Transcription and Replication of Oncogenic Viruses in Hypoxia

缺氧条件下致癌病毒的转录和复制

• 批准号: 10714172
• 负责人: ERLE S. ROBERTSON
• 金额: $ 269.7万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714172
• 关键词: Address; Antigens; Area; Automobile Driving; Basic Science; Biochemistry; Bioinformatics; Biological Assay; Biology; Burkitt Lymphoma; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell physiology; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; DNA Sequencing Facility; Development; Disease; Endothelium; Environment; Enzymes; Epigenetic Process; Epstein-Barr Virus latency; Event; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genome; Goals; Guide RNA; HIF1A gene; HIV; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; Human Herpesvirus 8; Hypoxia; Immunocompromised Host; Infection; Interdisciplinary Study; Intervention; Kaposi Sarcoma; Knock-out; Laboratories; Lentivirus; Libraries; Link; Lymphoma; Lymphoproliferative Disorders; Maintenance; Malignant Neoplasms; Mediating; Merkel Cells; Merkel cell carcinoma; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Metabolism; Modeling; Multicentric Angiofollicular Lymphoid Hyperplasia; Nasopharynx Carcinoma; Nature; Non-Hodgkin' s Lymphoma; Nucleotides; Oncogenic; Oncogenic Viruses; Oncology; Oxygen; Pathway interactions; Patients; Pennsylvania; Phenotype; Play; Pleural effusion disorder; Polyomavirus; Production; Proteins; Reagent; Recombinants; Regulation; Research Personnel; Role; Sampling; Skin; System; Therapeutic Intervention; Translational Research; Transplantation; Treatment-Related Cancer; Universities; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Inhibitors; burden of illness; cell transformation; data management; epigenome; experience; gammaherpesvirus; insight; knock-down; multidisciplinary; mutant; neoplastic cell; next generation sequencing; novel; post-transplant; preclinical development; preclinical study; prevent; programs; response; skills; small hairpin RNA; success; targeted treatment; therapeutic development; therapeutically effective; translational potential; tumorigenesis; vector; viral carcinogenesis; virus related cancer

Summary Oncogenic viruses are major contributors to approximately 20% of human cancers, with about 8 well-known viruses directly shown to be causative agents. Our program will focus on examining cellular processes that are usurped by these viral agents to drive the oncogenic phenotype. The transcription and replication of oncogenic viruses in the hypoxic microenvironment has not been extensively explored and here we will explore the mechanisms controlled by Merkel Cell Polyoma Virus (MCPyV), Epstein Barr virus (EBV) and Kaposi’s Sarcoma Associated Herpesvirus (KSHV). MCPyV is the causative agent of Merkel cell carcinomas, EBV is the causative agent linked to Nasopharyngeal carcinomas, Burkitt’s lymphomas, Hodgkin’s lymphomas, non- Hodgkin’s lymphomas, post-transplant lymphoproliferative disease in HIV patients that are immunocompromised, and KSHV is the causative agent for Kaposi’s sarcoma and pleural effusion lymphomas and is also associated with Multi-centric Castleman’s disease. These viral agents have been the focus of decades of studies but their function has not been examined extensively in hypoxia. The focus of this application is to bring together four prominent groups, led by investigators within the University of Pennsylvania community to join their scientific expertise to address the mechanism of viral-mediated oncogenesis. The overall goal will investigate the mechanism of transcription and replication control by viral-encoded antigens and the metabolic changes that are required for their function in hypoxia. These fundamental cellular processes targeted in hypoxia will provide novel information for successful establishment of viral infection in hypoxia. The program consists of four scientific projects, an administrative core, a virus, vector and cell culture core and a next generation sequencing core. The scientific projects are: 1. KSHV reprograms transcription and replication in hypoxia; 2. KSHV induces tumorigenesis by harnessing differentiation in hypoxia; 3. Skin hypoxia, MCPyV infection and MCC tumorigenesis; and 4. Regulation of EBV latency and oncogenesis by oxygen metabolism. The success of these projects will establish a comprehensive mechanistic view of oncogenic viral infection and pathogenesis in hypoxia, and provide new clues for the development of strategies to prevent and treat the associated cancers in HIV patients. In addition, the accumulation of new information on the biology of these viruses will be critical for insights into their mechanism of oncogenesis and so reduce the burden of disease in HIV infected, transplants and other immunocompromised patients.

总结 致癌病毒是约20%的人类癌症的主要贡献者，其中约8种是已知的致癌病毒。 病毒直接显示为病原体。我们的计划将集中在检查细胞的过程， 被这些病毒因子篡夺以驱动致癌表型。癌基因的转录和复制 病毒在缺氧微环境中的作用尚未得到广泛的研究，在这里，我们将探讨 由默克尔细胞多瘤病毒（MCPyV）、爱泼斯坦巴尔病毒（EBV）和卡波西氏病毒控制的机制 肉瘤相关疱疹病毒（KSHV）。MCPyV是默克尔细胞癌的病原体，EBV是 与鼻咽癌、伯基特淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、 霍奇金淋巴瘤，艾滋病患者的移植后淋巴组织增生性疾病， KSHV是卡波西肉瘤和胸腔积液淋巴瘤的病原体 并且还与多中心Castleman病有关。这些病毒因子一直是 几十年的研究，但他们的功能还没有得到广泛的研究，在缺氧。的重点 一个应用程序是汇集四个突出的小组，由宾夕法尼亚大学的调查人员领导 社区加入他们的科学专业知识，以解决病毒介导的肿瘤发生的机制。的 总体目标是研究病毒编码抗原的转录和复制控制机制 以及它们在缺氧环境中发挥功能所需的代谢变化。这些基本的细胞 缺氧靶向的过程将为成功建立病毒感染提供新的信息， 缺氧 该计划包括四个科学项目，一个行政核心，一个病毒，载体和细胞培养核心， 下一代测序核心科学项目是：1。KSHV重编程转录， 缺氧复制; 2. KSHV通过利用低氧分化诱导肿瘤发生; 3.皮肤 缺氧、MCPyV感染和MCC肿瘤发生;和4. EB病毒潜伏期和肿瘤发生的调节 氧代谢 这些项目的成功将建立一个全面的致癌病毒感染机制的观点， 缺氧的发病机制，并提供新的线索，以制定战略，以预防和治疗缺氧 艾滋病患者的相关癌症。此外，这些生物学的新信息的积累 病毒对于了解它们的肿瘤发生机制至关重要，因此可以减少疾病的负担， HIV感染者、移植者和其他免疫功能低下的患者。