The role of interferon-stimulated genes in antiviral immunity

描述(申请人提供)：干扰素(干扰素)是一种抗病毒细胞因子，通过诱导300+干扰素刺激基因(ISGs)来调节其活性。这些基因中的几个是众所周知的病毒复制抑制因子，但大多数ISG仍然没有关于它们的抗病毒潜力的特征。基因芯片和基因敲除研究表明，许多ISGs具有显著的抗病毒功能。该项目的长期目标是确定和表征对丙型肝炎病毒(丙型肝炎病毒)具有新的抗病毒活性的ISGs。丙型肝炎病毒是非甲非乙型病毒性肝炎的病原体。我们的实验方法依赖于生成一组基于慢病毒的载体，这些载体表达所有已知的ISG。这些收集将在高通量试验中进行筛选，以寻找在过度表达时抑制丙型肝炎病毒复制的基因。我们将利用最近发展的丙型肝炎病毒感染的细胞培养模型来进行这一筛查。候选的抗丙型肝炎病毒ISGs将进一步用功能分析来确定它们的作用机制。我们还计划利用我们的基于筛选的方法来识别对不同病毒家族表现出新的抗病毒活性的ISG。我们的分析将包括几种重要的人类病原体，包括登革热病毒(DV)和甲型流感病毒(FLUA)。来自每个病毒家族代表性成员的数据将被汇编成一份“ISG档案”，用于跨家族的比较分析。尽管病毒是导致人类疾病的重要因素，但干扰素等抗病毒疗法往往无效且有毒，这一事实突显了这项研究。丙型肝炎病毒影响着世界上大约3%的人口，并在很大程度上导致了肝硬变和肝癌；登革热是一个全球性的健康问题，感染了数百万人，并导致登革热和严重的登革热出血热；仅在美国，每年就有3万多人死于流感病毒。识别对这些病毒和其他病毒具有抗病毒活性的基因对于开发新型、高效的抗病毒治疗药物非常重要。

DESCRIPTION (provided by applicant): Interferon (IFN) is an antiviral cytokine that mediates its activity through the induction of 300+ interferon-stimulated genes (ISGs). Several of these genes are well-known inhibitors of virus replication, but the majority of the ISGs remain uncharacterized with respect to their antiviral potential. Microarray and knock-out studies suggest that many of these ISGs possess significant antiviral functions. The long-term objectives of this project are to identify and characterize ISGs that exhibit novel antiviral activity in response to hepatitis C virus (HCV), the etiological agent of non-A, non-B viral hepatitis. Our experimental approach relies on generating a collection of lentiviral-based vectors that express all known ISGs. The collection will be screened in a high-throughput assay for genes that inhibit HCV replication when overexpressed. We will take advantage of the recently developed cell culture model of HCV infection to carry out this screen. Candidate anti-HCV ISGs will be further characterized with functional assays to determine their mechanisms of action. We also plan to utilize our screen-based approach to identify ISGs that exhibit novel antiviral activity against different virus families. Several significant human pathogens, including Dengue virus (DV) and influenza A virus (FluA), will be included in our analysis. Data from representative members of each virus family will be assembled into an "ISG profile," which will be used for cross-family comparative analysis. This research is highlighted by the fact that although viruses are significant contributors to human disease, antiviral therapies such as IFN are often ineffective and toxic. HCV affects approximately 3 percent of the world's population and contributes significantly to cirrhosis and liver cancer; DV is a global health concern that infects millions of people and causes dengue fever and the severe dengue hemorrhagic fever; FluA results in the death of more than 30,000 people each year in the US alone. Identifying genes that exhibit antiviral activity against these and other viruses is important for generating novel, highly effective antiviral therapeutic agents.