MECHANISMS OF HERPES SIMPLEX VIRUS 1 NUCLEAR ENTRY

接触到宿主细胞的核是 复制许多病毒。单纯疱疹病毒1型(HSV-1)由 病毒衣壳太大而无法进入细胞核本身。 因此，将单纯疱疹病毒1型S的双链基因组引入到 在严格控制的去涂层步骤中，宿主细胞的细胞核。这个 控制疱疹病毒生命中这一关键步骤的病毒-宿主相互作用 周期在很大程度上仍然不为人知。 这项拟议的研究的目标是确定疱疹病毒的衣壳是如何 停靠在细胞的核孔上，脱去外衣，将其DNA送入 原子核。由于病毒经常利用正常的细胞过程，最近 将利用我们对一般核进口的理解方面的进展 研究疱疹病毒基因组核进入的具体问题。三 提出了细胞生物学、生物化学和遗传学的方法。 确定了介导这一过程的病毒和细胞因素。 研究这些重要的病毒-宿主相互作用将使我们更近距离地 为了理解病毒学中一个长期存在的谜团：为什么传入 衣壳很容易脱下外套，而新组装的外露衣壳却不会？ 此外，这项工作将进一步加深我们对核能的总体理解 运输。最后，拟议的实验结果可能会导致 开发更有效的抗病毒疗法以及更多 高效的基因传递系统。 拟议的项目将在耶鲁大学阿里·赫勒尼乌斯的实验室进行 大学医学院，将极大地提升我的体验 作为一名内科医生/科学家，因为它提供病毒学和 细胞生物学。此外，研究事业奖将提供 为了达到我的长期目标，我需要接受必要的培训：在 学术医学，主要强调独立研究 这项计划将产生与赫勒尼乌斯博士的工作。

Access to the nucleus of the host cell is a prerequisite for the replication of many viruses. Herpes simplex virus-1 (HSV-1) consists of a viral capsid that is too large to enter the nucleus itself. Therefore, HSV-1's double-stranded DNA genome is introduced into the nucleus of the host cell in a tightly regulated uncoating step. The viral-host interactions that control this key step in the herpes life cycle remain largely unknown. The goal of the proposed research is to determine how the herpes capsid docks at the cell's nuclear pore, uncoats, and delivers its DNA into the nucleus. Since viruses often exploit normal cellular processes, recent advances in our understanding of general nuclear import will be used to study the specific problem of herpes genome nuclear entry. Three approaches - cell biological, biochemical, and genetic - are proposed for defining the viral and cellular factors that mediate this process. Studying these important viral-host interactions will bring us closer to understanding a long-standing mystery in virology: why do incoming capsids readily uncoat, while newly-assembled outgoing capsids do not? In addition, this work will further our general understanding of nuclear transport. Finally, results of the proposed experiments may lead to the development of more effective antiviral therapies as well as more efficient gene delivery systems. The proposed project, to be conducted in Ari Helenius's lab at Yale University School of Medicine, will significantly enhance my experience as a physician/scientist, since it offers training in both virology and cell biology. Furthermore, the Research Career Award will provide the necessary training for me to reach my long-term goal: a career in academic medicine, with primary emphasis on an independent research program that will arise from this work with Dr. Helenius.