Implications of Circadian Clock Control on Glioblastoma
生物钟控制对胶质母细胞瘤的影响
基本信息
- 批准号:10318088
- 负责人:
- 金额:$ 4.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-12-01 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:ARNT geneARNTL geneAcetylationAgonistAngiogenic FactorApoptosisArginineAstrocytesAttenuatedBackBindingBiologic CharacteristicBlood - brain barrier anatomyBody RegionsBrainBrain NeoplasmsCell Cycle ArrestCell MaintenanceCellsChIP-seqChemoresistanceCircadian RhythmsCircadian gene expressionCitric Acid CycleClock proteinCollaborationsCombined Modality TherapyCuesDNADependenceDevelopmentE-Box ElementsEmploymentEnzymesEpigenetic ProcessExcisionExposure toFeedbackFoundationsGene ExpressionGene Expression ProfileGenesGeneticGenetic TranscriptionGlioblastomaGlutamatesGlycolysisGrowthHeterogeneityHistonesHomeostasisHormone secretionHourHypothalamic structureImmuneImmunoprecipitationImmunotherapyIn VitroIncidenceIndividualInvadedLaboratoriesLinkLysineMaintenanceMalignant - descriptorMalignant NeoplasmsMetabolicMetabolismMicrogliaMitochondriaModelingModificationMusMuscleNeurogliaNeuronsNuclear ReceptorsOncogenicOperative Surgical ProceduresOutputOxidative PhosphorylationPatientsPeripheralPharmacologyPharmacotherapyPhotosensitivityPhysiologicalPopulationPre-Clinical ModelPrimary Brain NeoplasmsPrimary NeoplasmProcessPrognosisProteinsPublishingQuality of lifeRadiation therapyResearch Project GrantsResistanceRetinal Ganglion CellsRoleSignal TransductionSleepSurvival RateSynaptic plasticityTimeTissuesToxic effectTransferaseTranslationsTumor BurdenUbiquitinationattenuationcancer stem cellcircadiancircadian pacemakercryptochrome 1efficacy testingepigenetic regulationexperimental studyextracellulargenetic corepressorhistone modificationimprovedin vivoknock-downmelanopsinnovelnovel strategiesnovel therapeuticspatient derived xenograft modelpatient prognosispreventpromoterprotein arginine methyltransferase 2recruitself-renewalsmall moleculestem cell growthstem cell proliferationstem cell self renewalstem cellsstemnesssuprachiasmatic nucleussynergismtargeted treatmenttranscription factortranscriptome sequencingtumortumor microenvironmenttumorigenic
项目摘要
PROJECT SUMMARY/ABSTRACT
Despite being thoroughly characterized, glioblastoma multiforme (GBM) remains one of the most common
malignant primary brain tumors. Currently, patient prognosis has remained poor in that treatment for GBM has
only moderately improved survival rates and quality of life even with the employment of aggressive multimodal
therapies. The unique heterogeneous genetic, epigenetic, and microenvironmental features of GBM and the
brain make tumors resistant to treatments that have otherwise been highly effective in treating cancers of other
tissues. In particular, GBM contains cancer stem cells, termed glioblastoma stem cells (GSCs), that are self-
renewing and tumorigenic, thereby supporting the progression and growth of the primary tumor even after
surgical resection. GSCs have the ability to actively remodel the tumor microenvironment and receive
maintenance cues from their surroundings. In recent published studies from our laboratory, GSCs have been
found to display unique circadian rhythms and dependence on core circadian clock transcription factors, Brain
and Muscle ARNT-Like 1 (BMAL1), otherwise known as Aryl Hydrocarbon Receptor Nuclear Translocator Like
(ARNTL), and Circadian Locomotor Output Cycles Kaput (CLOCK). This dependence was not observed in
normal neural cells nor differentiated glioblastoma cells (DGCs) and is consistent with associations between the
circadian rhythm and increased likelihood of tumor development. Loss of BMAL1 or CLOCK in GSCs induced
cell cycle arrest, apoptosis, attenuation of mitochondrial metabolic function, and reduced expression of the
tricarboxylic acid (TCA) cycle enzymes and stemness genes, such SOX2, OLIG2, and MYC. Additionally, novel
small molecule agonists and stabilizers of two independent negative core clock regulators, Cryptochrome 1/2
(CRY1/2) and REV-ERBa/b (REV-ERBs), were found to be able to downregulate stem cell regulators and reduce
GSC growth. In this study, I intend to elucidate the mechanisms in which epigenetic machineries, in particular
protein arginine methyl transferases (PRMTs), regulate transcription of circadian clock oscillators to promote
stemness and proliferation abilities of GSCs. I also aim to determine the efficacy of small molecule CRY
stabilizers and REV-ERB agonists, both independently and in combination with each other, in targeting GSCs
as novel GBM therapies. My findings will illuminate the epigenetic regulation of circadian clock components in
the context of GSC maintenance and progress a preclinical model for GBM treatment via pharmacological
targeting of the circadian clock.
项目总结/摘要
尽管被彻底表征,多形性胶质母细胞瘤(GBM)仍然是最常见的肿瘤之一。
恶性原发性脑肿瘤目前,患者预后仍然很差,因为GBM的治疗
即使采用积极的多模式治疗,
治疗GBM独特的异质性遗传、表观遗传和微环境特征,
大脑使肿瘤对治疗产生抗药性,而这些治疗在治疗其他癌症方面是非常有效的。
组织中特别地,GBM含有癌症干细胞,称为胶质母细胞瘤干细胞(GSC),其是自体的。
更新和致瘤性,从而支持原发性肿瘤的进展和生长,即使在
手术切除GSC具有主动重塑肿瘤微环境的能力,
来自周围环境的维持线索在我们实验室最近发表的研究中,
发现显示独特的昼夜节律和对核心昼夜节律钟转录因子的依赖,
和肌肉ARNT样1(BMAL 1),也称为芳烃受体核转运蛋白样
(ARNTL)和昼夜运动输出周期Kaput(CLOCK)。这种依赖性没有观察到,
正常神经细胞和分化的胶质母细胞瘤细胞(DGC)之间的关联是一致的,
昼夜节律和肿瘤发展的可能性增加。诱导的GSC中BMAL 1或CLOCK的缺失
细胞周期停滞、凋亡、线粒体代谢功能减弱和
三羧酸(TCA)循环酶和干性基因,如SOX 2、OLIG 2和MYC。此外,小说
两个独立的负核心时钟调节因子隐花色素1/2的小分子激动剂和稳定剂
(CRY1/2)和REV-ERBa/B(REV-ERBs),被发现能够下调干细胞调节因子,
GSC增长。在这项研究中,我打算阐明表观遗传机制,特别是
蛋白质精氨酸甲基转移酶(PRMT),调节生物钟振荡器的转录,以促进
干细胞和增殖能力。我还旨在确定小分子CRY
稳定剂和REV-ERB激动剂,独立地和彼此组合,
作为新的GBM疗法。我的研究结果将阐明生物钟成分的表观遗传调节,
GSC维持和进展的背景下,GBM治疗的临床前模型,通过药理学
生物钟的定位
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Priscilla Chan其他文献
Priscilla Chan的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Priscilla Chan', 18)}}的其他基金
Implications of Circadian Clock Control on Glioblastoma
生物钟控制对胶质母细胞瘤的影响
- 批准号:
10540362 - 财政年份:2020
- 资助金额:
$ 4.68万 - 项目类别: