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

描述（由研究者提供）：爱泼斯坦-巴尔病毒是一种与免疫低下个体淋巴瘤相关的致瘤性疱疹病毒。在体外，EBV将原代B细胞转化为无限增殖的淋巴母细胞样细胞系（LCLs），效率低于10%。虽然几乎所有受感染的细胞都表达病毒潜伏基因并开始增殖，但大多数细胞存在长期增殖障碍。最近的证据表明，激活的癌基因诱导肿瘤抑制DNA损伤反应（DDR）。在这个应用中，我们的目的是了解DDR作为EBV介导的转化的先天抑制因子的作用，以及EBV克服这种反应的机制。我们的工作假设是，在原发性B细胞感染时，EBV潜伏基因的初始表达程序依赖于高水平的EBNA2活性，EBNA2活性驱动初始超增殖状态，从而引发宿主DDR。长期生长依赖于EBNA3C通过降低EBNA2活性和B细胞增殖率来减轻DDR。提出这项研究的基本原理是，确定DDR抑制EBV转化的基本效应物有望为EBV相关恶性肿瘤的治疗干预提供候选靶点。此外，描述病毒蛋白在缓解DDR中的作用将有助于深入了解ebv诱导的肿瘤发生机制。我们计划通过三个具体目标来测试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感染后早期检测到的ATM/Chk2依赖性DDR的关键效应物。其次，我们将确定EBNA3C蛋白亚型在EBV感染后早期初始细胞分裂期间ddr相关变化的分子基础。第三，我们将明确EBNA3C在早期感染中减弱ebv诱导的DDR的遗传要求。这项研究具有重要意义，因为它旨在确定宿主抑制EBV永生化的关键机制，以及病毒如何克服这种先天肿瘤抑制途径。这一知识将有助于确定ebv相关恶性肿瘤的新治疗靶点。例如，一种新的治疗方法可以集中在加强这种肿瘤抑制效应来阻止EBV驱动的肿瘤的增殖。

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.