CHARACTERIZATION OF THE GAMMA HERPES VIRUS HV68 V CYCLIN

伽马疱疹病毒 HV68 V 细胞周期蛋白的特征

• 批准号: 7349160
• 负责人: SAMUEL H SPECK
• 金额: $ 4.01万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-09 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349160
• 关键词: cyclins; infection; role

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。本研究探讨了 g 疱疹病毒编码的细胞周期蛋白同源物（v 细胞周期蛋白）对 γ 疱疹病毒发病机制和潜伏期的影响机制。人类伽马疱疹病毒、KSHV 和 EBV 是癌症的重要病因，尤其是在免疫功能低下的个体中。由于这些病毒的特异性，发病机制的体内研究受到限制。我们和其他人一直在开发一种小动物模型系统，用 gHV68 感染近交小鼠，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和肿瘤诱导中的作用。 gHV68感染与淋巴瘤和淋巴增殖性疾病、严重的大弹性血管炎和脾纤维化的发生有关。迄今为止的研究表明，gHV68 与 EBV、KSHV 和 HVS 具有相同的发病机制，验证了其作为分析伽马疱疹病毒发病机制重要问题的模型。这项工作的重点是 gHV68 v-cyclin 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）均编码 D 型细胞周期蛋白的同源物，而 EBV 感染上调宿主 d 型细胞周期蛋白的表达。我们已经证明，gHV68 v-cyclin 是一种癌基因，可促进原代淋巴细胞的细胞周期进展，并且 gHV68 v-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 3 个具体目标。 目标 1. 确定 gHV68 v-cyclin 在潜伏期和重新激活中的作用。 目标 2. gHV68 v-细胞周期蛋白表达的特征性调节。 目标 3. 确定 gHV68 v 细胞周期蛋白与宿主 D 型和 E 型细胞周期蛋白功能差异的结构和生化基础。