Hepatitis C viral protein translation modulation

丙型肝炎病毒蛋白翻译调节

• 批准号: 298484-2013
• 负责人: Liu, Qiang
• 金额: $ 2.62万
• 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: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629763
• 关键词: Hepatitis; viral; protein; translation; modulation

The long-term goal of this research program is to study hepatitis C virus (HCV) protein translation. As an important step in virus lifecycle, HCV protein translation is primarily controlled by an internal ribosomal entry site (IRES) present in the 5'untranslated region (5'UTR). In addition, 3'UTR and nonstructural protein-5A (NS5A) have been shown to impact HCV protein translation. We have demonstrated that HCV NS5A inhibits HCV protein translation through binding to the poly-U/UC sequence in the 3'UTR. In addition, our ongoing research showed that a cellular kinase Akt3 is involved in modulating HCV protein translation. As such, the short-term goal of this proposal is to further characterize the molecular mechanisms by which HCV NS5A modulates HCV protein translation. We will test the hypothesis that HCV NS5A protein inhibits HCV protein translation through binding to HCV 3'UTR and through Akt3-mediated signal transduction pathways. Research will focus in three objectives.1. Further characterize HCV 3'UTR binding and HCV protein translation modulation by NS5A.2. Characterize how viral and cellular proteins modulate the effect of NS5A on HCV protein translation.3. Study the impact of Akt3 on HCV protein translation modulation by HCV NS5A. This proposal will provide an excellent opportunity for the training of graduate students and undergraduate summer students in virology and molecular biology. The proposed research is very important because HCV is infecting up to 3% of the population. No vaccines are available and the efficacy of current anti-virals is far from satisfactory. Knowledge gained from this proposal may lead to new anti-viral development targeting HCV protein translation, NS5A RNA binding, NS5A phosphorylation, and/or Akt3. HCV has a homolog virus in domestic dogs (canine hepacivirus). HCV is also very similar to a bovine pathogen bovine viral diarrhea virus (BVDV). Therefore, this proposal will have important implications in the research of animal viruses.

该研究计划的长期目标是研究丙型肝炎病毒（HCV）蛋白翻译。作为病毒生命周期的重要一步，HCV 蛋白翻译主要由 5' 非翻译区 (5'UTR) 中的内部核糖体进入位点 (IRES) 控制。此外，3'UTR 和非结构蛋白 5A (NS5A) 已被证明会影响 HCV 蛋白翻译。我们已经证明HCV NS5A 通过与3'UTR 中的poly-U/UC 序列结合来抑制HCV 蛋白翻译。此外，我们正在进行的研究表明，细胞激酶 Akt3 参与调节 HCV 蛋白翻译。因此，该提案的短期目标是进一步表征 HCV NS5A 调节 HCV 蛋白翻译的分子机制。我们将检验 HCV NS5A 蛋白通过与 HCV 3'UTR 结合并通过 Akt3 介导的信号转导途径抑制 HCV 蛋白翻译的假设。研究将集中在三个目标上： 1．进一步表征 NS5A.2 的 HCV 3'UTR 结合和 HCV 蛋白翻译调节。描述病毒和细胞蛋白如何调节 NS5A 对 HCV 蛋白翻译的影响。3．研究 Akt3 对 HCV NS5A 调节 HCV 蛋白翻译的影响。该提案将为病毒学和分子生物学研究生和本科生暑期学生的培训提供绝佳的机会。拟议的研究非常重要，因为 HCV 感染了高达 3% 的人口。目前还没有疫苗可用，目前的抗病毒药物的疗效也远不能令人满意。从该提案中获得的知识可能会导致针对 HCV 蛋白翻译、NS5A RNA 结合、NS5A 磷酸化和/或 Akt3 的新抗病毒开发。 HCV在家犬中有同源病毒（犬肝炎病毒）。 HCV 也与牛病原体牛病毒性腹泻病毒 (BVDV) 非常相似。因此，该提议将对动物病毒的研究具有重要意义。