Herpesviral Oncogenesis, Latency and Reactivation

疱疹病毒肿瘤发生、潜伏期和再激活

• 批准号: 9453088
• 负责人: BLOSSOM A DAMANIA
• 金额: $ 6.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9453088
• 关键词: Affect; Animal Model; Applications Grants; Awareness; Biochemical; Biochemistry; Bioinformatics; Biological; Biological Assay; Biometry; Biostatistics Core; Cancer Etiology; Cancer Patient; Cell Communication; Cell Culture Techniques; Cell Survival; Cell physiology; Cells; Cellular Morphology; Cellular biology; Characteristics; Complex; DNA replication origin; Data; Development; EBV-associated malignancy; Electron Microscopy; Environment; Experimental Animal Model; Gene Expression; Gene Proteins; Genes; Genomics; Goals; Herpesviridae; Human; Human Herpesvirus 4; Human Herpesvirus 8; In Vitro; Individual; Knowledge; LMP1; Laboratories; Lead; Link; Malignant Neoplasms; Mediating; Membrane; Messenger RNA; Methodology; MicroRNAs; Molecular; Neoplasm Metastasis; Oncogenic; Oncoproteins; Organ failure; Pathogenesis; Pathway interactions; Population; Postdoctoral Fellow; Process; Production; Program Research Project Grants; Property; Proteins; Proteome; Research; Role; Signal Pathway; Signal Transduction; Structure; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Training; Translating; Tumor Cell Biology; UCHL1 gene; Ubiquitination; Viral; Viral Genes; Viral Pathogenesis; Viral Proteins; Virus; Virus Diseases; angiogenesis; carcinogenesis; cell growth; cell motility; exosome; experimental study; genetic approach; graduate student; human disease; imaging modality; in vivo Model; light microscopy; mouse model; new therapeutic target; next generation sequencing; novel; novel therapeutics; programs; public health relevance; therapeutic target; trafficking; tumor; tumor microenvironment; tumorigenesis; virology; virus identification

DESCRIPTION (provided by applicant): This program project grant application focuses on the human oncogenic herpesviruses, 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. EBV and KSHV are linked to multiple cancers in the human population. This proposal will study the role of several viral and cellular genes and proteins in modulating EBV- and KSHV-mediated oncogenesis. To identify the mechanisms responsible for the oncogenic properties of these viruses, the projects will characterize the basic molecular properties of viral proteins and their interactions with cellular proteins. The experiments will identify how viral proteins interact with cellular proteins to change their function. Furthermore, the potential therapeutic benefits of targeting viral and cellular proteins will be tested in cell culture assays and animal models. This application consists of five projects and two cores. Project 1 will utilize electron microscopy to analyze the structure of KSHV proteins and replication complexes. Project 2 will elucidate the role of a cellular deubiquitinase, UCHL1, in membrane trafficking and cell-cell communication of EBV-infected cells. Project 3 will investigate how KSHV modulates the tumor microenvironment and the cellular and viral proteins involved in these processes. Project 4 will examine KSHV carcinogenesis using novel mouse models and cell culture assays, and Project 5 will investigate how the EBV oncoproteins, LMP1 and LMP2, modulate the cellular proteome and cellular pathways to contribute to EBV-associated malignancies. Core A provides administrative support for the overall program, while Core B provides state-of-the-art genomics and viral and cellular gene profiling, as well as biostatistics support for all the projects in this application.

DESCRIPTION（由申请人提供）：本项目资助申请重点关注人类致癌疱疹病毒，eb病毒（EBV）和卡波西肉瘤相关疱疹病毒（KSHV），以确定这些药物诱导癌症和解除细胞生长调控的关键机制。EBV和KSHV与人类多种癌症有关。本提案将研究几种病毒和细胞基因和蛋白在调节EBV和kshv介导的肿瘤发生中的作用。为了确定这些病毒致癌特性的机制，这些项目将描述病毒蛋白的基本分子特性及其与细胞蛋白的相互作用。该实验将确定病毒蛋白如何与细胞蛋白相互作用以改变其功能。此外，靶向病毒和细胞蛋白的潜在治疗效益将在细胞培养试验和动物模型中进行测试。该应用程序由五个项目和两个核心组成。项目一将利用电子显微镜分析KSHV蛋白和复制复合体的结构。项目2将阐明细胞去泛素酶UCHL1在ebv感染细胞的膜运输和细胞间通讯中的作用。项目3将研究KSHV如何调节肿瘤微环境以及参与这些过程的细胞和病毒蛋白。项目4将使用新型小鼠模型和细胞培养试验来研究KSHV的致癌作用，项目5将研究EBV癌蛋白LMP1和LMP2如何调节细胞蛋白质组和细胞通路，从而促进EBV相关的恶性肿瘤。核心A为整个项目提供行政支持，而核心B提供最先进的基因组学、病毒和细胞基因分析，以及本应用程序中所有项目的生物统计学支持。