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（HCV）蛋白的翻译。作为病毒生命周期中的一个重要步骤，HCV蛋白的翻译主要由位于5 '非翻译区（5' UTR）的内部核糖体进入位点（IRES）控制。此外，3 'UTR和非结构蛋白-5A（NS 5A）已显示影响HCV蛋白翻译。我们已经证明，HCV NS 5A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Akt 3参与调节HCV蛋白翻译。因此，本提案的短期目标是进一步表征HCV NS 5A调节HCV蛋白翻译的分子机制。我们将检验HCV NS 5A蛋白通过与HCV 3 'UTR结合和通过Akt 3介导的信号转导途径抑制HCV蛋白翻译的假设。研究将侧重于三个目标。 1. 进一步表征NS 5A对HCV 3 'UTR结合和HCV蛋白翻译的调节。 2. 描述病毒和细胞蛋白如何调节NS 5A对HCV蛋白翻译的影响。 3. 研究Akt 3对HCV NS 5A蛋白翻译调控的影响。 该提案将为病毒学和分子生物学研究生和本科暑期学生的培训提供一个极好的机会。这项研究非常重要，因为HCV感染了高达3%的人口。没有疫苗可用，目前的抗病毒药物的疗效远远不能令人满意。从该提案中获得的知识可能会导致新的抗病毒开发，靶向HCV蛋白翻译，NS 5A RNA结合，NS 5A磷酸化和/或Akt 3。HCV在家犬中有一种同源病毒（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，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.