Proteins Mediating Interaction of HIV-1 and JCV in CNS

介导中枢神经系统中 HIV-1 和 JCV 相互作用的蛋白质

基本信息

批准号：
7382577
负责人：
EDWARD M. JOHNSON
金额：
$ 42.35万
依托单位：
EASTERN VIRGINIA MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-02-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7382577
关键词：
Acquired Immunodeficiency Syndrome Affect Automobile Driving Binding Biological Assay Brain Categories Cells Conditioned Culture Media DNA biosynthesis Data Development Environment Exposure to Gene Chips Genes Genetic Transcription Goals HIV HIV tat Protein HIV-1 Immunocompromised Host Immunohistochemistry Immunologic Deficiency Syndromes Immunomodulators Immunosuppression Incidence Individual Infection Intervention JC Virus Knock-out LacZ Genes Late Gene Transcriptions Lesion Leukoencephalopathy Localized Mediating Mediation Methods Microglia Mus Neurodegenerative Disorders Neuroglia Nuclear Oligodendroglia PCNA gene Pathway interactions Patients Plasmids Play Procedures Process Production Progressive Multifocal Leukoencephalopathy Proteins PurA protein Regulatory Pathway Reporter Genes Research Personnel Role Signal Pathway Signal Transduction Smad Proteins Smad protein T-Lymphocyte Testing Therapeutic immunosuppression Tissues Transgenic Organisms Virus Activation Virus Diseases brain tissue chromatin immunoprecipitation cyclin T1 cytokine in vivo macrophage monocyte mouse model programs promoter research study tat Protein viral DNA

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to elucidate the mechanisms by which activation of JC virus in glial cells of the brain is influenced by HIV-1 infection. JC virus (JCV) is the etiologic agent of the neurodegenerative disease, progressive multifocal leukoencephalopathy (PML). JCV is normally latent in non-immunocompromised people, but it is activated in brains of individuals with AIDS. Because of the high incidence of PML in AIDS, we have hypothesized that HIV-1 plays a role greater than that expected of immunosuppression alone. We shall capitalize upon our extensive results of the last few years, which can be grouped in two categories. In one we have demonstrated the role of the Tat protein of HIV-1 in stimulating JCV late gene transcription and JCV DMA replication. In the other we have demonstrated that HIV-1 infection alters pathways of production and signal transduction of immunomodulators, including TGF-01, in the CNS. We propose to determine how the Smad nuclear effectors of TGF-31 interact with Tat and its cellular partner proteins Pura and Cyclin T1/ Cdk9 at JCV and PCNA promoter sequences. Our new double chromatin immunoprecipitation method will be employed in conjunction with functional studies on JCV DMA replication and gene transcription. We shall employ a microarray to identify genes in glial cells regulated by exposure to cytokines produced by HIV-1-infected cells. We shall employ a transgenic mouse model to test the hypothesis that factors produced by HIV-1-infected cells can influence JCV promoters in the CNS and play a role in early steps of PML development. Tissue from the Manhattan HIV Brain Bank will be used to determine whether TGF-P1 or its nuclear effectors, Smad3, Smad4 or Fasti, are localized or activated in specific cells of PML lesions. Results will help elucidate pathways of activation of JCV in the brain and will help target particular molecular interactions for therapy.

描述（由申请人提供）：该项目的总体目标是阐明大脑神经胶质细胞中JC病毒激活的机制受HIV-1感染的影响。 JC病毒（JCV）是神经退行性疾病，进行性多灶性白血病（PML）的病因学药。 JCV通常在非免疫力低下的人群中潜在潜在，但在有艾滋病的个体的大脑中被激活。由于PML在艾滋病中的发生率很高，我们假设HIV-1的作用大于仅免疫抑制的预期。我们将利用过去几年的广泛成果，这可以分为两类。在其中，我们证明了HIV-1的TAT蛋白在刺激JCV晚期基因转录和JCV DMA复制中的作用。在另一种情况下，我们证明了HIV-1感染改变了CNS中的免疫调节剂的生产和信号转导途径，包括TGF-01。我们建议在JCV和PCNA启动子序列上确定TGF-31的SMAD核效应如何与TAT及其细胞伴侣蛋白Pura和Cyclin T1/ CDK9相互作用。我们的新双重染色质免疫沉淀方法将与JCV DMA复制和基因转录的功能研究一起使用。我们将采用微阵列来鉴定受HIV-1感染细胞产生的细胞因子调节的神经胶质细胞中的基因。我们将采用转基因小鼠模型来检验以下假设：HIV-1感染细胞产生的因素可以影响中枢神经系统中的JCV启动子，并在PML发育的早期步骤中发挥作用。曼哈顿HIV脑库的组织将用于确定TGF-P1或其核效应子SMAD3，SMAD4或FASTI是否在PML病变的特定细胞中局部或激活。结果将有助于阐明大脑中JCV激活的途径，并有助于靶向特定的分子相互作用进行治疗。