Defining the Function of Age-Related Epimutation in Intestinal Tumorigenesis
定义年龄相关表突变在肠道肿瘤发生中的功能
基本信息
- 批准号:10676178
- 负责人:
- 金额:$ 35.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-08 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:APC mutationAberrant DNA MethylationAccelerationAgingApcMin/+ miceApplications GrantsBRAF geneBindingBinding ProteinsBiologicalBiological AssayBiological ModelsCCAAT-Enhancer-Binding ProteinsCDKN2A geneCancer BiologyCancer EtiologyCarcinomaCatalogsCell AgingCell Cycle RegulationCell physiologyCessation of lifeChIP-seqChromatinClustered Regularly Interspaced Short Palindromic RepeatsColonColon CarcinomaColorectal CancerCommunitiesComplexCpG IslandsCyclin-Dependent Kinase Inhibitor 2ADNADNA MethylationDNA Sequence AlterationDNA-Binding ProteinsDataDefectDevelopmentEngineeringEpigenetic ProcessEtiologyEventFluorouracilGene ExpressionGene SilencingGenesGoalsHeritabilityHumanHypermethylationImmunocompetentIn VitroInterventionIntestinal CancerIntestinal NeoplasmsKDM1A geneLaboratoriesLentivirus VectorMAP Kinase GeneMaintenanceMalignant - descriptorMalignant NeoplasmsMediatingMethylationMitoticModelingMolecularMonitorMusMutationNuRD complexOncogenicOrganoidsPathogenesisPathogenicityPathway interactionsPatientsPatternPhenotypePreventionProteinsPublic HealthPublishingRas/RafReaderResearchRobin birdRoleSignal PathwayStressSystemTestingTherapeutic InterventionTissuesTumor Suppressor GenesWorkadenomaage relatedanticancer researchbeta cateninbisulfite sequencingcancer cellcancer initiationcancer preventioncancer therapycarcinogenesischemotherapyclinical carecolon cancer patientscolon tumorigenesisdemethylationdesignepigenetic regulationepigenetic silencingepigenetic therapyepigenomicsexperimental studygene functiongenome-wideimprovedin vivoin vivo Modelintestinal tumorigenesismouse modelnew therapeutic targetnovelorganoid transplantationpromoterrecruitresponsetargeted treatmenttranscription factortranscriptome sequencingtreatment responsetumortumor growthtumor initiationtumor progressiontumorigenic
项目摘要
PROJECT SUMMARY
Epimutation – mitotically stable gene silencing associated with epigenetic alteration in DNA methylation – is
now recognized as a common feature of human cancer. Indeed, recent epigenomic studies revealed that
nearly all tumor types harbor hundreds of aberrantly hypermethylated and silenced promoter CpG island-
associated (CGI-associated) genes, highlighting the need to identify driver epimutations. In this regard, we
developed a novel mouse model of epimutation in a tumor suppressor gene p16 (also known as cyclin-
dependent kinase inhibitor 2A). We found that engineered promoter methylation leads to accelerated p16
epimutation in mouse somatic tissues during aging. We demonstrated that p16 epimutation predisposes mice
to spontaneous tumor development. In addition, our preliminary work shown that p16 epimutation can
cooperate with mutational Apc to accelerate intestinal tumorigenesis using the ApcMin/+ mice. Importantly, we
found that p16 epimutation functions beyond the classically known cell-cycle control to induce malignant
transformation of intestinal neoplasms. Therefore, based on our strong preliminary data, we hypothesize that
p16 epimutation, commonly observed in human sporadic CRCs as part of the age-related epigenetic alteration,
cooperates with genetic alterations to drive intestinal cancer initiation and progression. We will test this by 1)
Determine how p16 epimutation promotes intestinal tumorigenesis. We will assess the biological
consequences of p16 epimutation through its interactions with two key signaling pathways: WNT-APC-β-
catenin and MAPK-RAS-RAF; 2) Determine whether reversal of epigenetic defects in p16 suppresses tumor
growth. We will evaluate tumor responses to the reversal of p16 epimutation by applying a CRISPR-based
targeted p16 promoter demethylation; and 3) Determine whether transcription factors as a reader of
methylated DNA mediate the function of p16 epimutation. We will investigate the molecular events by which
p16 epigenetic silencing is a result from DNA methylation dependent trans-acting protein binding which
subsequently recruits chromatin repressive complexes. These studies will elucidate how aberrant DNA
methylation, an important epigenetic mechanism regulating the expression of tumor suppressor genes, drives
colorectal tumorigenesis. The results derived from this proposal could have a unique impact in the design of
colon cancer epigenetic therapies.
项目摘要
脱位 - 与DNA甲基化表观遗传学改变相关的有线稳定基因沉默 -
现在被认为是人类癌症的共同特征。的确,最近的表观基因质研究表明
几乎所有肿瘤类型都具有数百种异常高度甲基化和沉默的启动子CpG岛 -
相关(CGI相关的)基因,强调了鉴定驱动器表现的需求。在这方面,我们
在肿瘤抑制基因p16中开发了一种新型的小鼠模型(也称为细胞周期蛋白)
依赖性激酶抑制剂2a)。我们发现工程启动子甲基化导致加速P16
衰老过程中小鼠体细胞组织中的缩合。我们证明了p16的epimuntion使小鼠容易
致力于肿瘤的发展。此外,我们的初步工作表明p16 epimuntion可以
与突变APC合作,使用APCMIN/+小鼠加速肠道肿瘤。重要的是,我们
发现p16的示例功能超出了经典已知的细胞周期控制以诱导恶性肿瘤
肠道肿瘤的转化。因此,根据我们的强大初步数据,我们假设
p16的epimimuntion,通常在人类零星CRC中观察到与年龄相关的表观遗传改变的一部分,
与遗传改变合作,以推动肠癌倡议和进展。我们将通过1个测试)
确定p16释放如何促进肠道肿瘤发生。我们将评估生物学
p16释放与两个关键信号通路的相互作用的后果:wnt-apc-β-
Catenin和Mapk-Ras-Raf; 2)确定p16中表观遗传缺陷的逆转是否抑制肿瘤
生长。我们将通过应用基于CRISPR的
靶向P16启动子脱甲基化; 3)确定转录因子是否作为读者
甲基化的DNA介导p16 epimuntion的功能。我们将研究分子事件
P16表观遗传沉默是由DNA甲基化依赖性的反式蛋白结合的结果
随后募集染色质反射复合物。这些研究将阐明异常DNA
甲基化是调查肿瘤抑制基因表达的重要表观遗传机制,驱动
结直肠肿瘤发生。从该提案中得出的结果可能会对设计产生独特的影响
结肠癌表观遗传疗法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lanlan Shen其他文献
Lanlan Shen的其他文献
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{{ truncateString('Lanlan Shen', 18)}}的其他基金
Epigenetically Engineered Mouse Model for Lung Cancer Therapy
用于肺癌治疗的表观遗传工程小鼠模型
- 批准号:
10668346 - 财政年份:2021
- 资助金额:
$ 35.09万 - 项目类别:
Epigenetically Engineered Mouse Model for Lung Cancer Therapy
用于肺癌治疗的表观遗传工程小鼠模型
- 批准号:
10437934 - 财政年份:2021
- 资助金额:
$ 35.09万 - 项目类别:
Epigenetically Engineered Mouse Model for Lung Cancer Therapy
用于肺癌治疗的表观遗传工程小鼠模型
- 批准号:
10272375 - 财政年份:2021
- 资助金额:
$ 35.09万 - 项目类别:
Early Environment, Developmental Epigenetics, and Adult Colonic Diseases
早期环境、发育表观遗传学和成人结肠疾病
- 批准号:
10350569 - 财政年份:2020
- 资助金额:
$ 35.09万 - 项目类别:
Early Environment, Developmental Epigenetics, and Adult Colonic Diseases
早期环境、发育表观遗传学和成人结肠疾病
- 批准号:
10579855 - 财政年份:2020
- 资助金额:
$ 35.09万 - 项目类别:
Defining the Function of Age-Related Epimutation in Intestinal Tumorigenesis
定义年龄相关表突变在肠道肿瘤发生中的功能
- 批准号:
10219193 - 财政年份:2019
- 资助金额:
$ 35.09万 - 项目类别:
Defining the Function of Age-Related Epimutation in Intestinal Tumorigenesis
定义年龄相关表突变在肠道肿瘤发生中的功能
- 批准号:
10460369 - 财政年份:2019
- 资助金额:
$ 35.09万 - 项目类别:
Defining the Function of Age-Related Epimutation in Intestinal Tumorigenesis
定义年龄相关表突变在肠道肿瘤发生中的功能
- 批准号:
10411412 - 财政年份:2019
- 资助金额:
$ 35.09万 - 项目类别:
Massively Parallel Sequencing Technology for Cancer Epigenome.
癌症表观基因组大规模并行测序技术。
- 批准号:
7796888 - 财政年份:2009
- 资助金额:
$ 35.09万 - 项目类别:
Massively Parallel Sequencing Technology for Cancer Epigenome.
癌症表观基因组大规模并行测序技术。
- 批准号:
8012969 - 财政年份:2009
- 资助金额:
$ 35.09万 - 项目类别:
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