CHARACTERIZATION OF THE GAMMA HERPES VIRUS HV68 V CYCLIN

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。本研究探讨了由g-疱疹病毒编码的细胞周期蛋白同源物(v-Cyclin)在伽马疱疹病毒致病和潜伏时间中的作用机制。人类伽马疱疹病毒，KSHV和EBV，是癌症的重要原因，特别是在免疫功能低下的人中。由于这些病毒的特殊性，对其发病机制的体内研究一直很有限。我们和其他人一直在开发一个小型动物模型系统，即近交系小鼠感染gHV68，用于分析伽马疱疹病毒感染的发病机制，以及单个伽马疱疹病毒基因在潜伏期和肿瘤诱导中的作用。GHV68感染与淋巴瘤和淋巴组织增生性疾病、严重的弹力性大血管炎和脾纤维化的发生有关。到目前为止的研究表明，gHV68与EBV、KSHV和HVS具有相同的致病机制，验证了它是分析伽马疱疹病毒致病机制中重要问题的模型。这项工作的重点是gHV68v-细胞周期蛋白在疾病发病机制中的作用。值得注意的是，G2-疱疹病毒(HVS、KSHV和gHV68)都编码D型细胞周期蛋白的同源物，而EBV感染则上调宿主D型细胞周期蛋白的表达。我们已经证明，gHV68v-Cyclin是一种促进原代淋巴细胞细胞周期进展的癌基因，并且gHV68v-Cyclin突变体对潜伏感染的MM和/或B细胞的反应效率低下。这些观察结果导致了以下三个具体目标。目的1.确定gHV68v-Cyclin在潜伏期和再激活中的作用(S)。目的2.gHV68v-Cyclin表达的特征性调控。目的3.明确gHV68v-细胞周期蛋白与宿主D、E型细胞周期蛋白功能差异的结构和生化基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This research investigates the mechanisms by which cyclin homologs encoded by g-herpesviruses (v-cyclin) contribute to gammaherpesvirus pathogenesis and latency. The human gammaherpesviruses, KSHV and EBV, are important causes of cancer, especially in immunocompromised individuals. Because of the specificity of these viruses, in vivo studies of the pathogenesis have been limited. We and others have been developing a small animal model system, infection of inbred mice with gHV68, for analysis of the pathogenesis of gammaherpesvirus infection and the role of individual gammaherpesvirus genes in latency and tumor induction. gHV68 infection is associated with the development of lymphoma and lymphoproliferative disease, severe vasculitis of the great elastic vessels and splenic fibrosis. Studies to date indicate that gHV68 share pathogenetic mechanisms with EBV, KSHV and HVS, validating it as a model for analysis of important questions in gammaherpesvirus pathogenesis. This work is focused on the role of the gHV68 v-cyclin in disease pathogenesis. Notably, the g2-herpesvirus (HVS, KSHV and gHV68) all encode homologs of D-type cyclins, while EBV infection up regulates expression of host d-type cyclins. We have shown that the gHV68 v-cyclin is an oncogene that promotes cell cycle progression in primary lymphocytes and that a gHV68 v-cyclin mutant reacts inefficiently from latently infected MM and or B cells. These observations lead to the following 3 specific aims. Aim 1. Determine the role(s) of the gHV68 v-cyclin in latency and reactivation. Aim 2. Characterized regulation of gHV68 v-cyclin expression. Aim 3. Define the structural and biochemical basis of differences in the functions of the gHV68 v-cyclin and host D and E type cyclins.