出了特定的证据 细胞因子，Yb-1和JCV T抗原与 表明两种蛋白质在J表达中都起着重要作用。此外， 我们最近发布和未发表的数据表明JCV晚期Agno 蛋白质，抗原似乎在两个病毒基因中都具有调节作用 通过与病毒和细胞相互作用的表达和DNA复制 蛋白质，尤其是T-抗原和YB-1。因此，我们在这里提出调查 功能与JCV调控有关的分子机制 T-抗原，Agno和YB-1之间的相互作用。通过采用分子生物学， 遗传学和病毒学方法，我们将进行彻底的分子 病毒学研究以确定AGNO在JCV基因调节中的作用 通过检查其身体和功能的转录和复制 与T-抗原和YB-1的相互作用； ii）研究功能重要性 通过两种异位表达Agno的Agno早期的异位表达 感染突变分析； iii）表征潜力 Agno蛋白的磷酸化位点，并研究JCV寿命中的作用 循环。这样的全面研究的结果将提供有价值的 JCV基因调节和 复制；因此，JCV诱导的中枢神经系统疾病的进展。