Type I interferon-stimulated genes and the antiviral immune response

I 型干扰素刺激基因和抗病毒免疫反应

基本信息

批准号：
8611896
负责人：
Charles M Rice
金额：
$ 42.25万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8611896
关键词：
Acute Address Adverse effects Antiviral Agents Arteriviridae Biological Assay Biology Cataloging Catalogs Cells Cessation of life Chikungunya virus Chronic Color Communicable Diseases DNA Viruses Data Development Dissection Environment Event Exhibits Family Flaviviridae Flow Cytometry Gene Expression Gene Expression Profile Gene Library Genes HCV screening HIV HIV-1 Hepatitis C Hepatitis C virus Herpesviridae Human IRF1 gene Immune response Individual Infection Influenza Influenza A virus Interferon Type I Interferons Knowledge LY6E gene Lentivirus Vector Life Cycle Stages Longevity Lung diseases MAP3K14 gene Mediating Molecular Probes Orthomyxoviridae Outcome Paramyxoviridae Pathology Pathway interactions Phylogenetic Analysis Poxviridae Primary carcinoma of the liver cells Proteins RNA Viruses Reoviridae Reporting Rhabdoviridae Role Series Signal Pathway Specificity System TREX1 gene Testing Therapeutic Time Togaviridae Translating Validation Venezuelan Equine Encephalitis Virus Viral Virus Virus Diseases West Nile virus Yellow fever virus base cell type combat cytokine gene function global health influenzavirus insight interest member overexpression pandemic disease pathogen public health relevance response screening

项目摘要

DESCRIPTION (provided by applicant): Type I interferons (IFNs) are well-characterized cytokines that inhibit a wide range of viruses. The cellular proteins that mediate the antiviral functions of IFN are derived from interferon-stimulated genes (ISGs), and are potentially exploitable for the development of pan-tropic antiviral drugs. Unfortunately, very little is known about which ISGs are antiviral, their specificity is largely undetermined, and their mechanisms of action remain elusive. We propose to address this gap in scientific knowledge by conducting a series of large-scale screens to determine the "ISG profile" of diverse viruses. We have cloned over 380 commonly upregulated ISGs into a lentiviral vector and optimized conditions to correlate the expression of these genes with viral replication using a two-color flow cytometric assay. The ISG library will be used to probe ISG antiviral function against an array of viruses form diverse families, with a special emphasis on hepatitis C virus (HCV) and influenza virus A (FluA). Each of these viruses has a significant impact on global health, with pathologies ranging from hepatocellular carcinoma to severe respiratory disease, and potential outcomes spanning life-long chronic infection to acute pandemic events. Comparison of ISG profiles from across viral species, genera, and families will begin to reveal the range of ISG specificities. Screens of select viruses under different cellular conditions will address the depth of ISG function. Validation and mechanistic dissection of the most interesting hits will clarify the roles of ISGs in combating infection, and may yield new strategies for translating naturally occurring broad-spectrum antiviral activities into clinically useful compounds.

描述（由申请人提供）：I型干扰素（IFN）是抑制广泛病毒的特征性细胞因子。介导IFN抗病毒功能的细胞蛋白来自干扰素刺激的基因（ISGS），并且有可能利用用于开发泛热抗病毒药物。不幸的是，对于哪些ISG是抗病毒，其特异性在很大程度上不确定，并且其作用机理仍然难以捉摸。我们建议通过进行一系列大规模屏幕来确定各种病毒的“ ISG概况”，以解决科学知识中的这一差距。我们已经将380多个通常上调的ISG克隆到慢病毒载体中，并使用两种颜色的流式细胞仪测定法将这些基因的表达与病毒复制相关联。 ISG文库将用于探测ISG抗病毒功能，以构成各种家族的病毒，并特别强调丙型肝炎病毒（HCV）和流感病毒A（FLUA）。这些病毒中的每一个都对全球健康都有重大影响，从肝细胞癌到严重的呼吸道疾病，病理不等，以及跨越终身慢性感染再到急性大流行事件的潜在结果。跨病毒物种，属和家族的ISG谱的比较将开始揭示ISG特异性的范围。在不同的细胞条件下，精选病毒的筛选将解决ISG功能的深度。最有趣的热门单曲的验证和机理解剖将阐明ISG在打击感染中的作用，并可能产生新的策略，以将天然发生的广谱抗病毒活性转化为临床上有用的化合物。