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.

项目总结 放射治疗是胶质母细胞瘤最有效的非手术治疗方法；然而，治疗效果是 由于辐射抗性(RR)的发展而严重受限。希望能克服这个紧急的临床问题 为了解决这一问题，重要的研究集中在确定RR的分子机制上。整体而言 本申请的目的是确认ETC组装成线粒体呼吸超复合体 (SCS)作为RR的一种新机制。这一建议的中心假设是，GBM中的RR是 COX4-1的表达触发ETC复合体重排为SCs，从而促进 胶质瘤细胞生物能量学从以有氧糖酵解为主向线粒体氧化的重新编程 磷酸化，从而减少线粒体产生的活性氧物种(ROS)。这个 提出的特定目标将使用已建立的胶质瘤细胞系、患者来源的异种移植系、临床前动物 模型和患者肿瘤样本，以严格评估这一假说的有效性。目标1将决定 CcO在SC组装和线粒体代谢中的作用目标2将评估SC对 对ROS的监管。目的3将评估干细胞在IR反应中的作用。我们希望产生的数据 将垂直推进我们对呼吸干细胞如何影响GBM预后的理解，并揭示 RR GBM中的治疗脆弱性超过了SC干扰剂可以利用的程度。