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

基本信息

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
项目类别：
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

项目摘要

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 EB 病毒 (EBV) 与 2% 的人类癌症有关，包括各种 B 细胞淋巴瘤、在当前的资助期内，我们开发了一种治疗鼻咽癌和某些胃癌的药物。感染 EBV 的新上皮细胞系可用于识别调节从使用这种和其他 EBV 感染的上皮细胞分化过程中发生的裂解感染潜伏期。细胞系中，我们确定了多种细胞因子，它们在确定 EBV 是否残留中发挥关键作用我们还发现了三类新的药物（铁螯合剂、 NEDdylation 抑制剂和免疫调节药物（如泊马度胺）可诱导重新激活潜在的 EBV 进入裂解复制，其中两种已获得 FDA 批准用于其他用途。研究结果表明，我们认为 p53 家族成员和 NEDDylation 是调节在此，我们建议通过确定以下内容来检验这一假设：(i) p53 所扮演的角色。（癌症中最常见的突变蛋白）及其密切家族成员 ΔNp63 在调节 EBV 生命中的作用 EBV感染的上皮细胞分化过程中的循环以及用诱导的药物处理这些细胞裂解性 EBV 复制；以及 (ii) NEDdylation 抑制剂 MLN4924 和铁螯合剂去铁胺如何诱导潜伏感染该病毒的细胞中的裂解性 EBV 复制。然后将使用实验来最佳地识别这些药物以及 FDA 的其他药物的组合。已获批准，用于有效诱导药物 EBV 进入潜伏的癌细胞中进行裂解性感染。希望这些研究能够带来新的裂解诱导疗法，用于治疗 EBV 相关患者癌症。