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

 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癌症患者的特定亚群。最近，NCI提出了一个新的研究重点，以设计严谨和创新的研究策略，以解决癌症研究中的具体问题和悖论。这项研究方案解决了NCI的一个重点：即指导生命周期的蛋白质如何影响癌症发展的分子机制，至少在某些方面是这样。此外，能否更好地理解直接衰老的机制，以加强对癌症的预防和/或治疗？在这方面，有人认为Clock/NAD+/SIRT3轴在预防IR损伤中发挥作用。在小鼠中，Clock/NAD+/SIRT3轴基因的缺失将导致建立新的小鼠模型，用于研究人类疾病，包括与衰老或Clock/NAD+/SIRT3轴基因有强烈遗传联系的人类恶性肿瘤。在这方面，我们的初步结果表明，昼夜节律时钟蛋白协调线粒体代谢，部分是通过调节蛋白质乙酰化，包括MnSOD，调节到具有昼夜节律的代谢和氧化途径。根据我们的结果和其他人的结果，我们假设Clock/NAD+/SIRT3信号轴通过K68和K122的脱乙酰化调节MnSOD线粒体的解毒活性，从而保护IR诱导的损伤、细胞毒性、基因组不稳定和癌症发生。此外，有人认为这个轴是一个潜在的分子轴，使肿瘤细胞对包括IR在内的细胞毒策略敏感。

 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.