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：
Corinne E. Griguer
金额：
$ 43.84万
依托单位：
UNIVERSITY OF IOWA
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：
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

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

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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.

项目摘要放射疗法是胶质母细胞瘤的最有效的非手术治疗。但是，治疗功效是由于辐射抗性（RR）的发展而受到严重限制。希望克服这种紧急临床问题，重大研究集中在定义RR的分子机制上。总体该应用的目的是确认将ETC组装到线粒体呼吸超复合物中（SC）是RR的新型机制。该提议的中心假设是GBM中的RR是A的结果 COX4-1表达触发的ETC复合物的重排向SCS，促进从主要有氧糖酵解到线粒体氧化的神经胶质瘤细胞生物能的重编程磷酸化，因此减少了活性氧（ROS）的线粒体产生。这提出的具体目的将使用已建立的神经胶质瘤细胞系，患者衍生的异种移植线，临床前动物模型和患者肿瘤样品严格评估了该假设的有效性。 AIM 1将确定 CCO在SC组装和线粒体代谢中的作用。 AIM 2将评估SC对 ROS的调节。 AIM 3将评估SC在IR响应中的作用。我们期望生成数据将垂直促进我们对呼吸SC在GBM中如何影响结果的理解，并揭示 RR GBM中的治疗脆弱性比破坏药剂可以利用的脆弱性。