Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation

调节 Epstein-Barr 病毒介导的 B 细胞生长转化的宿主途径

基本信息

批准号：
8843606
负责人：
Micah A. Luftig
金额：
$ 6.04万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8843606
关键词：
Address Adult African African Burkitt&apos s lymphoma Ataxia-Telangiectasia-Mutated protein kinase Attenuated Automobile Driving B Cell Proliferation B lymphocyte immortalization B-Lymphocytes Cell Cycle Cell division Cells Central Nervous System Lymphoma Cytotoxic T-Lymphocytes DNA Damage DNA-Binding Proteins Data Down-Regulation EBV-associated malignancy Epstein-Barr Virus Infections Epstein-Barr pathogenesis Gene Expression Genes Genetic Germ Cells Goals Growth HIV HIV Infections Herpesviridae High Prevalence Hodgkin Disease Human Human Herpesvirus 4 Immune Immune response Immunosuppression In Vitro Individual Infection Knowledge Lead Length Lymphoma Lymphomagenesis Lymphoproliferative Disorders Malignant Neoplasms Mediating Modeling Molecular Nasopharynx Carcinoma Nature Oncogenes Oncogenic Pathogenesis Pathway interactions Phase Physiological Process Proliferating Protein Isoforms Proteins Research Research Personnel Role Signal Pathway Stress Testing Therapeutic Intervention Time Transplantation Tumor Suppressor Proteins Viral Viral Proteins Virus Work attenuation base c-myc Genes cell growth epstein barr virus mediated immortalization genome-wide innovation insight latent gene expression lymphoblastoid cell line mRNA Expression new therapeutic target novel therapeutic intervention positional cloning programs research study response small hairpin RNA therapeutic target tumor tumorigenesis

项目摘要

DESCRIPTION (provided by investigator): Epstein-Barr virus is an oncogenic herpes virus associated with lymphoma in immune-compromised individuals. In vitro EBV transforms primary B cells into indefinitely proliferating lymphoblastoid cell lines (LCLs) with an efficiency of less than 10%. While nearly all infected cells express viral latent genes and begin to proliferate, a block to long term proliferation exists in the majority of these cells. Recent evidence suggests that activated oncogenes induce a tumor suppressive DNA damage response (DDR). In this application, we aim to understand the role of the DDR as an innate suppressor of EBV-mediated transformation and the mechanisms by which EBV overcomes this response. It is our working hypothesis that the initial EBV latent gene expression program upon primary B cell infection depends on high-level EBNA2 activity, which drives an initial hyper-proliferative state that provokes the host DDR. Long-term outgrowth depends on EBNA3C mitigating the DDR through attenuation of EBNA2 activity and the B cell proliferation rate. The rationale for the proposed research is that determining the essential effectors of the DDR suppressing EBV transformation is expected to lead to candidate targets for therapeutic intervention in EBV-associated malignancies. Further, delineating the role of viral proteins in mitigating the DDR will provide insight into the mechanism of EBV-induced oncogenesis. We plan to test our hypothesis and complete the objectives outlined in this application through three specific aims. First, we will determine the critical effectors of the ATM/Chk2 dependent DDR detected early after EBV infection. Second, we will determine the molecular basis for the DDR-correlated change in EBNA3C protein isoform during early initial cell divisions following EBV infection. Third, we will define the genetic requirements of EBNA3C in attenuating the EBV-induced DDR in early infection. The proposed research is significant because it aims to determine a critical mechanism by which EBV immortalization is suppressed by the host and how the virus overcomes this innate tumor suppressor pathway. This knowledge will be informative towards identifying novel therapeutic targets for EBV-associated malignancy. For example, a novel therapeutic approach could be focused on accentuation of such tumor suppressor effectors to block proliferation of EBV- driven tumors.

描述（研究人员提供）：爱泼斯坦 - 巴尔病毒是一种与淋巴瘤相关的致癌疱疹病毒。体外EBV将原代B细胞转变为无限期增殖的淋巴细胞细胞系（LCLS），效率小于10％。虽然几乎所有感染的细胞都表达病毒潜在基因并开始增殖，但大多数细胞中都存在长期增殖的块。最近的证据表明，活化的癌基因诱导肿瘤抑制性DNA损伤反应（DDR）。在此应用程序中，我们旨在了解DDR作为EBV介导的转换的先天抑制剂的作用以及EBV克服这一响应的机制。我们有效的假设是，初次B细胞感染的初始EBV潜在基因表达程序取决于高级EBNA2活性，这驱动了引起宿主DDR的初始高增殖状态。长期生长取决于EBNA3C通过衰减EBNA2活性和B细胞增殖率来减轻DDR。拟议的研究的基本原理是，确定DDR抑制EBV转化的基本效应因素有望导致候选目标对与EBV相关的恶性肿瘤的治疗干预。此外，描述病毒蛋白在减轻DDR中的作用将提供对EBV诱导的肿瘤发生机制的见解。我们计划通过三个特定目标来检验我们的假设并完成本应用程序中概述的目标。首先，我们将确定EBV感染后尽早检测到的ATM/CHK2依赖性DDR的关键效应子。其次，我们将确定在EBV感染后早期初始细胞分裂期间EBNA3C蛋白同工型中DDR相关变化的分子基础。第三，我们将定义EBNA3C在早期感染中衰减EBV诱导的DDR时的遗传要求。拟议的研究很重要，因为它旨在确定宿主抑制EBV永生化以及病毒如何克服这种先天肿瘤抑制途径的关键机制。这些知识将为识别与EBV相关的恶性肿瘤的新型治疗靶标提供信息。例如，一种新型的治疗方法可以集中于这种肿瘤抑制效应子的强调，以阻止EBV驱动肿瘤的增殖。