Loss of Mitochondrial Sirt3, Decreased MnSOD Activity, and IR Induced Genomic Instability

线粒体 Sirt3 缺失、MnSOD 活性降低和 IR 诱导的基因组不稳定

基本信息

批准号：
9440346
负责人：
David Gius
金额：
$ 36.13万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-07 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9440346
关键词：
ARNTL gene Acetylation Address Affect Aging Apoptosis Binding Biochemical Bioenergetics Biological Availability Brain Breast Cancer Patient Cell Death Cell Proliferation Cell Respiration Cells Chemical Agents Circadian Rhythms Clock protein Cytotoxic Chemotherapy Data Deacetylation Detoxification Process Development Drug Metabolic Detoxication Exhibits Feedback Funding Gene Deletion Generations Genes Genetic Genetic Transcription Genome Genomic Instability Genotoxic Stress Glycolysis Hour Human In Vitro Investigation Ionizing radiation Knockout Mice Knowledge Laboratories Link Longevity Lysine Malignant Neoplasms Mammalian Cell Mediating Metabolic Metabolism Mitochondria Mitochondrial Proteins Molecular Mus Mutant Strains Mice Oncogenic Oranges Organism Pathway interactions Periodicity Phenotype Play Predisposition Prevention Process Prodrugs Production Protein Acetylation Proteins Radiation induced damage Reactive Oxygen Species Regulation Research Research Proposals Respiration Rodent Role SOD2 gene Science Signal Transduction Subgroup Supplementation Testing Therapeutic Tissues Transcription Repressor/Corepressor Translations Work Xenograft procedure anticancer research base biological adaptation to stress cancer therapy carcinogenesis circadian pacemaker cytotoxic cytotoxicity design honokiol in vivo innovation mitochondrial metabolism mouse model neoplastic cell personalized cancer therapy prevent public health relevance response tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): One idea of personalized cancer therapy is to identify specific subgroups of cancer patients that will benefit from specific therapeutic strategies. Recently, the NCI has proposed a new research emphasis to design rigorous and innovative research strategies to solve specific problems and paradoxes in cancer research. This research proposal addresses an NCI emphasis: that is how do the proteins that direct life span, at least in some part, affect the molecular mechanisms of cancer development. In addition, can a greater understanding of the mechanisms that direct aging be used to enhance the prevention and/or treatment of cancer? In this regard, it is proposed that the CLOCK/NAD+/SIRT3 axis plays a role in the prevention of damage for IR the deletion of the genes in the axis in mice should result in the creation of new murine models for the investigation of human illness, including human malignancies, that have a strong genetic connection to aging or the genes in the CLOCK/NAD+/SIRT3 axis. In this regard, our preliminary results suggest that circadian CLOCK proteins coordinate mitochondrial metabolism, in part via the modulation of protein acetylation, including MnSOD, to metabolic and oxidative pathways with circadian rhythms. Based on our results, and those or others, it is hypothesized that the CLOCK/NAD+/SIRT3 signaling axis protects against IR-induced damage, cytotoxicity, genomic instability, and carcinogenesis, through the regulation of MnSOD mitochondrial detoxification activity via deacetylation of K68 and K122. In addition, it is proposed that this axis is a potentil molecular axis to sensitize tumor cells to cytotoxic strategies, including IR.

描述（由申请人提供）：个性化癌症治疗的一个想法是确定将从特定治疗策略中受益的特定癌症患者亚群。最近，NCI 提出了一个新的研究重点，旨在设计严格和创新的研究策略来解决这一问题。癌症研究中的具体问题和悖论影响了 NCI 的重点：即指导寿命的蛋白质（至少在某种程度上）如何影响癌症发展的分子机制。直接衰老的机制可用于增强预防和/或治疗癌症？在这方面，有人提出CLOCK/NAD+/SIRT3轴在IR损伤中发挥作用，在小鼠中删除预防轴中的基因应该会导致产生用于研究人类疾病（包括人类恶性肿瘤）的新小鼠模型，这些疾病与衰老或 CLOCK/NAD+/SIRT3 轴中的基因有很强的遗传联系。在这方面，我们的初步结果表明昼夜节律 CLOCK 蛋白进行协调。线粒体代谢，部分通过调节蛋白质乙酰化（包括 MnSOD）来调节具有昼夜节律的代谢和氧化途径。通过 K68 和 MnSOD 脱乙酰化调节 MnSOD 线粒体解毒活性，诱导损伤、细胞毒性、基因组不稳定性和致癌作用此外，有人提出该轴是使肿瘤细胞对细胞毒性策略（包括 IR）敏感的潜在分子轴。