CHARACTERIZATION OF THE GAMMA HV68 V CYCLIN

这是一个新的RO 1赠款提案，通过以下方式调查机制： 由γ-疱疹病毒编码的细胞周期蛋白同源物（v-细胞周期蛋白） γ-疱疹病毒的发病机制和潜伏期。人类γ疱疹病毒 和EB病毒，是癌症的重要原因，特别是在免疫功能低下的 个体由于这些病毒的种属特异性， 其发病机制的研究有限。该提案利用了一个 小动物模型系统，用γ HV 68感染近交系小鼠， γ-疱疹病毒感染的发病机制分析 潜伏期和肿瘤诱导中的单个γ-疱疹病毒基因。GammaHV68 感染与淋巴瘤的发展有关， 淋巴组织增生性疾病、大弹性血管的严重血管炎， 脾纤维化迄今为止的研究表明，γ HV 68共享致病性 机制与EB病毒，KSHV，和HVS，验证它作为一个模型的分析， γ疱疹病毒发病机制中的重要问题。该补助金的重点是 γ HV 68 v-细胞周期蛋白在疾病发病机制中的作用。特别是 γ 2-疱疹病毒（HVS、KSHV和γ HV 68）均编码D型同源物 细胞周期蛋白，而EBV感染上调宿主D型细胞周期蛋白的表达。的 研究者已经表明γ HV 68 v-细胞周期蛋白是一种致癌基因， 促进原代淋巴细胞的细胞周期进程， v-细胞周期蛋白突变体从潜伏感染的Msigma中无效地再活化，和/或 B细胞。这些观察导致以下3个具体目标， 建议：1）确定γ HV 68 v-细胞周期蛋白在潜伏期中的作用， 重新激活2)表征γ HV 68 v-细胞周期蛋白表达的调控。第三章 确定功能差异的结构和生化基础 γ HV 68 v-细胞周期蛋白和宿主D型和E型细胞周期蛋白。

This is a new RO1 grant proposal to investigate the mechanisms by which cyclin homologs encoded by gamma-Herpesviruses (v-cyclin) contribute to gamma-herpesvirus pathogenesis and latency. The human gamma-herpesviruses, KSHV and EBV, are important causes of cancer especially in immunocompromised individuals. Because of the species specificity of these viruses, in vivo studies of their pathogenesis have been limited. This proposal makes use of a small animal model system, infection of inbred mice with gammaHV68, for analysis of the pathogenesis of gamma-herpesvirus infection and the role of individual gamma-herpesvirus genes in latency and tumor induction. GammaHV68 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 the gammaHV68 shares pathogenetic mechanisms with EBV, KSHV, and HVS, validating it as a model for analysis of important questions in gammaherpesvirus pathogenesis. This grant is focused on the role of the gammaHV68 v-cyclin in disease pathogenesis. Notably, the gamma2- herpesviruses (HVS, KSHV and gammaHV68) all encode homologs of D-type cyclins, while EBV infection upregulates expression of host D-type cyclins. The investigators have shown that the gammaHV68 v-cyclin is an oncogene that promotes cell cycle progression in primary lymphocytes and that a gammaHV68 v-cyclin mutant reactivates inefficiently from latently infected Msigma and/or B cells. These observations lead to the following 3 specific aims of this proposal: 1) Determine the role(s) of the gammaHV68 v-cyclin in latency and reactivation. 2) Characterize regulation of gammaHV68 v-cyclin expression. 3) Determine the structural and biochemical basis of differences in the functions of the gammaHV68 v-cyclin and host D and E type cyclins.