Transcription and Replication of Oncogenic Viruses in Hypoxia

缺氧条件下致癌病毒的转录和复制

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

概括致癌病毒是约 20% 人类癌症的主要致病因素，其中约 8 种众所周知直接显示为病原体的病毒我们的计划将重点检查细胞过程。被这些病毒因子篡夺来驱动致癌表型致癌基因的转录和复制。缺氧微环境中的病毒尚未得到广泛研究，在这里我们将探讨由默克尔细胞多瘤病毒 (MCPyV)、EB 病毒 (EBV) 和卡波西病毒控制的机制肉瘤相关疱疹病毒 (KSHV) 是默克尔细胞癌的病原体，EBV 是默克尔细胞癌的病原体。与鼻咽癌、伯基特淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤，HIV 患者移植后淋巴组织增生性疾病免疫功能低下，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卡斯尔曼病有关，这些病毒因子一直是研究的焦点。几十年的研究，但它们的功能尚未在缺氧条件下得到广泛研究。申请的目的是将四个著名团体聚集在一起，由宾夕法尼亚大学的研究人员领导社区联合他们的科学专业知识来解决病毒介导的肿瘤发生机制。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情况下发挥功能所需的代谢变化。针对缺氧的过程将为病毒感染的成功建立提供新的信息缺氧。该计划由四个科学项目组成：一个行政核心项目、一个病毒、载体和细胞培养核心项目以及下一代测序核心的科学项目是： 1. KSHV 重新编程转录和缺氧条件下复制；2. KSHV 利用缺氧条件下的分化诱导肿瘤发生；缺氧、MCPyV 感染和 MCC 肿瘤发生；以及 4. EBV 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关于致癌病毒感染和癌症的全面机制观点。缺氧的发病机制，为制定预防和治疗策略提供新线索此外，有关这些癌症的生物学新信息的积累。病毒对于深入了解其肿瘤发生机制至关重要，从而减轻疾病负担 HIV感染者、移植者和其他免疫功能低下的患者。