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