The role of dicer and argonaute in HCV replication

Dicer 和 argonute 在 HCV 复制中的作用

• 批准号: 342475-2007
• 负责人: Wilson, Joyce
• 金额: $ 2.13万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2010
• 资助国家: 加拿大
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=458808
• 关键词: role; dicer; argonaute; HCV; replication

Our research focuses on how Hepatitis C virus replicates in human cells. Because viruses are obligate intracellular parasites they must avoid cellular defense mechanisms and take over basic cellular operations in order to grow. Thus studying how viruses replicate often reveals novel cellular processes. We are interested in how the replication of HCV is influenced by host cell RNA interference (RNAi) activity. Andrew Fire and Craig Mello first discovered RNAi in 1998 and were recently awarded a Nobel Prize for their work. In plants, RNAi is an important antiviral defense mechanism in which single stranded viral genomic RNA is targeted for destruction by the presence of double stranded viral RNA intermediates. In mammalian cells RNAi works quite differently. Naturally occurring short double stranded RNAs, called microRNA activate similar machinery, but instead of targeting viral RNA for destruction they inhibit messenger RNA from being used for protein synthesis. We are interested in the influence of RNA interference activity on the human virus Hepatitis C. We disabled RNAi activity in cells and were surprised to find that virus replication decreased. This suggested that instead of limiting virus replication as it does in plants, RNAi activity appears to benefit the replication of HCV. Subsequent evidence suggests that this RNAi activity may be novel since it does not resemble other RNAi functions. Our research program is designed to further our knowledge of this undefined cellular regulation mechanism and determine how HCV, a model virus of the Flaviviridae family of single stranded viruses uses this system for its own benefit. In particular we will study the biochemical interactions between HCV and RNAi related proteins, and to find genetic links between HCV and RNA interference activity. These studies will further our knowledge of cell regulation and virus replication and may reveal links between virus replication and pathogenesis.

我们的研究重点是丙型肝炎病毒如何在人体细胞中复制。 由于病毒是专性细胞内寄生虫，它们必须避开细胞防御机制，并接管基本的细胞操作才能生长。 因此，研究病毒如何复制往往揭示新的细胞过程。 我们感兴趣的是HCV的复制是如何受到宿主细胞RNA干扰（RNAi）活性的影响。 安德鲁·费尔和克雷格·梅洛在1998年首次发现了RNAi，最近因他们的工作获得了诺贝尔奖。 在植物中，RNAi是一种重要的抗病毒防御机制，其中单链病毒基因组RNA被双链病毒RNA中间体的存在靶向破坏。 在哺乳动物细胞中，RNAi的工作方式完全不同。 天然存在的短双链RNA，称为microRNA，激活类似的机制，但不是靶向病毒RNA进行破坏，而是抑制信使RNA用于蛋白质合成。 我们感兴趣的是RNA干扰活性对人类丙型肝炎病毒的影响。 我们在细胞中禁用了RNAi活性，并惊讶地发现病毒复制减少了。 这表明，RNAi活性似乎有利于HCV的复制，而不是像在植物中那样限制病毒复制。 随后的证据表明，这种RNAi活性可能是新颖的，因为它不类似于其他RNAi功能。 我们的研究计划旨在进一步了解这种未定义的细胞调节机制，并确定HCV（黄病毒科单链病毒家族的模型病毒）如何使用该系统为其自身利益服务。 特别是，我们将研究HCV和RNA干扰相关蛋白之间的生物化学相互作用，并找到HCV和RNA干扰活性之间的遗传联系。 这些研究将进一步加深我们对细胞调控和病毒复制的认识，并可能揭示病毒复制和发病机制之间的联系。