Hepatitis C viral protein translation modulation

该研究项目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步骤，HCV蛋白翻译主要受5‘非翻译区（5’UTR）内核糖体进入位点（IRES）控制。此外，3'UTR和非结构蛋白5a （NS5A）已被证明影响HCV蛋白翻译。我们已经证明HCV NS5A通过结合3'UTR中的poly-U/UC序列抑制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，本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。我们将验证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。进一步表征HCV 3'UTR结合和NS5A.2对HCV蛋白翻译的调节作用。描述病毒和细胞蛋白如何调节NS5A对HCV蛋白翻译的影响。研究Akt3对HCV NS5A对HCV蛋白翻译调节的影响。本项目将为培养病毒学和分子生物学的研究生和本科生暑期生提供一个极好的机会。拟议的研究非常重要，因为丙型肝炎病毒感染率高达3%。没有可用的疫苗，而且目前的抗病毒药物的疗效远不能令人满意。从这一建议中获得的知识可能会导致新的抗病毒开发针对HCV蛋白翻译、NS5A RNA结合、NS5A磷酸化和/或Akt3。HCV在家养狗中有同源病毒（犬肝病毒）。丙型肝炎病毒也非常类似于牛病原体牛病毒性腹泻病毒（BVDV）。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.