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：
8796707
负责人：
Russell O. Pieper
金额：
$ 32.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8796707
关键词：
Brain Neoplasms CSPG4 gene Cell division Cells Enzymes Epidermal Growth Factor Receptor Event Generations Genetic Glioma Gliomagenesis Glucose Glycolysis Growth Health Hexokinase 2 Human Link Malignant - descriptor Malignant Neoplasms Mediating Metabolic Metabolism Mus Normal Cell Oligodendroglia Outcome Pathway interactions Play Population Process Production Protein Isoforms Pyruvate Kinase RNA Splicing Role Stem cells Testing Work c-myc Genes daughter cell hexokinase improved macromolecule mutant new therapeutic target oligodendrocyte precursor oligodendroglioma precursor cell self-renewal tumor tumor metabolism tumorigenesis ubiquitin ligase

Brain Neoplasms CSPG4 gene Cell division Cells Enzymes Epidermal Growth Factor Receptor Event Generations Genetic Glioma Gliomagenesis Glucose Glycolysis Growth Health Hexokinase 2 Human Link Malignant - descriptor Malignant Neoplasms Mediating Metabolic Metabolism Mus Normal Cell Oligodendroglia Outcome Pathway interactions Play Population Process Production Protein Isoforms Pyruvate Kinase RNA Splicing Role Stem cells Testing Work c-myc Genes daughter cell hexokinase improved macromolecule mutant new therapeutic target oligodendrocyte precursor oligodendroglioma precursor cell self-renewal tumor tumor metabolism tumorigenesis ubiquitin ligase

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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）：该提案的长期目标是通过更好地理解胶质性作用改变的作用来改善神经胶质瘤的治疗。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剂。正常细胞表达HK1和PKM1同工型，优先将葡萄糖用于ATP的产生，而Gliomas相反，Gliomas表示Express HK2和PKM2，并使用葡萄糖来合成增殖所需的大分子。然而，神经胶质肿瘤不是来自分化细胞，而是来自祖细胞的所有HK和PKM同工型的水平较低。因此，神经胶质发生可能不会由从HK1/PKM1转换为HK2/PKM2表达的简单转换，而是由代谢酶相关的变化驱动的，这些变化有利于异常的祖细胞群体中的异常分化。尚不清楚HK和PKM表达如何沿分化途径变化，驱动这些变化的原因或这些转移对正常细胞命运的决策和神经胶质作用的重要性。但是，我们已经表明，少突胶质细胞前体细胞（OPC）通过将NG2隔离到自我更新的子细胞和Trim32（C-Myc的泛素连接酶）来启动细胞命运决定，从而启动了c-Myc的泛素连接酶，以差异化。相比之下，恶性OPC会产生对称表达NG2/EGFR的后代，无法表达TRIM32或分化，并引起寡头瘤。由于NG2和TRIM32都有可能调节代谢酶表达的潜力，因此我们假设HK-和PKM-相关参数沿细胞命运途径发生了变化，并且细胞命运决定簇NG2和TRIM32对这些事件的控制驱动了正常的细胞命中率，在异常的病例中，促进了gliomagagenesess。 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神经胶质作用。