Epigenomic Drivers of EBV Epithelial Cancers

EB 病毒上皮癌的表观基因组驱动因素

基本信息

批准号：
10627690
负责人：
PAUL M LIEBERMAN
金额：
$ 46.97万
依托单位：
WISTAR INSTITUTE
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：
2023-05-11 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627690
关键词：
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine 3-Dimensional ARID1A gene Accounting Affect Automobile Driving Carcinoma Chromosomes Collaborations CpG Islands DNA Binding DNA Crosslinking DNA Damage DNA Methylation Epigenetic Process Episome Epithelial Cells Epithelium Epstein-Barr Virus latency Genes Genetic Transcription Genome Goals Human Herpesvirus 4 Investigation LMP1 Lytic Maintenance Malignant Neoplasms Medical Metabolic Metabolic Control Methylation Molecular Conformation Mutation Nasopharynx Carcinoma Oncogenic PIK3CA gene PIK3CG gene Pathway interactions Phenotype Proteins Regulatory Element Repression Role Site Stomach Carcinoma Stress Testing Transcriptional Regulation Transcriptional Silencer Elements Viral Viral Genome Viral Oncogene Virus Virus Latency Work carcinogenesis epigenome epigenomics inhibitor insight latent infection methylation pattern mouse model novel therapeutic intervention replication stress response small molecule inhibitor therapeutic evaluation therapeutic target

2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine 3-Dimensional ARID1A gene Accounting Affect Automobile Driving Carcinoma Chromosomes Collaborations CpG Islands DNA Binding DNA Crosslinking DNA Damage DNA Methylation Epigenetic Process Episome Epithelial Cells Epithelium Epstein-Barr Virus latency Genes Genetic Transcription Genome Goals Human Herpesvirus 4 Investigation LMP1 Lytic Maintenance Malignant Neoplasms Medical Metabolic Metabolic Control Methylation Molecular Conformation Mutation Nasopharynx Carcinoma Oncogenic PIK3CA gene PIK3CG gene Pathway interactions Phenotype Proteins Regulatory Element Repression Role Site Stomach Carcinoma Stress Testing Transcriptional Regulation Transcriptional Silencer Elements Viral Viral Genome Viral Oncogene Virus Virus Latency Work carcinogenesis epigenome epigenomics inhibitor insight latent infection methylation pattern mouse model novel therapeutic intervention replication stress response small molecule inhibitor therapeutic evaluation therapeutic target

展开

项目摘要

PROJECT 1 – PROJECT SUMMARY The long-term goal of this project is to determine how EBV establishes an oncogenic latent epigenome in EBV- associated epithelial cancers and to leverage this information to develop new therapeutic strategies to target EBV latent infection in epithelial cancers. All EBV cancers share the common feature of maintaining latent viral genomes that express a restricted subset of viral oncogenes. EBV epithelial cancers also have the distinguishing feature of CpG Island Methylation Phenotype (CIMP). The role of EBV latent infection in driving CIMP, and the role of CIMP in regulating oncogenic EBV latency are not fully elucidated, but critical for understanding EBV carcinogenesis. In Aim 1, we propose to investigate how EBV latent infection promotes CIMP. We will test the specific hypothesis that EBNA1-driven episome maintenance induces a PARP1-dependent DNA-damage response that drives CIMP. In collaboration with Project 2, we will investigate the role of PARP1 and UHRF1 in the formation of site-specific viral and host DNA methylation. In collaboration with Project 3, we will explore the role of PI3K activation in controlling replication stress in epithelial cancers. In Aim 2, we will test the hypothesis that CIMP and other somatic changes, such as PI3K and ARID1A mutations, facilitate the formation of a viral type II latency. In collaboration with Project 2, we will examine the role of CTCF and CIMP on EBV 3D conformation. With Project 3, we will investigate how metabolic changes favor establishment of type II latency in epithelial cancers. Finally, we will work in collaboration with Projects 2, 3 and all Cores to identify new therapeutic approaches to treat EBV(+) epithelial cancers. To this end, we have developed new small molecule inhibitors and mouse models of EBV epithelial cancers to better understand these mechanisms and test therapeutic strategies. The overarching hypothesis of Project 1 is that EBV epithelial malignancies depend on the establishment of a distinct epigenetic state involving CpG methylator phenotype (CIMP) and that key regulators of this epigenetic state are therapeutic targets in EBV epithelial carcinogenesis.

项目1 - 项目摘要该项目的长期目标是确定EBV如何在EBV- 相关的上皮癌症，并利用这些信息来制定新的治疗策略以靶向上皮癌中的EBV潜在感染。所有EBV癌症都共享维持潜在病毒的共同特征表达病毒癌基因的受限子集的基因组。 EBV上皮癌也有区别 CpG岛甲基化表型（CIMP）的特征。 EBV潜在感染在驾驶CIMP和 CIMP在控制致癌性EBV潜伏期中的作用尚未完全阐明，但对于理解EBV至关重要致癌作用。在AIM 1中，我们建议研究EBV潜在感染如何促进CIMP。我们将测试 EBNA1驱动的发作维持诱导PARP1依赖性DNA破坏的特定假设驱动CIMP的响应。通过与项目2合作，我们将调查PARP1和UHRF1在位点特异性病毒和宿主DNA甲基化的形成。与项目3合作，我们将探索 PI3K激活在控制上皮癌中复制应力中的作用。在AIM 2中，我们将检验假设 CIMP和其他躯体变化，例如PI3K和ARID1A突变，促进了病毒的形成 II型潜伏期。在与项目2的合作中，我们将研究CTCF和CIMP在EBV 3D上的作用构象。通过项目3，我们将研究代谢变化如何偏爱II型潜伏期的建立在上皮癌中。最后，我们将与项目2、3和所有核心合作，以确定新的治疗EBV（+）上皮癌的治疗方法。为此，我们开发了新的小分子 EBV上皮癌的抑制剂和小鼠模型，以更好地了解这些机制并进行测试治疗策略。项目1的总体假设是EBV上皮malignancys 取决于建立涉及CPG甲基表型（CIMP）的独特表观遗传状态这种表观遗传状态的关键调节剂是EBV上皮致癌作用中的治疗靶标。