Targeting B Cell MicroRNA in Post-Transplant EBV-Associated B Cell Lymphoma

移植后 EBV 相关 B 细胞淋巴瘤中靶向 B 细胞 MicroRNA

• 批准号: 9111697
• 负责人: Olivia M Martinez
• 金额: $ 23.74万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111697
• 关键词: 3' Untranslated Regions; Acquired Immunodeficiency Syndrome; Antibodies; Apoptosis; B-Cell Lymphomas; B-Lymphocytes; Binding; Cancer Etiology; Cell Line; Cell Proliferation; Cell physiology; Cells; Classification; Development; Diagnosis; Elderly; Epithelial; Epstein-Barr Virus Infections; Epstein-Barr pathogenesis; Family; Gene Expression; Gene Expression Regulation; Genes; Growth; HIV; Herpesviridae; Human; Human Herpesvirus 4; Immune system; Immunity; Immunocompromised Host; Immunosuppressive Agents; In Vitro; Individual; Infection; Infectious Mononucleosis; Interleukin-10; Knowledge; Laboratories; Link; Lymphoid; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Mediating; Memory B-Lymphocyte; MicroRNAs; NOD/SCID mouse; Pathogenesis; Pathway interactions; Patients; Play; Population; Porifera; Process; Production; Regulation; Regulatory T-Lymphocyte; Risk; Role; Signal Transduction; Silicon Dioxide; Sirolimus; Subfamily lentivirinae; System; T-Lymphocyte; Testing; Time; Transplant Recipients; Transplantation; Untranslated RNA; Viral Pathogenesis; Virus; attenuation; autocrine; cell growth regulation; cell mediated immune response; cellular targeting; clinically relevant; effective therapy; falls; immunosuppressed; in vivo; inducible gene expression; infected B cell; innovation; insight; latent infection; mouse model; neoplastic cell; neutralizing antibody; novel; overexpression; prevent; public health relevance; receptor; restraint; rituximab; therapeutic target; treatment strategy; tumor growth

 DESCRIPTION (provided by applicant): Epstein Barr Virus (EBV) is a gamma herpes virus that has infected >90% of the human population. EBV infection is usually asymptomatic and is controlled by a robust T cell-mediated immune response. However, EBV can also cause infectious mononucleosis and is linked to a variety of lymphoid and epithelial malignancies. Immunosuppressed transplant recipients and individuals who are immunocompromised such as AIDS patients or the elderly, are at increased risk of developing EBV+ B cell lymphomas. While impaired immunity clearly contributes to the emergence of EBV+ B cell lymphomas in these populations, the mechanisms by which EBV drives tumor cell proliferation are poorly understood. Recent studies in our laboratory indicate that EBV infection significantly alters the cellular microRNA (miRNA) profile within infected B cells. miRNA constitute an important network of small, non-coding RNA that control gene expression at the post-transcriptional level and thereby impacts cellular function. Of the miRNA that we observed are modulated by EBV, a subset is predicted to target the 3' untranslated region (UTR) of human IL-10, a known autocrine growth factor for EBV+ B cell lymphomas in transplant recipients. We have shown that one of these miRNA, miR-194, is suppressed upon EBV infection of B cells. We further show that miR-194 binds to the 3'UTR of IL- 10 and that overexpression of miR-194 in EBV+ B cell lines from transplant recipients with post-transplant lymphoproliferative disorder (PTLD) significantly inhibits IL-10 production. In this project we test the hypothesis that EBV hijacks host B cell miRNA to promote cell proliferation through constitutive production of IL-10 and that this is a novel, but targetable, mechanism of pathogenesis in EBV+ B cell lymphomas. This hypothesis will be tested in two specific aims. First, we will establish whether EBV induces human IL-10 through modulation of host cell miRNA. Second, we will determine whether targeting EBV regulation of host cell miRNA can prevent proliferation of EBV+ B cell lymphomas in vivo. The proposed studies are innovative and of potentially high impact because they will identify and define a novel mode of virally-induced pathogenesis for EBV+ B cell lymphomas and evaluate whether this constitutes a potential therapeutic target. Moreover, they will provide fundamental knowledge on regulation of IL-10 expression that could have important implications for other IL-10 producing cells.

 描述（由申请人提供）：EB 病毒 (EBV) 是一种伽玛疱疹病毒，已感染超过 90% 的人群。EBV 感染通常无症状，并受到强大的 T 细胞介导的免疫反应的控制。也可引起传染性单核细胞增多症，并与多种淋巴和上皮恶性肿瘤有关，包括免疫抑制的移植受者和免疫功能低下的个体，例如艾滋病患者或艾滋病患者。老年人患 EBV+ B 细胞淋巴瘤的风险增加，虽然免疫力受损显然导致了这些人群中 EBV+ B 细胞淋巴瘤的出现，但我们实验室最近的研究表明，人们对 EBV 驱动肿瘤细胞增殖的机制知之甚少。 EBV 感染显着改变了受感染 B 细胞内的细胞 microRNA (miRNA) 谱，miRNA 构成了一个重要的小非编码 RNA 网络，可在转录后水平控制基因表达，从而影响 miRNA 的细胞功能。我们观察到受 EBV 调节，预计有一个子集以人 IL-10 的 3' 非翻译区 (UTR) 为目标，IL-10 是移植受者中 EBV+ B 细胞淋巴瘤的已知自分泌生长因子。 miR-194在B细胞的EBV感染后被抑制，我们进一步表明miR-194与IL-10的3'UTR结合并且过度表达。来自患有移植后淋巴增殖性疾病 (PTLD) 的移植受者的 EBV+ B 细胞系中的 miR-194 显着抑制 IL-10 的产生。在这个项目中，我们测试了 EBV 劫持宿主 B 细胞 miRNA 以通过 IL 的组成型产生来促进细胞增殖的假设。 -10，这是 EBV+ B 细胞淋巴瘤的一种新颖但可靶向的发病机制。这一假设将在两个具体目标上进行检验。首先，我们将确定 EBV 是否存在。其次，我们将确定宿主细胞 miRNA 的靶向 EBV 调节是否可以阻止体内 EBV+ B 细胞淋巴瘤的增殖。并定义了病毒诱导的 EBV+ B 细胞淋巴瘤发病机制的新模式，并评估这是否构成潜在的治疗靶点。此外，他们还将提供有关 IL-10 表达调节的基础知识，这可能对其他 IL-10 产生重要影响。产生细胞。