CHARACTERIZATION OF THE GAMMA HERPES VIRUS HV68 V CYCLIN

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。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-细胞周期蛋白）对γ-疱疹病毒致病和潜伏的作用机制。人类γ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个体中。由于这些病毒的特异性，在体内的发病机制的研究受到限制。我们和其他人一直在开发一种小动物模型系统，用gHV 68感染近交系小鼠，用于分析γ疱疹病毒感染的发病机制以及单个γ疱疹病毒基因在潜伏期和肿瘤诱导中的作用。gHV 68感染与淋巴瘤和淋巴增生性疾病、大弹性血管的严重血管炎和脾纤维化的发展相关。迄今为止的研究表明，gHV 68与EBV、KSHV和HVS具有共同的致病机制，验证了其作为分析γ疱疹病毒致病机制中重要问题的模型。这项工作的重点是gHV 68 v-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gHV 68）都编码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。我们已经表明，gHV 68 v-细胞周期蛋白是一种致癌基因，促进细胞周期的进展，在初级淋巴细胞和gHV 68 v-细胞周期蛋白突变体反应无效，从潜伏感染的MM和/或B细胞。这些意见导致以下三个具体目标。 目标1.确定gHV 68 v-细胞周期蛋白在潜伏期和再激活中的作用。 目标2.表征gHV 68 v-细胞周期蛋白表达的调节。 目标3.定义gHV 68 v-细胞周期蛋白与宿主D和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.