Mitochondria electron transport chain complexes adaptative responses to cellular stress
线粒体电子传递链复合对细胞应激的适应性反应
基本信息
- 批准号:10732145
- 负责人:
- 金额:$ 43.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAmino AcidsAnimal ModelBioenergeticsBiological MarkersBiopsy SpecimenCellsCellular StressClinicalComplexCoupledDNADataDevelopmentDissociationElectron TransportGlioblastomaGliomaGlycolysisGoalsHydrogen PeroxideHypoxiaIonizing radiationLaboratoriesLipidsLong-Term SurvivorsMGMT geneMalignant NeoplasmsMediatingMetabolicMetabolismMethylationMitochondriaModelingMolecularMolecular TargetMolecular WeightN-terminalNuclearOutcomeOxidative PhosphorylationPatientsPhenotypePhysiologicalProcessProductionProtein IsoformsProteinsRadiationRadiation ToleranceRadiation therapyReactive Oxygen SpeciesRegulationResearchResistanceResistance developmentRoleSamplingStructureSuperoxidesTherapeuticTreatment EfficacyTreatment FailureU251Workaerobic glycolysiscancer cellcytochrome c oxidaseglioma cell linein vivoinhibitormitochondrial genomemitochondrial metabolismneoplastic cellnormoxianovelnovel therapeuticsoxidative damagepatient derived xenograft modelpre-clinicalprognostic toolprogramspromoterprospectivepublic health relevanceradiation resistanceradioresistantrespiratoryresponsestandard of carestem cellstherapy resistanttumor
项目摘要
PROJECT SUMMARY
Radiotherapy is the most effective nonsurgical treatment for glioblastoma; however, therapeutic efficacy is
severely limited due to the development of radioresistance (RR). In the hope of overcoming this urgent clinical
problem, significant research has focused on defining the molecular mechanisms underlying RR. The overall
objective of this application is to confirm the assembly of the ETC into mitochondrial respiratory supercomplexes
(SCs) as a novel mechanism of RR. The central hypothesis of this proposal is that RR in GBM is the result of a
rearrangement of the ETC complexes into SCs triggered by the expression of COX4-1, which promotes
reprograming of glioma cell bioenergetics from predominantly aerobic glycolysis to mitochondrial oxidative
phosphorylation and, consequently, reduces the mitochondrial production of reactive oxygen species (ROS). The
specific aims proposed will use established glioma cell lines, patient-derived xenograft lines, preclinical animal
models, and patient tumor samples to rigorously assess the validity of this hypothesis. Aim 1 will determine the
role of CcO in SC assembly and mitochondrial metabolism. Aim 2 will evaluated the effects of SC on the
regulation of ROS. Aim 3 will evaluate the role of SCs in the response of IR. We expect that data generated
will vertically advance our understanding of how respiratory SCs affect outcomes in GBM and reveal the
therapeutic vulnerability in RR GBM than can be exploited by SC- disrupting agents.
项目概要
放射治疗是胶质母细胞瘤最有效的非手术治疗方法;但治疗效果是
由于辐射抗性(RR)的发展而受到严重限制。希望能够克服这一临床紧迫问题
问题,重要的研究集中在定义 RR 背后的分子机制。整体
本申请的目的是确认 ETC 组装成线粒体呼吸超复合物
(SC)作为 RR 的一种新机制。该提案的中心假设是 GBM 中的 RR 是以下因素的结果
COX4-1 的表达触发 ETC 复合物重排成 SC,从而促进
神经胶质瘤细胞生物能从主要有氧糖酵解到线粒体氧化的重编程
磷酸化,从而减少线粒体产生活性氧 (ROS)。这
提出的具体目标将使用已建立的神经胶质瘤细胞系、患者来源的异种移植系、临床前动物
模型和患者肿瘤样本来严格评估该假设的有效性。目标 1 将确定
CcO 在 SC 组装和线粒体代谢中的作用。目标 2 将评估 SC 对
ROS 的调节。目标 3 将评估 SC 在 IR 响应中的作用。我们期望生成的数据
将垂直推进我们对呼吸 SC 如何影响 GBM 结果的理解,并揭示
RR GBM 的治疗脆弱性比 SC 破坏剂可利用的脆弱性。
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)
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Corinne E. Griguer其他文献
Targeting glioblastoma multiforme cells with pharmacological ascorbate: Disrupting DNA damage response and mTOR cascades emvia/em extracellular Hsub2/subOsub2/sub
用药理抗坏血酸靶向多形性胶质母细胞瘤细胞:通过细胞外 H₂O₂ 破坏 DNA 损伤反应和 mTOR 级联反应
- DOI:
10.1016/j.freeradbiomed.2025.06.008 - 发表时间:
2025-09-01 - 期刊:
- 影响因子:8.200
- 作者:
Naphat Chantaravisoot;Kittipong Sanookpan;Onsurang Wattanathamsan;Rungnapa Bootsri;Tankun Banlue;Chatchapon Chuenjit;Nuttiya Kalpongnukul;Claudia R. Oliva;Corinne E. Griguer;Visarut Buranasudja - 通讯作者:
Visarut Buranasudja
Corinne E. Griguer的其他文献
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{{ truncateString('Corinne E. Griguer', 18)}}的其他基金
Paracrine Signaling in Glioma: Bioenergetics Heterogeneity and Chemoresistance
神经胶质瘤中的旁分泌信号传导:生物能异质性和化疗耐药性
- 批准号:
9221192 - 财政年份:2016
- 资助金额:
$ 43.84万 - 项目类别:
Mitochondrial Dysfunction and Chemoresistance in Malignant Gliomas
恶性胶质瘤的线粒体功能障碍和化疗耐药
- 批准号:
8007374 - 财政年份:2010
- 资助金额:
$ 43.84万 - 项目类别:
Mitochondrial Dysfunction and Chemoresistance in Malignant Gliomas
恶性胶质瘤的线粒体功能障碍和化疗耐药
- 批准号:
7787101 - 财政年份:2010
- 资助金额:
$ 43.84万 - 项目类别:
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