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。