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
• 负责人: Russell O. Pieper
• 金额: $ 31.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8607914
• 关键词: Brain Neoplasms; CSPG4 gene; Cell division; Cells; Enzymes; Epidermal Growth Factor Receptor; Event; Generations; Genetic; Glioma; Gliomagenesis; Glucose; Glycolysis; Growth; 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; public health relevance; self-renewal; tumor; tumor metabolism; tumorigenesis; ubiquitin ligase

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了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HK1和PKM1亚型，并优先使用葡萄糖生成ATP，而胶质瘤则表达HK2和PKM2，并使用葡萄糖合成增殖所需的大分子。然而，神经胶质肿瘤不是由分化细胞产生的，而是由表达所有HK和PKM亚型的低水平祖细胞产生的。因此，胶质瘤的形成可能不是由HK1/PKM1到HK2/PKM2表达的简单转换驱动的，而是由代谢酶相关的变化驱动的，这种变化有利于祖细胞群体的异常分化和正常分化。目前尚不清楚HK和PKM表达如何沿着分化途径改变，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形成有多重要。然而，我们已经证明，少突胶质前体细胞（OPCs）通过将NG2分离到自我更新的子细胞，并将TRIM32 （c-myc的泛素连接酶）分离到注定分化的后代，从而启动细胞命运决定。相反，恶性OPCs产生的后代对称表达NG2/EGFR，不能表达TRIM32或分化，并导致少突胶质细胞瘤。由于NG2和TRIM32都具有调节代谢酶表达的潜力，我们假设HK-和PKM-相关参数沿着细胞命运途径改变，并且通过细胞命运决定因素NG2和TRIM32控制这些事件驱动正常细胞命运决定，并在异常情况下促进胶质瘤形成。这一假设将通过以下方法得到验证：1)确定代谢酶的表达和代谢如何沿着正常和恶性OPC命运通路发生变化；2)确定NG2和/或TRIM32是否调节OPC中HK或PKM的表达和代谢；3)确定HK或PKM相关事件是否控制OPC代谢和细胞命运决定，并在此过程中促进胶质瘤形成。