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: 6214774
• 负责人: Kamel Khalili
• 金额: $ 7.43万
• 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 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6214774
• 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）：免疫协调 据信，对病毒感染和大脑疾病的反应涉及 免疫系统和中枢神经之间的双向对话 系统（中枢神经系统）。 进行性多灶性白质脑病 (PML) 是一种 与多种神经系统疾病相关的神经退行性疾病 损伤和神经行为功能障碍，包括皮质下痴呆。 人类多瘤病毒 (JCV)，感染超过 70% 的成年人 人群，是本病的病原体。 JCV感染 发生在儿童时期，病毒处于潜伏状态，没有 明显的临床症状。 然而，在免疫抑制的条件下， 病毒进入裂解周期，并在神经胶质细胞被细胞裂解破坏后， 导致 PML。 研究人员假设双模态相互作用 免疫和神经系统促进调节机制 JCV感染的细胞抑制病毒复制并维持 病毒处于潜伏状态。 因此，缺乏这种负调节剂 受感染的细胞导致 JCV 重新激活并发展 PML。 为了支持这一假设，研究人员证明了 来自非 PML 个体的免疫细胞的分泌因子 刺激神经胶质细胞中细胞蛋白的表达，该蛋白与 病毒DNA复制起点，抑制神经胶质细胞中JCV DNA复制。 在这个研究项目中，研究人员建议：（i）确定 免疫细胞诱导神经胶质细胞的负调节因子 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； (三) 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。