Epigenomic Drivers of EBV Epithelial Cancers
Epigenomic Drivers of EBV Epithelial Cancers
批准号:
10627690
负责人:
PAUL M LIEBERMAN
金额:
$46.97万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-11 至 2028-04-30
关键词:
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine3-DimensionalARID1A geneAccountingAffectAutomobile DrivingCarcinomaChromosomesCollaborationsCpG IslandsDNA BindingDNA CrosslinkingDNA DamageDNA MethylationEpigenetic ProcessEpisomeEpithelial CellsEpitheliumEpstein-Barr Virus latencyGenesGenetic TranscriptionGenomeGoalsHuman Herpesvirus 4InvestigationLMP1LyticMaintenanceMalignant NeoplasmsMedicalMetabolicMetabolic ControlMethylationMolecular ConformationMutationNasopharynx CarcinomaOncogenicPIK3CA genePIK3CG genePathway interactionsPhenotypeProteinsRegulatory ElementRepressionRoleSiteStomach CarcinomaStressTestingTranscriptional RegulationTranscriptional Silencer ElementsViralViral GenomeViral OncogeneVirusVirus LatencyWorkcarcinogenesisepigenomeepigenomicsinhibitorinsightlatent infectionmethylation patternmouse modelnovel therapeutic interventionreplication stressresponsesmall molecule inhibitortherapeutic evaluationtherapeutic target
中文摘要
项目1--项目总结
该项目的长期目标是确定EBV如何在EBV中建立致癌的潜在表观基因组。
并利用这一信息开发新的治疗策略以靶向
上皮性癌中EB病毒潜伏感染的研究所有的EB病毒癌症都有一个共同的特征,那就是保持潜伏的病毒
表达有限的病毒致癌基因子集的基因组。EB病毒上皮癌也有明显的区别
CpG岛甲基化表型的特征。EB病毒潜伏感染在CIMP发病中的作用
CIMP在调节致癌EBV潜伏期中的作用尚未完全阐明,但对于理解EBV是至关重要的
致癌。在目标1中,我们建议研究EBV潜伏感染是如何促进CIMP的。我们将测试
EBNA1驱动的Episome维持诱导依赖PARP1的DNA损伤的特定假设
推动CIMP的响应。与项目2合作,我们将调查PARP1和uhrf1在
形成特定部位的病毒和宿主DNA甲基化。与Project 3合作,我们将探索
PI3K激活在控制上皮癌复制应激中的作用。在目标2中,我们将检验假设
CIMP和其他躯体变化,如PI3K和ARID1A突变,促进了病毒的形成
第二类延迟。与项目2合作,我们将研究CTCF和CIMP在EBV 3D中的作用
构象。在项目3中,我们将研究代谢变化如何有利于II型潜伏期的建立
在上皮性癌症中。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()上皮癌的方法。为此,我们开发了新的小分子
抑制EBV上皮性肿瘤的药物和小鼠模型,以更好地了解这些机制并进行测试
治疗策略。项目1的首要假设是EBV上皮性恶性肿瘤
依赖于涉及CpG甲基化表型(CIMP)的独特表观遗传状态的建立
这种表观遗传状态的关键调节因子是EB病毒上皮癌发生的治疗靶点。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Project 4: Regulation of EBV Latency and Oncogenesis by Hypoxia
-
批准号:10714176
-
项目类别:
-
资助金额:$47.49万
-
财政年份:2023
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Targeting the Epigenetic and Metabolic Control of EBV-Epithelial Cancers
-
批准号:10627689
-
项目类别:
-
资助金额:$243.61万
-
财政年份:2023
-
负责人:PAUL M LIEBERMAN
-
依托单位:
EBNA1 Inhibitor for Treatment of EBV-positive DLBCL
-
批准号:10719866
-
项目类别:
-
资助金额:$74.58万
-
财政年份:2023
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Administrative and Biostatistics
-
批准号:10627693
-
项目类别:
-
资助金额:$15.99万
-
财政年份:2023
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Epigenetic Regulation of Epstein-Barr Virus
-
批准号:10363894
-
项目类别:
-
资助金额:$36.46万
-
财政年份:2022
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Epigenetic Regulation of Epstein-Barr Virus
-
批准号:10550255
-
项目类别:
-
资助金额:$36.46万
-
财政年份:2022
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Drugging EBNA1 to Treat EBV-Associated Cancers - Diversity Supplement
-
批准号:10818976
-
项目类别:
-
资助金额:$13.58万
-
财政年份:2021
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Drugging EBNA1 to Treat EBV-Associated Cancers
-
批准号:10185459
-
项目类别:
-
资助金额:$58.25万
-
财政年份:2021
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Regulation of EBV Latency by Purine Metabolism and Signaling
-
批准号:10298045
-
项目类别:
-
资助金额:$45.76万
-
财政年份:2021
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Regulation of EBV Latency by Purine Metabolism and Signaling
-
批准号:10407656
-
项目类别:
-
资助金额:$45.76万
-
财政年份:2021
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Development of a Small Molecule Inhibitor for KSHV LANA
-
批准号:8856529
-
项目类别:
-
资助金额:$38.39万
-
财政年份:2014
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Development of a Small Molecule Inhibitor for KSHV LANA
-
批准号:8732352
-
项目类别:
-
资助金额:$38.39万
-
财政年份:2014
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Development of a Small Molecule Inhibitor for KSHV LANA
-
批准号:9057999
-
项目类别:
-
资助金额:$39.43万
-
财政年份:2014
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Chromatin Regulation of KSHV Primary Infection
-
批准号:8874167
-
项目类别:
-
资助金额:$15.52万
-
财政年份:2013
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Chromatin Regulation of KSHV Primary Infection
-
批准号:8541139
-
项目类别:
-
资助金额:$40.17万
-
财政年份:2013
-
负责人:PAUL M LIEBERMAN
-
依托单位:
ChIP Sequencing Core
-
批准号:8874170
-
项目类别:
-
资助金额:$12.55万
-
财政年份:2013
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Purchase of a Biacore T200 Surface Plasmon Resonance Label-free Detection System
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批准号:8447935
-
项目类别:
-
资助金额:$36.73万
-
财政年份:2013
-
负责人:PAUL M LIEBERMAN
-
依托单位:
ChIP Sequencing Core
-
批准号:8541143
-
项目类别:
-
资助金额:$32.49万
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财政年份:2013
-
负责人:PAUL M LIEBERMAN
-
依托单位:
Conference Support for International Congress on Oncogenic Herpesviruses
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批准号:8400154
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项目类别:
-
资助金额:$0.7万
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财政年份:2012
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负责人:PAUL M LIEBERMAN
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依托单位:
Development of a Small Molecule Inhibitor for EBV Latent Infection
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批准号:8781640
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项目类别:
-
资助金额:$75.0万
-
财政年份:2012
-
负责人:PAUL M LIEBERMAN
-
依托单位:
海外基金