Hepatitis C viral protein translation modulation

该研究计划的长期目标是研究丙型肝炎病毒(丙型肝炎病毒)的蛋白翻译。作为病毒生命周期中的重要一步，丙型肝炎病毒蛋白的翻译主要由位于5‘非翻译区的内部核糖体进入位点(IRES)控制。此外，3‘非结构蛋白-5A(NS5A)和3’端非结构蛋白-5A(NS5A)对丙型肝炎病毒蛋白的翻译也有影响。我们已经证明，丙型肝炎病毒NS5A通过与3‘非编码区的聚U/UC序列结合来抑制丙型肝炎病毒的蛋白翻译。此外，我们正在进行的研究表明，细胞激酶AKT3参与调节丙型肝炎病毒蛋白的翻译。因此，这项建议的短期目标是进一步表征丙型肝炎病毒NS5A调节丙型肝炎病毒蛋白翻译的分子机制。我们将验证这一假设，即丙型肝炎病毒NS5A蛋白通过与丙型肝炎病毒3‘端非编码区结合以及通过AKT3介导的信号转导途径抑制丙型肝炎病毒蛋白的翻译。研究将集中在三个目标上。 1.进一步研究NS5A对丙型肝炎病毒3‘端非编码区的结合及对丙型肝炎病毒蛋白翻译的调控。 2.研究病毒和细胞蛋白如何调节NS5A对丙型肝炎病毒蛋白翻译的影响。 3.研究AKT3在丙型肝炎病毒NS5A对丙型肝炎病毒蛋白翻译调控中的作用。 这项建议将为研究生和本科生暑期学生提供一个很好的机会来培训病毒学和分子生物学。这项拟议的研究非常重要，因为丙型肝炎病毒感染了高达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远不能令人满意。从这项建议中获得的知识可能会导致针对丙型肝炎病毒蛋白翻译、NS5A RNA结合、NS5A磷酸化和/或AKT3的新的抗病毒开发。丙型肝炎病毒在家犬中有一种同源病毒(犬肝炎病毒)。丙型肝炎病毒也与牛病原体牛病毒性腹泻病毒(BVDV)非常相似。因此，这一建议将对动物病毒的研究具有重要意义。

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.