Role of Glutaminolysis in the Myc-induced Metabolic Phenotype of Tumor Cells
谷氨酰胺分解在 Myc 诱导的肿瘤细胞代谢表型中的作用
基本信息
- 批准号:8191915
- 负责人:
- 金额:$ 13.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-05 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAntioxidantsBehaviorBiochemical PathwayBurkitt LymphomaCancerousCarbonCell ProliferationCellsComprehensive Cancer CenterComputer SimulationConsumptionDataDevelopmentDrug Delivery SystemsDrug Metabolic DetoxicationEmbryoEnzymesEquilibriumEventFibroblastsFundingFutureGene ExpressionGenomicsGliomaGlucoseGlutamineGlycolysisGoalsGrowthHome environmentHomeostasisIn VitroIndividualInvestigationIsocitrate DehydrogenaseIsotopesKnowledgeLinkLipidsMaintenanceMalignant - descriptorMalignant NeoplasmsMeasurementMedical centerMedicineMetabolicMetabolic PathwayMetabolismMolecularMolecular BiologyMolecular TargetMusNADPNatureNon-Essential Amino AcidNude MiceOncogene ProteinsOncogenicOutcomeOxidation-ReductionOxidative StressPathway interactionsPhenotypePlayProcessProductionProliferatingProteinsPublishingReactionReactive Oxygen SpeciesRegulationReportingResearchResearch PersonnelResourcesRoleRouteShapesSignal TransductionSupporting CellSystemTestingTherapeuticTracerUnited States National Institutes of HealthWorkXenograft procedureaerobic glycolysisbasecancer cellcancer therapycell growthcombatcytotoxicexperiencegain of function mutationinhibitor/antagonistinnovationinsightmetabolomicsneoplastic cellnovelnovel strategiesoverexpressiontumortumor progression
项目摘要
DESCRIPTION (provided by applicant): Reprogramming of glucose and glutamine metabolism is a key event in malignant transformation. However, the functional drivers and molecular pathways underlying these adaptations are only now starting to emerge. Our long-term goal is to understand mechanisms of metabolic reprogramming in tumor cells so that these processes can be targeted by molecular cancer therapeutics. The overall objective of the current application is to apply systems approaches to elucidate the functional role of the glutaminolytic phenotype elicited by overexpression of the Myc oncoprotein. Myc is an important regulator of both aerobic glycolysis as well as glutaminolysis in tumor cells, the latter of which is characterized by avid consumption of the non-essential amino acid glutamine. Our central hypothesis is that the glutaminolytic phenotype induced by Myc overexpression is important for combating oxidative stress and fueling lipid synthesis in rapidly dividing cells. The rationale for the proposed research is that, once we have identified the functional significance of Myc- induced metabolic reprogramming, these processes can be targeted to undermine the advantages they confer on tumor cells. We plan to test our central hypothesis by pursuing the following specific aims: (1) to determine the role of glutaminolysis in detoxification of reactive oxygen species and (2) to determine the role of glutaminolysis in promoting lipid synthesis. The proposed research is innovative because it applies systems approaches to quantitatively elucidate the global behavior of integrated metabolic networks, rather than individual reactions or nodes in isolation. We will apply metabolic flux analysis (MFA) to quantify metabolic phenotypes in P493-6 Burkitt's lymphoma cells as well as mouse embryonic fibroblasts that are dependent on Myc for their malignant transformation. These cells contain Myc constructs that can be modulated to achieve tuned levels of overexpression. The cells will be subjected to different treatments intended to elucidate the role of glycolysis and glutaminolysis in both cellular redox balancing and anaplerotic processes. In particular, we will simultaneously quantify flux through all three major routes of cytosolic NADPH production, which are important for maintenance of redox homeostasis in proliferating cells. Furthermore, we will investigate the regulation of pathways that serve to convert glucose and glutamine into lipid intermediates required to support cell growth. As a result of this work, we expect to contribute a deeper understanding of how Myc regulates cellular metabolism and how these adaptations provide a growth advantage to tumor cells. This is significant because it will stimulate the search for novel drug targets that can inhibit the progression of Myc-dependent tumors. This work will also provide an avenue toward personalized medicine by identifying the unique metabolic signatures of Myc overexpression.
PUBLIC HEALTH RELEVANCE: The proposed research will have an important positive impact in the search for novel drug targets for cancer therapy. In addition, it will provide fundamental insights into the nature of metabolic reprogramming in cancer cells and how these events contribute to malignancy. Because direct inhibitors of Myc are not currently available to clinicians, reversal of Myc-induced metabolic phenotypes may provide a surrogate strategy to suppress the growth of Myc-dependent tumors.
描述(由申请人提供):葡萄糖和谷氨酰胺代谢的重新编程是恶性转化的关键事件。然而,这些适应背后的功能驱动因素和分子途径现在才刚刚开始出现。我们的长期目标是了解肿瘤细胞代谢重编程的机制,以便这些过程可以成为分子癌症治疗的靶点。目前应用的总体目标是应用系统方法来阐明由Myc癌蛋白过表达引起的谷氨酰胺分解表型的功能作用。MYC是肿瘤细胞有氧糖酵解和谷氨酰胺分解的重要调节因子,后者的特点是贪婪地消耗非必需氨基酸谷氨酰胺。我们的中心假设是,Myc过表达诱导的谷氨酰胺分解表型对于对抗氧化应激和促进快速分裂细胞的脂质合成是重要的。这项拟议研究的基本原理是,一旦我们确定了Myc诱导的代谢重编程的功能意义,这些过程就可以有针对性地破坏它们赋予肿瘤细胞的优势。我们计划通过追求以下具体目标来验证我们的中心假设:(1)确定谷氨酰胺分解在活性氧解毒中的作用;(2)确定谷氨酰胺分解在促进脂质合成中的作用。这项拟议的研究具有创新性,因为它应用了系统方法来定量阐明综合代谢网络的全球行为,而不是孤立地单个反应或节点。我们将应用代谢流量分析(MFA)来量化P493-6 Burkitt淋巴瘤细胞以及依赖Myc进行恶性转化的小鼠胚胎成纤维细胞的代谢表型。这些细胞含有Myc结构,可以被调节以实现可调节的过度表达水平。这些细胞将受到不同的处理,旨在阐明糖酵解和谷氨酰胺分解在细胞氧化还原平衡和逆转录过程中的作用。特别是,我们将同时量化胞浆NADPH产生的所有三个主要途径的通量,这对于维持增殖细胞的氧化还原动态平衡非常重要。此外,我们将研究将葡萄糖和谷氨酰胺转化为支持细胞生长所需的脂肪中间体的途径的调节。作为这项工作的结果,我们希望对Myc如何调节细胞代谢以及这些适应如何为肿瘤细胞提供生长优势做出更深入的了解。这一点意义重大,因为它将刺激人们寻找可以抑制Myc依赖肿瘤进展的新药物靶点。这项工作还将通过识别Myc过度表达的独特代谢特征,为个性化药物提供一条途径。
公共卫生相关性:拟议的研究将对寻找癌症治疗的新药物靶点产生重要的积极影响。此外,它还将提供对癌细胞代谢重编程的本质以及这些事件如何导致恶性肿瘤的基本见解。由于Myc的直接抑制剂目前还不为临床医生所用,逆转Myc诱导的代谢表型可能提供一种替代策略来抑制Myc依赖性肿瘤的生长。
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 }}
Jamey D. Young其他文献
Hypoxia uncouples HIF gene transcription and metabolic flux in proliferating primary cells
缺氧使增殖原代细胞中的 HIF 基因转录和代谢通量解耦
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
Courtney A. Copeland;B. Olenchock;Jamey D. Young;J. Loscalzo;W. Oldham - 通讯作者:
W. Oldham
Pool size measurements improve precision of flux estimates but increase sensitivity to unmodeled reactions outside the core network in isotopically nonstationary metabolic flux analysis (INST‐MFA)
池大小测量提高了通量估计的精度,但提高了同位素非平稳代谢通量分析 (INST-MFA) 中对核心网络外部未建模反应的敏感性
- DOI:
10.1002/biot.202000427 - 发表时间:
2022 - 期刊:
- 影响因子:4.7
- 作者:
Amy O Zheng;Anna Sher;Daniel Fridman;C. Musante;Jamey D. Young - 通讯作者:
Jamey D. Young
Award Number: W81XWH-12-1-0383 TITLE: Targeting Redox Homeostasis in LKB1-Deficient NSCLC
奖项编号:W81XWH-12-1-0383 标题:针对 LKB1 缺陷型 NSCLC 中的氧化还原稳态
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Jamey D. Young - 通讯作者:
Jamey D. Young
Learning from the Steersman: A Natural History of Cybernetic Models
向舵手学习:控制论模型的自然史
- DOI:
10.1021/acs.iecr.5b01315 - 发表时间:
2015 - 期刊:
- 影响因子:4.2
- 作者:
Jamey D. Young - 通讯作者:
Jamey D. Young
Accelerating Strain Engineering using Desorption Electrospray Ionization-Imaging Mass Spectrometry and Untargeted Molecular Analysis of Intact Microbial Colonies
使用解吸电喷雾电离成像质谱和完整微生物菌落的非靶向分子分析加速菌株工程
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
Berkley M. Ellis;P. Babele;Jody C. May;C. Johnson;Brian F. Pfleger;Jamey D. Young;J. McLean - 通讯作者:
J. McLean
Jamey D. Young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('Jamey D. Young', 18)}}的其他基金
Integrated multi-tissue 13C flux analysis platform to assess renal metabolism in vivo
用于评估体内肾脏代谢的集成多组织 13C 通量分析平台
- 批准号:
10727785 - 财政年份:2023
- 资助金额:
$ 13.04万 - 项目类别:
In Vivo 2H/13C Metabolic Flux Analysis of NASH Pathogenesis
NASH 发病机制的体内 2H/13C 代谢通量分析
- 批准号:
9276004 - 财政年份:2015
- 资助金额:
$ 13.04万 - 项目类别:
In Vivo 2H/13C Metabolic Flux Analysis of NASH Pathogenesis
NASH 发病机制的体内 2H/13C 代谢通量分析
- 批准号:
8946823 - 财政年份:2015
- 资助金额:
$ 13.04万 - 项目类别:
Role of Glutaminolysis in the Myc-induced Metabolic Phenotype of Tumor Cells
谷氨酰胺分解在 Myc 诱导的肿瘤细胞代谢表型中的作用
- 批准号:
8296584 - 财政年份:2011
- 资助金额:
$ 13.04万 - 项目类别:
Nonstationary Isotopic Tracer Analysis of Hepatocytes
肝细胞的非稳态同位素示踪分析
- 批准号:
7159345 - 财政年份:2005
- 资助金额:
$ 13.04万 - 项目类别:
相似海外基金
Enhancing gamete cryoprotective properties of graphene oxide by dual functionalization with antioxidants and non-penetrating cryoprotectant molecules
通过抗氧化剂和非渗透性冷冻保护剂分子的双重功能化增强氧化石墨烯的配子冷冻保护特性
- 批准号:
24K18002 - 财政年份:2024
- 资助金额:
$ 13.04万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
SBIR Phase I: Sustainable antioxidants for industrial process fluids
SBIR 第一阶段:工业过程流体的可持续抗氧化剂
- 批准号:
2222215 - 财政年份:2023
- 资助金额:
$ 13.04万 - 项目类别:
Standard Grant
Development of a new bone augmentation method that enables long-term survival and long-term functional expression of transplanted cells by antioxidants
开发一种新的骨增强方法,通过抗氧化剂使移植细胞能够长期存活和长期功能表达
- 批准号:
23K09272 - 财政年份:2023
- 资助金额:
$ 13.04万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Non-Invasive Probing Cellular Oxidative Stress and Antioxidants Therapeutic Effectiveness
非侵入性探测细胞氧化应激和抗氧化剂的治疗效果
- 批准号:
10652764 - 财政年份:2023
- 资助金额:
$ 13.04万 - 项目类别:
Mitochondria-targeting Novel Cationic Hydrazone Antioxidants for the Treatment of Preeclampsia
线粒体靶向新型阳离子腙抗氧化剂用于治疗先兆子痫
- 批准号:
10730652 - 财政年份:2023
- 资助金额:
$ 13.04万 - 项目类别:
Effects of different doses of antioxidants(Vitamin E) intake on exercise induced oxidative stress, antioxidative capacity and chronic inflammation
不同剂量抗氧化剂(维生素E)摄入对运动引起的氧化应激、抗氧化能力和慢性炎症的影响
- 批准号:
22K11609 - 财政年份:2022
- 资助金额:
$ 13.04万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Contribution of antioxidants to regeneration of rotator cuff insertion
抗氧化剂对肩袖插入再生的贡献
- 批准号:
22K16720 - 财政年份:2022
- 资助金额:
$ 13.04万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Latent Antioxidants for Environmentally Responsible Polymer Formulations
用于环保聚合物配方的潜在抗氧化剂
- 批准号:
RGPIN-2018-04107 - 财政年份:2022
- 资助金额:
$ 13.04万 - 项目类别:
Discovery Grants Program - Individual
Polyunsaturated fatty acid (PUFA), inflammation and antioxidants
多不饱和脂肪酸 (PUFA)、炎症和抗氧化剂
- 批准号:
RGPIN-2019-05674 - 财政年份:2022
- 资助金额:
$ 13.04万 - 项目类别:
Discovery Grants Program - Individual
Suppressed methemoglobin formation of artificial red cell by liposomal antioxidants and its mechanism.
脂质体抗氧化剂抑制人工红细胞高铁血红蛋白形成及其机制
- 批准号:
22K12824 - 财政年份:2022
- 资助金额:
$ 13.04万 - 项目类别:
Grant-in-Aid for Scientific Research (C)