Herpesviral, Oncogenesis, Latency and Reactivation

描述(由申请人提供)：该计划继续关注人类致癌疱疹病毒、爱泼斯坦-巴尔病毒(EBV)和卡波西肉瘤相关疱疹病毒(KSHV)，以确定这些药物诱发癌症和放松对细胞生长调控的关键机制。为了确定这些制剂致癌特性的机制，这些项目将表征病毒蛋白质的基本分子特性以及它们与细胞蛋白质的相互作用。在项目1中，Jack Griffith博士将继续他对由ICP8和UL12组成的HSV重组酶复合体的研究，并将应用他开发的成像技术来分析EBV和KSHV蛋白质的结构以及KSHV蛋白质与DNA的关联。项目2继续约瑟夫·帕加诺博士对一种新的脱泛素酶UCHL1的研究，该酶的表达是由EBV诱导的。该项目将确定这种蛋白质的特性，并与Raab-Traub博士和Dittmer博士合作，在他们在项目4和5中开发的小鼠模型中确定其抗生长特性。达马尼亚博士将在项目3中开发系统，以确定KSHV如何诱导血管生成、细胞存活和迁移。Raab-Traub博士和Dittmer博士将在项目4和5中开发和表征转基因小鼠模型中转化和肿瘤发生所必需的途径。EBV和KSHV对转基因癌症细胞miRNAs的影响也将在这两个项目中确定。需要一个新的核心，病毒基因组学核心，它将为该计划的所有5个项目提供基因表达阵列支持，细胞miRNAs图谱，以及表达阵列和ChlP-Seq方法的生物信息学服务。

DESCRIPTION (provided by applicant): The program continues its focus on the human oncogenic herpesvirus, Epstein-Barr Virus (EBV) and Kaposi Sarcoma-associated Herpesvirus (KSHV) to identify the critical mechanisms by which these agents induce cancer and deregulate cell growth. To identify the mechanisms responsible for the oncogenic properties of these agents, the projects will characterize the basic molecular properties of viral proteins and their interactions with cellular proteins. In Project 1, Dr. Jack Griffith will continue his studies of the HSV recombinase complex consisting of ICP8 and UL12, and will apply the imaging skills that he has developed to analyze the structure of EBV and KSHV proteins and the association of KSHV proteins with DNA. Project 2 continues the study by Dr, Joseph Pagano on a novel deubiquitinase, UCHL1, whose expression is induced by EBV. This project will characterize the properties of this protein and in collaboration with Drs. Raab-Traub and Dittmer, determine its anti-growth properties in the mouse models that they have developed in Projects 4 and 5. Dr. Damania in Project 3 will develop systems to determine how KSHV induces angiogenesis, cell survival and migration. Drs. Raab-Traub and Dittmer in Projects 4 and 5 will develop and characterize the pathways that are essential for transformation and oncogenesis in transgenic murine models. The effects of EBV and KSHV on cellular miRNAs in the transgenic cancers will also be determined in both projects. A new core is requested, the Virogenomics Core, that will provide gene expression array support for all 5 projects on this program, profiling of the cellular miRNAs, and bioinformatic services for expression arrays and ChlP-Seq approaches.