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（由适用提供）：个性化癌症治疗的一种想法是确定将受益于特定治疗策略的癌症患者的特定亚组。最近，NCI提出了一种新的研究重点，以设计严格而创新的研究策略，以解决癌症研究中的特定问题和悖论。这项研究提案解决了NCI的重点：那就是直接寿命的蛋白质至少在某些部分如何影响癌症发展的分子机制。另外，可以对直接衰老的机制有更深入的了解来增强癌症的预防和/或治疗？在这方面，建议时钟/NAD+/SIRT3轴在预防IR的损害中发挥作用，在小鼠中删除轴的基因应该导致创建新的小鼠模型，以研究人类疾病，包括人类恶性肿瘤，这些模型在包括与衰老的基因或基因之间具有强烈的遗传或nAD/nAD/nAD+/nAD+/sipt+/sipt 3轴的基因相关。在这方面，我们的初步结果表明，昼夜节律蛋白质坐标的线粒体代谢部分是通过蛋白质乙酰化的调节（包括MNSOD）的调节，以昼夜节律的方式对代谢和氧化途径进行调节。根据我们的结果以及那些或其他的结果，可以假设通过MNSOD线粒体解毒活性通过K68和K68和K122的deacetylation来调节，时钟/NAD/NAD+/SIRT3信号轴可防止IR诱导的损伤，细胞毒性，基因组不稳定性和致癌作用。另外，有人提出该轴是一种潜在的分子轴，可以将肿瘤细胞感知到包括IR在内的细胞毒性策略。