NEUROIMMUNOLOGY OF HUMAN NEUROTROPIC JCV DNA REPLICATION

人类神经营养 JCV DNA 复制的神经免疫学

• 批准号: 6186328
• 负责人: Kamel Khalili
• 金额: $ 20.71万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-05 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6186328
• 关键词: DNA binding protein; DNA replication; HIV infections; Polyomavirus hominis 2; gel mobility shift assay; gene expression; glia; human tissue; microorganism immunology; molecular cloning; neuroimmunomodulation; progressive multifocal leukoencephalopathy; protein structure function; tissue /cell culture; transfection; virus infection mechanism; virus replication

DESCRIPTION (Adapted from applicant's abstract): Coordination of the immune response to viral infection and disease in the brain is believed to involve bi-directional discourse between the immune system and the central nervous system (CNS). Progressive multifocal leukoencephalopathy (PML) is a neurodegenerative disease associated with a wide range of neurological impairments and neurobehavioral dysfunction including subcortical dementia. The human polyomavirus, JCV, which infects greater than 70% of the adult population, is the etiological agent of this disease. Infection with JCV occurs during childhood and the virus remains at the latent state with no apparent clinical symptoms. However, under immunosuppressed conditions, the virus enters the lytic cycle, and upon cytolytic destruction of glial cells, causes PML. The investigators hypothesize that the bi-modal interaction of immune and nervous systems promotes a regulatory mechanism in the JCV-infected cells which suppresses viral replication and maintains the virus in the latent state. Thus, the absence of this negative regulator in the infected cells leads to the reactivation of JCV and the development of PML. In support of this hypothesis the investigators have demonstrated that secretory factor from immune cells derived from non-PML individuals and that stimulate expression of a cellular protein in glial cells which binds to the viral origin of DNA replication, inhibit JCV DNA replication in glial cells. In this research project, the investigators propose to: (i) determine the immune cell induced negative regulatory factors from glial cells which are responsible for suppression of JCV replication, (ii) evaluate the ability of immune cells from PML patients in suppressing JCV DNA replication and inducing the activity of the candidate suppressor protein; and (iii) molecularly clone the gene encoding the suppressor protein and assess its expression and function in PML and non-PML individuals.

描述（改编自申请人的摘要）：免疫的协调 人们认为对大脑病毒感染和疾病的反应涉及 免疫系统与中枢神经之间的双向话语 系统（CNS）。 进行性多灶性白血病（PML）是一个 神经退行性疾病与广泛的神经学有关 障碍和神经行为功能障碍，包括皮质下痴呆。 人类多瘤病毒JCV，它感染了超过70％的成年人 人口，是该疾病的病因。 JCV感染 发生在童年时期，病毒仍处于潜在状态，没有 明显的临床症状。 但是，在免疫抑制条件下 病毒进入裂解周期，并在神经胶质细胞的细胞溶解时， 导致PML。 研究人员假设双模式相互作用 免疫和神经系统促进了一种调节机制 JCV感染的细胞抑制病毒复制并保持 病毒处于潜在状态。 因此，没有这种负调节剂 感染的细胞导致JCV的重新激活和发展 PML。 为了支持这一假设，研究人员表明 来自非PML个体的免疫细胞的分泌因子， 刺激在神经胶质细胞中的细胞蛋白的表达，与 DNA复制的病毒起源，抑制神经胶质细胞中的JCV DNA复制。 在该研究项目中，研究人员建议：（i）确定 免疫细胞引起的神经胶质细胞的负调控因子是 负责抑制JCV复制，（ii）评估 PML患者的免疫细胞抑制JCV DNA复制和 诱导候选抑制蛋白的活性； （iii） 分子克隆编码抑制蛋白的基因并评估其 PML和非PML个体中的表达和功能。