Understanding the role of altered metabolism in gliomagenesis
了解代谢改变在神经胶质瘤发生中的作用
基本信息
- 批准号:8458871
- 负责人:
- 金额:$ 32.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-02-01 至 2018-01-31
- 项目状态:已结题
- 来源:
- 关键词:Brain NeoplasmsCSPG4 geneCell divisionCellsEnzymesEpidermal Growth Factor ReceptorEventGenerationsGeneticGliomaGliomagenesisGlucoseGlycolysisGrowthHexokinase 2HumanLinkMalignant - descriptorMalignant NeoplasmsMediatingMetabolicMetabolismMusNormal CellOligodendrogliaOutcomePathway interactionsPlayPopulationProcessProductionProtein IsoformsPyruvate KinaseRNA SplicingRoleStem cellsTestingWorkc-myc Genesdaughter cellhexokinaseimprovedmacromoleculemutantnew therapeutic targetoligodendrocyte precursoroligodendrogliomaprecursor cellpublic health relevanceself-renewaltumortumor metabolismtumorigenesisubiquitin ligase
项目摘要
DESCRIPTION (provided by applicant): The long term objective of this proposal is to improve the therapy of glioma by better understanding the role altered metabolism plays in gliomagenesis. Two metabolic enzymes, hexokinase (HK) and pyruvate kinase (PK) are key regulators of the metabolic changes that accompany tumorigenesis. Normal cells express the HK1 and PKM1 isoforms and preferentially use glucose for ATP generation while gliomas, in contrast, express HK2 and PKM2 and use glucose to synthesize macromolecules needed for proliferation. Glial tumors, however, don't arise from differentiated cells but from progenitor cels which express low levels of all HK and PKM isoforms. Gliomagenesis may therefore not be driven by a simple switch from HK1/PKM1 to HK2/PKM2 expression but rather by metabolic enzyme-related changes that favor aberrant vs normal differentiation in progenitor cell populations. It is not known how HK and PKM expression changes along differentiation pathways, what drives these changes, or how important these shifts are to normal cell fate decisions and gliomagenesis. We have shown, however, that oligodendrocyte precursor cells (OPCs) initiate cell fate decisions by segregating NG2 to self-renewing daughter cells, and TRIM32, a ubiquitin ligase for c-myc, to progeny destined for differentiation. Malignant OPCs in contrast generate progeny that symmetrically express NG2/EGFR, fail to express TRIM32 or differentiate, and give rise to oligodendroglioma. Because NG2 and TRIM32 both have the potential to regulate metabolic enzyme expression, we hypothesize that HK- and PKM- related parameters change along cell fate pathways, and that control of these events by the cell fate determinants NG2 and TRIM32 drive normal cell fate decisions, and in aberrant cases, contribute to gliomagenesis. This hypothesis will be tested by 1) defining how metabolic enzyme expression and metabolism change along normal and malignant OPC fate pathways, 2) determining if NG2 and/or TRIM32 regulate HK or PKM expression and metabolism in OPCs, and 3) determining if HK- or PKM-related events control OPC metabolism and cell fate decisions, and in doing so contribute to gliomagenesis.
描述(由申请人提供):本提案的长期目标是通过更好地理解代谢改变在胶质瘤形成中的作用来改善胶质瘤的治疗。两种代谢酶,己糖激酶(HK)和丙酮酸激酶(PK)是伴随肿瘤发生的代谢变化的关键调节因子。正常细胞表达HK 1和PKM 1同种型,并优先使用葡萄糖生成ATP,而胶质瘤,相反,表达HK 2和PKM 2,并使用葡萄糖合成增殖所需的大分子。然而,神经胶质瘤不是由分化的细胞产生的,而是由低水平表达所有HK和PKM同种型的祖细胞产生的。因此,神经胶质瘤的发生可能不是由HK 1/PKM 1到HK 2/PKM 2表达的简单转换驱动的,而是由代谢酶相关的变化驱动的,这些变化有利于祖细胞群体的异常分化与正常分化。目前尚不清楚HK和PKM表达如何沿沿着分化途径变化,是什么驱动这些变化,或者这些变化对正常细胞命运决定和胶质瘤发生有多重要。然而,我们已经表明,少突胶质细胞前体细胞(OPC)启动细胞命运的决定,隔离NG 2自我更新的子细胞,和TRIM 32,泛素连接酶的c-myc,注定分化的后代。相反,恶性OPC产生对称表达NG 2/EGFR的后代,不能表达TRIM 32或分化,并产生少突胶质细胞瘤。由于NG 2和TRIM 32都具有调节代谢酶表达的潜力,我们假设HK和PKM相关参数沿着沿着细胞命运途径改变,并且细胞命运决定子NG 2和TRIM 32对这些事件的控制驱动正常细胞命运决定,并且在异常情况下,有助于胶质瘤形成。该假设将通过1)定义代谢酶表达和代谢如何沿着沿着正常和恶性OPC命运途径改变,2)确定NG 2和/或TRIM 32是否调节OPC中的HK或PKM表达和代谢,和3)确定HK或PKM相关事件是否控制OPC代谢和细胞命运决定,并且在这样做时有助于神经胶质瘤形成。
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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Russell O. Pieper其他文献
Chapter 2 – Molecular and Cell Biology
第 2 章 – 分子和细胞生物学
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:0
- 作者:
Russell O. Pieper;Joseph F. Costello - 通讯作者:
Joseph F. Costello
Russell O. Pieper的其他文献
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{{ truncateString('Russell O. Pieper', 18)}}的其他基金
Contributions of IDH1 mutation to alternative lengthening of telomeres in lower-grade glioma
IDH1 突变对低级别胶质瘤端粒选择性延长的贡献
- 批准号:
10171926 - 财政年份:2017
- 资助金额:
$ 32.53万 - 项目类别:
Understanding the role of altered metabolism in gliomagenesis
了解代谢改变在神经胶质瘤发生中的作用
- 批准号:
8607914 - 财政年份:2013
- 资助金额:
$ 32.53万 - 项目类别:
Understanding the role of altered metabolism in gliomagenesis
了解代谢改变在神经胶质瘤发生中的作用
- 批准号:
8796707 - 财政年份:2013
- 资助金额:
$ 32.53万 - 项目类别:
Training Program in Translational Brain Tumor Research
转化脑肿瘤研究培训计划
- 批准号:
8324744 - 财政年份:2010
- 资助金额:
$ 32.53万 - 项目类别:
Training Program in Translational Brain Tumor Research
转化脑肿瘤研究培训计划
- 批准号:
8726309 - 财政年份:2010
- 资助金额:
$ 32.53万 - 项目类别:
Training Program in Translational Brain Tumor Research
转化脑肿瘤研究培训计划
- 批准号:
8126261 - 财政年份:2010
- 资助金额:
$ 32.53万 - 项目类别:
Training Program in Translational Brain Tumor Research
转化脑肿瘤研究培训计划
- 批准号:
8546196 - 财政年份:2010
- 资助金额:
$ 32.53万 - 项目类别:
Training Program in Translational Brain Tumor Research
转化脑肿瘤研究培训计划
- 批准号:
7942293 - 财政年份:2010
- 资助金额:
$ 32.53万 - 项目类别: