Using viruses as tools to elucidate the molecular mechanisms for transport into the nucleus

所有真核细胞都有一个独特的核，其中包括细胞所属有机体的遗传蓝图。执行基因蓝图中包含的指令需要在细胞质和细胞核之间运输分子--这一过程被称为核运输。这种运输对所有真核细胞都是必不可少的，也调节着细胞生理的许多方面。尽管核运输具有明显的重要性，尽管该领域最近取得了许多进展，但其分子机制、结构基础或调控的许多方面仍然难以捉摸。我的研究计划的长期目标是阐明大分子进入原子核的机制。由于许多病毒病原体在细胞核内进行复制，因此必须将它们的基因组和亚病毒颗粒运送到它们的宿主细胞的细胞核中，我们正在使用病毒作为工具来了解核运输的分子机制。在我们的研究中，我们使用了结构、功能、生化和遗传方法的组合。此外，我们广泛使用高分辨率电子显微镜来跟踪病毒的移动和进入细胞核。这些研究的结果将揭示核运输的基本机制，并将对了解病毒进入细胞核的运输，更广泛地说，将DNA输送到细胞核，这也是基因治疗中的转基因和基因输送的关键步骤做出重大贡献。因此，我们对病毒核转运的研究也有助于开发高效的转基因技术和基因治疗载体。

All eukaryotic cells have a distinct nucleus containing, among other things, the genetic blueprint of the organism to which the cell belongs. Carrying out the instructions contained in the genetic blueprint requires trafficking of molecules between the cytoplasm and the nucleus - a process known as nuclear transport. This trafficking is essential to all eukaryotic cells, and also regulates many aspects of cell physiology. Despite the obvious importance of nuclear transport and despite many recent advances in this field, many aspects of its molecular mechanism, its structural basis, or its regulation remain elusive. The long-term objective of my research program is to elucidate the mechanisms by which macromolecules enter the nucleus. Because many viral pathogens undertake their replication within the nucleus, and therefore must deliver their genome and subviral particles into the nucleus of their host cells, we are using viruses as tools to understand the molecular mechanisms for nuclear transport. In our studies we use a combination of structural, functional, biochemical, and genetic approaches. In addition, we extensively use high-resolution electron microscopy to track the virus' movement and entry into the nucleus. Findings from these studies will shed new light on the fundamental mechanisms of nuclear transport, and will make significant contributions to understanding the transport of viruses into the nucleus, and more generally the delivery of DNA to nucleus, which is for example also an essential step in transfection and gene delivery in gene therapy. Therefore, our studies of nuclear trafficking of viruses could also help developing efficient transfection techniques and gene therapy vectors.