Exploring the Therapeutic Potential of Stem Cell Biology in Gliomas
探索干细胞生物学在神经胶质瘤中的治疗潜力
基本信息
- 批准号:10014742
- 负责人:
- 金额:$ 22.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:BioinformaticsBiologicalBiological ModelsBiologyBrain NeoplasmsCancer cell lineCell Culture TechniquesCell LineCellsCellular biologyCharacteristicsCiliary Neurotrophic FactorClinicClinicalCollaborationsComputer AnalysisCytostaticsEmbryoEquilibriumExpression ProfilingFundingGene ExpressionGene Expression ProfilingGenesGeneticGenomicsGenotypeGlioblastomaGliomaHomeostasisHumanIn VitroLaboratoriesMalignant NeoplasmsMalignant neoplasm of central nervous systemMessenger RNAMicroRNAsModelingMolecularMusNormal tissue morphologyOncogenesPathway interactionsPatientsPhenotypePre-Clinical ModelPrimary NeoplasmSerumSignal PathwaySignal TransductionStem cellsStudy modelsSystemTechnical ExpertiseTherapeuticTherapeutic AgentsTretinoinTumor Cell LineTumor InitiatorsTumor Stem CellsTumor Suppressor ProteinsTumor-DerivedUrsidae Familybaseexperimental studygene functiongenome-wideglioma cell lineimprovedin vivoneoplastic cellnerve stem cellnew therapeutic targetnovel therapeuticsoligodendrogliomapersonalized medicinepre-clinicalprogramsrepositoryscreeningself-renewalstem cell biologystem cell differentiationtooltranscriptometumortumor xenografttumorigenesis
项目摘要
We have performed experiments to improve our understanding of the molecular mechanisms of deregulated differentiation pathways in TSCs: The delicate balance between stem cell self-renewal and differentiation is controlled by various cell intrinsic and extrinsic factors that are critical for normal tissue homeostasis. Despite extensive phenotypic and functional similarities between GSCs and normal stem cells, the differentiation potentials of GSCs are not entirely normal. Elucidation of the differentiation pathways that are operative in both normal stem cells and GSCs will be critical for fully understanding tumorigenesis and will likely lead to novel therapeutic targets. We have also identified a set of deregulated differentiation pathways in GSCs derived from human primary GBM. Elucidation of underlying molecular mechanism will provide important clues for predicting sensitivity of differentiation therapeutic approach. Characterization of TSCs in aspect of differentiation-inducing agents further revealed the limitations of traditional glioma cell lines grown in serum. For example, retinoic acid treatment and CNTF exposure potently induce differentiation in most GBM tumor initiate cells (TICs) but not of traditional cell lines. This prompted us to question whether many of potential tumor suppressors and/or cytostatic genes previously studied in cell lines, were not recognized. Given the ever-increasing number of potential GSGs and oncogenes in glioblastoma TSCs identified from bioinformatics approaches and technical expertise of stem cell culture accumulated in the laboratories, we have set up screening systems to study the function of these genes in stem cell cultures. In addition, we have made significant progress on one of keystone projects that is to understand the genomic and molecular signaling similarities and differences between our glioma TSCs and normal neural stem cells (NSC). We have performed a very large scale study of 7 different GBM-derived TSCs and normal embryonic NSC lines under both proliferative and differentiating conditions and derived high-throughput mRNA and microRNAs profiling. Since November of 2014, when Dr Gilbert initiated the new glioma stem cell project, we have created 8 more glioma-derived TSCs, introduced 3 low-grade TSCs, and subsequently performed the computational analyses for characterization of the genetics and signaling pathways in these GSCs, enabling these cell lines to be used to explore the therapeutic potential of glioma stem cell biology. As described above, the evolving collaboration with the NCI Patient Derived Models Repository will increase our portfolio of tumor models over the coming year.
我们已经进行了实验,以提高我们对TSCs中非调控分化途径的分子机制的理解:干细胞自我更新和分化之间的微妙平衡受到各种细胞内在和外在因素的控制,这些因素对正常组织的动态平衡至关重要。尽管GSCs和正常干细胞在表型和功能上有广泛的相似性,但GSCs的分化潜能并不完全正常。阐明在正常干细胞和GSCs中均可操作的分化途径对于全面了解肿瘤的发生至关重要,并可能导致新的治疗靶点。我们还鉴定了一组来自人类原发GBM来源的GSCs的非调控分化途径。阐明其潜在的分子机制将为预测分化治疗方法的敏感性提供重要线索。TSCs在分化诱导剂方面的特性进一步揭示了传统的胶质瘤细胞系在血清中生长的局限性。例如,维甲酸处理和CNTF暴露可以有效地诱导大多数GBM肿瘤起始细胞(TICs)分化,但不能诱导传统细胞系分化。这促使我们质疑之前在细胞系中研究的许多潜在的肿瘤抑制基因和/或细胞抑制基因是否没有被识别。鉴于从生物信息学方法和实验室积累的干细胞培养技术专业知识中鉴定出的胶质母细胞瘤干细胞中潜在的GSG和癌基因的数量不断增加,我们建立了筛选系统来研究这些基因在干细胞培养中的功能。此外,我们在Keystone项目之一上取得了重大进展,即了解我们的胶质瘤TSC和正常神经干细胞(NSC)之间的基因组和分子信号的异同。我们对7个不同的GBM来源的TSC和正常胚胎NSC系在增殖和分化条件下进行了非常大规模的研究,并获得了高通量的mRNA和microRNAs图谱。自2014年11月Gilbert博士启动新的胶质瘤干细胞项目以来,我们又创造了8个胶质瘤来源的TSC,引入了3个低级别TSC,并随后对这些GSC中的遗传学和信号通路进行了计算分析,使这些细胞系能够用于探索胶质瘤干细胞生物学的治疗潜力。如上所述,与NCI患者衍生模型存储库不断发展的合作将在未来一年增加我们的肿瘤模型组合。
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)
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Mark Gilbert其他文献
Mark Gilbert的其他文献
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{{ truncateString('Mark Gilbert', 18)}}的其他基金
Identifying New Glioma-Associated Tumor Suppressors and Oncogenes
鉴定新的神经胶质瘤相关肿瘤抑制因子和癌基因
- 批准号:
10014745 - 财政年份:
- 资助金额:
$ 22.91万 - 项目类别:
Exploring the Therapeutic Potential of Stem Cell Biology in Gliomas
探索干细胞生物学在神经胶质瘤中的治疗潜力
- 批准号:
10262378 - 财政年份:
- 资助金额:
$ 22.91万 - 项目类别:
Brain Tumor Animal Therapeutics Core (Scientific Cores)
脑肿瘤动物治疗核心(科学核心)
- 批准号:
9154353 - 财政年份:
- 资助金额:
$ 22.91万 - 项目类别:
Identifying New Glioma-Associated Tumor Suppressors and Oncogenes
鉴定新的神经胶质瘤相关肿瘤抑制因子和癌基因
- 批准号:
10486899 - 财政年份:
- 资助金额:
$ 22.91万 - 项目类别:
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