Characterization of the gamma HV68 v-cyclin

γ HV68 v-细胞周期蛋白的表征

• 批准号: 7463881
• 负责人: SAMUEL H SPECK
• 金额: $ 31.6万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463881
• 关键词: Acute; Animal Model; B-Lymphocytes; Binding; Biological Models; Cancer Etiology; Cell Cycle Progression; Chronic; Cyclin Gene; Cyclin-Dependent Kinases; Cyclins; Defect; Development; Disease; Dose; Epstein-Barr Virus Infections; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Grant; Herpesviridae; Herpesviridae Infections; Homologous Gene; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immune system; Immunocompromised Host; Inbred Mouse; Individual; Infection; Kaposi Sarcoma; Lead; Lymphocyte; Lytic Phase; Methods; Modeling; Mus; Oncogenes; Pathogenesis; Phenotype; Primates; Progress Reports; RNA Splicing; Regulation; Role; Route; Saimiriine Herpesvirus 2; Simplexvirus; Species Specificity; Transcript; Transcriptional Regulation; Viral Proteins; Virus; Virus Diseases; Virus Replication; domain mapping; in vivo; insight; mutant; null mutation; reactivation from latency; tissue culture; tumor; viral cyclin

DESCRIPTION (provided by applicant): This is the first renewal of a grant to investigate the mechanisms by which cyclin homologs encoded by ?-herpesviruses (v-cyclins) contribute to ?-herpesvirus pathogenesis and latency. The human ?-herpes viruses 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. We and others have been developing a small animal model system, infection of inbred mice with murine gammaherpesvirus 68 (yHV68), for analysis of the pathogenesis of ?-herpesvirus infection. This application focuses on the role of the ?HV68 v-cyclin in disease pathogenesis. Notably, the ?2-herpesviruses (HVS, KSHV and yHV68) all encode homologs of D-type cyclins, while EBV infection upregulates expression of host D-type cyclins. Thus, we expect analysis of the ?HV68 v-cyclin will provide important insights into a conserved pathogenic mechanism. We have shown that the ?HV68 v-cyclin is an oncogene that promotes cell cycle progression in primary lymphocytes and that a ?HV68 v-cyclin mutant reactivates inefficiently from latently infected M? and/or B cells (Progress Report). These observations lead to the following 4 aims. Aim 1. Role of v-cyclin during chronic infection [assess impact of dose and route of infection on acute virus replication, latency and reactivation; in vivo infection competition analysis with wt and v-cyclin null yHV68; further characterize v-cyclin null yHV68 reactivation defect; characterization of chimeric virus harboring KSHV v-cyclin]. Aim 2. Transcriptional regulation of v-cyclin gene expression [role of lytic cycle-associated v-cyclin gene transcription; analysis of latency/reactivation-associated spliced v-cyclin gene transcripts; characterization of P1- and P2-initiated LANA/v-cyclin spliced transcripts]. Aim 3. Develop and characterize tissue culture models to investigate v-cyclin functions [CDK-dependent function during acute virus replication; CDK-independent function during virus reactivation from latency]. Aim 4. Characterize CDK-independent v-cyclin function [map domains required for virus reactivation; gene expression profiling comparing wt and CDK-binding mutant v-cyclin; identify and characterize cellular and viral proteins interacting with v-cyclin].

描述（由申请人提供）：这是研究细胞周期蛋白同源物由？-疱疹病毒（v-细胞周期蛋白）导致？-疱疹病毒的发病机制和潜伏期。人类？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。由于这些病毒的物种特异性，其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，用小鼠γ疱疹病毒68 （yHV68）感染近交系小鼠，以分析？疱疹病毒感染。这个应用程序关注的是？HV68 v-cyclin在疾病发病机制中的作用。值得注意的是？2-疱疹病毒（HVS、KSHV和yHV68）均编码d型细胞周期蛋白的同源物，而EBV感染可上调宿主d型细胞周期蛋白的表达。因此，我们期望对？HV68 v-cyclin将为保守的致病机制提供重要见解。我们已经证明了？HV68 v-cyclin是一种癌基因，可促进原发性淋巴细胞的细胞周期进展。HV68 v-cyclin突变体从潜伏感染的M？和/或B细胞（进展报告）。这些观察结果引出了以下4个目标。