Project 4 - Controlling the Latent-to-Lytic Switch in Epstein-Barr Virus

项目 4 - 控制 Epstein-Barr 病毒中的潜伏至裂解转换

• 批准号: 10910338
• 负责人: Janet Elaine Mertz
• 金额: $ 15.85万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10910338
• 关键词: Affect; Air; B cell differentiation; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; BZLF1 gene; Bioinformatics; Cell Death; Cell Differentiation process; Cell Line; Cells; Chemicals; Collaborations; DNA biosynthesis; Deferoxamine; Deferoxamine Methanesulfonate; Drug Combinations; EBV reactivation from latency; Epithelial Cells; Epithelium; Epstein Barr Virus associated tumor; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Epstein-Barr Virus-Related Malignant Neoplasm; Equilibrium; Equipment; FDA approved; Family member; Fluorescence Microscopy; Funding; Ganciclovir; Generations; Genes; Genetic Transcription; Genome; Growth; Histology; Histone Deacetylase Inhibitor; Human; Human Genetics; Human Herpesvirus 4; Immune system; In Vitro; Infection; Iron Chelation; Life Cycle Stages; Liquid substance; Lymphoma; Lytic; Lytic Phase; Malignant Neoplasms; Mediating; Molecular Biology; Molecular Genetics; Mus; Mutate; Nasopharynx Carcinoma; Neoadjuvant Therapy; Oncogenic Viruses; PRDM1 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Prodrugs; Production; Protein Kinase; Proteins; Regulation; Resolution; Role; Signal Pathway; TP53 gene; Testing; Toxic effect; Undifferentiated; Virion; Virus; Virus Replication; Xenograft procedure; cancer cell; cell type; experimental study; gammaherpesvirus; immune modulating agents; immunoregulation; in vivo; inhibitor; inhibitor therapy; latent infection; lytic replication; malignant stomach neoplasm; mouse model; mutant; neoplastic cell; novel; novel drug class; novel drug combination; nucleoside analog; pomalidomide; promoter; statistics; transcription factor; tumor; tumorigenesis

PROJECT 4 – PROJECT SUMMARY/ABSTRACT Epstein-Barr virus (EBV) is associated with 2% of human cancers, including a variety of B-cell lymphomas, nasopharyngeal carcinomas, and some gastric cancers. Over the current funding period, we developed a new epithelial cell line infected with EBV that can be used to identify factors that regulate the switch from latency to lytic infection that occurs during differentiation of epithelial cells. Using this and other EBV-infected cell lines, we identified multiple cellular factors that play key roles in determining whether EBV remains dormant or reactivates into lytic replication. We also discovered three novel classes of drugs (iron chelators, NEDDylation inhibitors, and immunomodulatory drugs such as pomalidomide) that induce reactivation of latent EBV into lytic replication, two of which are already FDA-approved for other uses. Based upon our findings, we hypothesize that p53 family members and NEDDylation are key contributors to regulation of the EBV latent-to-lytic switch. Here, we propose to test this hypothesis by determining: (i) the roles played by p53 (the most commonly mutated protein in cancers) and its close family member, ΔNp63, in regulating EBV’s life cycle during differentiation of EBV-infected epithelial cells and treatment of these cells with drugs that induce lytic EBV replication; and (ii) how the NEDDylation inhibitor, MLN4924, and the iron chelator, deferoxamine, induce lytic EBV replication in cells latently infected with this virus. The information obtained from these experiments will then be used to identify optimal combinations of these drugs, together with other FDA- approved drugs, for efficiently inducing EBV into lytic infection in cancer cells in which it is latent. We are hopeful that these studies will lead to new lytic-induction therapies for treating patients with EBV-associated cancers.

项目4 - 项目摘要/摘要 爱泼斯坦 - 巴尔病毒（EBV）与2％的人类癌症有关，包括各种B细胞淋巴瘤， 鼻咽癌和一些胃癌。在当前的资金期间，我们开发了 被EBV感染的新上皮细胞系，可用于识别调节转换的因素 在分化上皮细胞期间发生的裂解感染的潜伏期。使用此和其他EBV感染 细胞系，我们确定了多个细胞因素，这些因素在确定EBV是否仍然存在中起着关键作用 休眠或重新激活裂解复制。我们还发现了三种新型药物（铁螯合物， 尼迪抑制剂和免疫调节药物，例如pomalidomide），影响影响的重新激活 潜在的EBV进入裂解复制，其中两个已经被FDA批准用于其他用途。基于我们 调查结果，我们假设p53家族成员和尼迪底化是监管的关键因素 EBV潜伏开关。在这里，我们建议通过确定来检验这一假设：（i）P53扮演的角色 （癌症中最常见的突变蛋白）及其亲密的家庭成员ΔNP63，以调节EBV的生活 在分化EBV感染的上皮细胞的循环以及用影响的药物对这些细胞进行处理 Lytic EBV复制； （ii）Neddylation抑制剂MLN4924和铁螯合剂，脱铁胺，如何 诱导该病毒潜在感染的细胞中诱导裂解EBV复制。从这些获得的信息 然后，实验将用于鉴定这些药物的最佳组合以及其他FDA- 批准的药物有效地诱导了潜在的癌细胞中EBV进入裂解感染。我们是 希望这些研究将导致新的裂解诱导疗法，以治疗与EBV相关的患者 癌症。