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：
8433379
负责人：
Charles M Rice
金额：
$ 39.72万
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/8433379
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) 是特征明确的细胞因子，可抑制多种病毒。介导 IFN 抗病毒功能的细胞蛋白源自干扰素刺激基因 (ISG)，可用于开发泛热带抗病毒药物。不幸的是，人们对哪些 ISG 具有抗病毒作用知之甚少，它们的特异性在很大程度上尚未确定，而且它们的作用机制仍然难以捉摸。我们建议通过进行一系列大规模筛选来确定不同病毒的“ISG 图谱”，以解决科学知识方面的这一差距。我们已将超过 380 个通常上调的 ISG 克隆到慢病毒载体中，并使用双色流式细胞术测定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 针对不同家族的一系列病毒的抗病毒功能，特别是丙型肝炎病毒 (HCV) 和甲型流感病毒 (FluA)。这些病毒中的每一种都对全球健康产生重大影响，其病理范围从肝细胞癌到严重呼吸道疾病，潜在后果涵盖终身慢性感染到急性大流行事件。对不同病毒种、属和科的 ISG 图谱进行比较将开始揭示 ISG 特异性的范围。在不同细胞条件下筛选选定的病毒将解决 ISG 功能的深度问题。对最有趣的命中的验证和机制剖析将阐明 ISG 在对抗感染中的作用，并可能产生将天然存在的广谱抗病毒活性转化为临床有用的化合物的新策略。