Role of Methyltransferases in MYC-driven Medulloblastoma
甲基转移酶在 MYC 驱动的髓母细胞瘤中的作用
基本信息
- 批准号:10270673
- 负责人:
- 金额:$ 45.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-04-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAddressAffectAgeAllograftingAutomobile DrivingBinding ProteinsBlood - brain barrier anatomyBrainBrain NeoplasmsCell LineCell modelChIP-seqChildChromatinChromatin Remodeling FactorChromatin StructureClinical TrialsComplexDataDependenceDevelopmentDiseaseDropoutEZH2 geneEnzymesEpigenetic ProcessFDA approvedFundingFutureGene ExpressionGenesGoalsGrantHistonesHumanIn VitroIncidenceKnockout MiceLeadLibrariesLuciferasesLysineMaintenanceMalignant - descriptorMalignant Childhood NeoplasmMalignant neoplasm of brainMass Spectrum AnalysisMethylationMethyltransferaseModificationMolecularMusMutationNeoplasm MetastasisNeoplasmsNuclearOncogenesOperative Surgical ProceduresPathway interactionsPatientsPatternPediatric NeoplasmPharmaceutical PreparationsPharmacologyPost-Translational Protein ProcessingPrognosisProteinsProteomeProteomicsRadiationRecurrenceRepressor ProteinsRoleSHH geneSMYD3 geneShapesSubgroupSystems BiologyTestingTherapeuticTherapeutic InterventionTransgenic MiceTumor Suppressor ProteinsWorkXenograft procedurebasechemotherapycombinatorialepigenetic regulationexpectationexperiencefunctional lossgain of functiongenome-widehindbrainhistone methyltransferaseimprovedin vivoinhibitor/antagonistmedulloblastomamouse modelnew therapeutic targetnovelnovel therapeuticsoverexpressionprogramssmall hairpin RNAsuccesstherapeutic targettranscriptometranscriptomicstreatment effecttumortumorigenesis
项目摘要
Project Summary/Abstract
Medulloblastoma (MB) is a tumor of the hindbrain that occurs in children with a peak incidence between the ages
of 3 and 7. Based on extensive molecular evidence, medulloblastoma is classified into four major groups, among
which Group (G3) MB with MYC overexpression, carry the worse prognosis. Thus, novel therapies are needed
to effectively treat these aggressive brain tumors in children. Recent genome wide sequencing and 850K
methylation profiling showed that G3MB has a paucity of mutations, most of which occur in epigenetic regulatory
enzymes that modify histones. However, a significant proportion of MYC-driven G3 MBs do not harbor any
mutations suggesting that additional non-mutated epigenetic regulators, so called “hidden drivers”, might act as
oncogenes or tumor-suppressors, implicated in shaping the chromatin structure and driving G3 MB genesis. We
performed a dropout shRNA screen of 243 unique mouse epigenetic regulators, and the top hit was SMYD3, a
H4K5me1 methyltransferase that importantly regulates MYC expression. Systems biology reveals that SMYD3
is most overexpressed in G3 MBs that specifically overexpress MYC (type II) compared to the other G3 MB
subtypes and MB Groups. To address the role of SMYD3 in driving G3 MB, we will use multiple complementary
approaches in vitro and in vivo in both mouse and human G3MB to 1) assess how SMYD3 overexpression
contributes to G3MB tumorigenesis, 2) use mass spectrometry to identify interacting proteins and define the role
of SMYD3 in shaping the transcriptome, proteome and phosphoproteome, and 3) evaluate whether SMYD3 and
other epigenetic regulators could be considered as therapeutic targets for future clinical trials in MYC-driven
G3MB. Our ultimate goal is to identify epigenetic vulnerabilities that can be therapeutically targeted to treat the
most aggressive forms of the disease.
项目总结/摘要
髓母细胞瘤(MB)是一种发生在儿童后脑的肿瘤,
3和7。基于广泛的分子证据,髓母细胞瘤分为四个主要组,
其中MYC过表达的(G3)MB组预后较差。因此,需要新的治疗方法
来有效地治疗这些儿童侵袭性脑瘤。最近的全基因组测序和850 K
甲基化分析显示,G3 MB具有少量突变,其中大部分发生在表观遗传调节基因中。
修饰组蛋白的酶。然而,很大一部分MYC驱动的G3 MB并不包含任何
突变表明,额外的非突变表观遗传调节因子,所谓的“隐藏驱动程序”,可能会作为
癌基因或肿瘤抑制因子,参与染色质结构的形成和G3 MB的发生。我们
对243种独特的小鼠表观遗传调节因子进行了dropout shRNA筛选,最高命中率是SMYD 3,
H4 K5 me 1甲基转移酶,重要调节MYC表达。系统生物学表明SMYD 3
与其他G3 MB相比,在特异性过表达MYC(II型)的G3 MB中过表达最多
子类型和MB组。为了解决SMYD 3在推动G3 MB方面的作用,我们将使用多个互补
在小鼠和人G3 MB中的体外和体内方法,以1)评估SMYD 3过表达如何
有助于G3 MB肿瘤发生,2)使用质谱法鉴定相互作用的蛋白质并确定其作用
SMYD 3在形成转录组、蛋白质组和磷酸化蛋白质组中的作用,以及3)评估SMYD 3和
其他表观遗传调节因子可以被认为是未来MYC驱动的临床试验的治疗靶点。
G3MB。我们的最终目标是确定表观遗传的脆弱性,可以治疗靶向治疗,
最具侵略性的疾病。
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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MARTINE F. ROUSSEL (SHERR)其他文献
MARTINE F. ROUSSEL (SHERR)的其他文献
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{{ truncateString('MARTINE F. ROUSSEL (SHERR)', 18)}}的其他基金
2023 Cell Growth and Proliferation Gordon Research Conference and Seminar
2023年细胞生长与增殖戈登研究会议暨研讨会
- 批准号:
10748652 - 财政年份:2023
- 资助金额:
$ 45.06万 - 项目类别:
FUNCTION OF INK4A/ARF IN PEDIATRIC NEOPLASIA
INK4A/ARF 在儿科肿瘤中的作用
- 批准号:
6595011 - 财政年份:2002
- 资助金额:
$ 45.06万 - 项目类别:
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