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

• 批准号: 10732145
• 负责人: Corinne E. Griguer
• 金额: $ 43.84万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10732145
• 关键词: Affect; Amino Acids; Animal Model; Bioenergetics; Biological Markers; Biopsy Specimen; Cells; Cellular Stress; Clinical; Complex; Coupled; DNA; Data; Development; Dissociation; Electron Transport; Glioblastoma; Glioma; Glycolysis; Goals; Hydrogen Peroxide; Hypoxia; Ionizing radiation; Laboratories; Lipids; Long-Term Survivors; MGMT gene; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Methylation; Mitochondria; Modeling; Molecular; Molecular Target; Molecular Weight; N-terminal; Nuclear; Outcome; Oxidative Phosphorylation; Patients; Phenotype; Physiological; Process; Production; Protein Isoforms; Proteins; Radiation; Radiation Tolerance; Radiation therapy; Reactive Oxygen Species; Regulation; Research; Resistance; Resistance development; Role; Sampling; Structure; Superoxides; Therapeutic; Treatment Efficacy; Treatment Failure; U251; Work; aerobic glycolysis; cancer cell; cytochrome c oxidase; glioma cell line; in vivo; inhibitor; mitochondrial genome; mitochondrial metabolism; neoplastic cell; normoxia; novel; novel therapeutics; oxidative damage; patient derived xenograft model; pre-clinical; prognostic tool; programs; promoter; prospective; public health relevance; radiation resistance; radioresistant; respiratory; response; standard of care; stem cells; therapy resistant; tumor

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.

项目摘要 放射治疗是胶质母细胞瘤最有效的非手术治疗;然而，治疗效果有待进一步研究。 由于放射抗性（RR）的发展而严重受限。希望能克服这一紧迫的临床 问题，重要的研究集中在定义RR的分子机制。整体 本申请的目的是证实ETC组装成线粒体呼吸超复合物 (SCs)作为RR的一种新机制。该建议的中心假设是，GBM中的RR是 ETC复合物重排为SC，由COX 4 -1的表达触发，其促进 胶质瘤细胞生物能学从有氧糖酵解到线粒体氧化的重编程 在一些实施方案中，本发明的化合物通过磷酸化来抑制线粒体内的活性氧，并因此减少活性氧（ROS）的线粒体产生。的 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物系、临床前动物 模型和患者肿瘤样本，以严格评估这一假设的有效性。目标1将决定 CcO在SC组装和线粒体代谢中的作用。目的2将评估SC对 ROS的调控。目的3将评估SC在IR反应中的作用。我们希望所产生的数据 将垂直推进我们对呼吸系统SC如何影响GBM结果的理解，并揭示 在RR GBM中的治疗脆弱性可以被SC破坏剂利用。