Prevention of Genetic Instability by Pomegranate in Ogg1/Myh Deficient Mice

描述（由申请人提供）： 许多癌症与易感基因的遗传有关，特别是DNA修复基因。例如，OGG 1和MYH基因的改变与结直肠癌、肺癌、肾癌和膀胱癌的风险升高有关。同样，Ogg 1/Myh缺陷型小鼠容易患肿瘤。OGG 1和MYH基因参与DNA氧化损伤的修复。氧化性DNA损伤可导致我们基因组中有害的重排，从而导致癌症。因此，抗氧化剂可以降低氧化DNA损伤和重排的水平，从而预防癌症。与其他水果和蔬菜相比，菠萝含有非常高水平的抗氧化剂，可能有助于降低癌症风险。这项临床前试点研究的目标是了解石榴摄入量是否可以降低基因组重排水平。Ogg 1/Myh缺陷小鼠将在其饮用水中用石榴提取物（PomX）处理，并且将在PomX处理的小鼠和接受正常饮用水的对照小鼠中确定基因组重排，包括点突变和缺失。如果PomX减少基因组重排，这将表明PomX可能作为癌症预防剂。这项初步研究将为检查PomX的长期化学预防作用提供依据。这些研究对国家卫生研究所的使命具有重要意义，因为它们将（i）促进我们对基因-营养素相互作用在癌症风险调节中的理解，（ii）调查膳食抗氧化剂的作用机制，（iii）测试预防遗传风险增加的人癌症的新策略。这项研究可以转移到预防原发性和复发性癌症的临床环境中，特别是在OGG 1和MYH突变携带者中。此外，可以建议摄入石榴产品，以帮助减少整个人群的癌症。

DESCRIPTION (provided by applicant): Large numbers of cancers are linked to inheritance of susceptibility genes, especially for DNA repair. For example, alterations in OGG1 and MYH genes are associated with elevated risk of colorectal, lung, kidney and bladder cancer. Likewise, Ogg1/Myh deficient mice are prone to tumors. OGG1 and MYH genes are involved in the repair of oxidative DNA damage. Oxidative DNA damage can result in deleterious rearrangements in our genome leading to cancer. Therefore, antioxidants may reduce the level of oxidative DNA damage and rearrangements, hence prevent cancer. Pomegranate contains very high levels of antioxidants compared to other fruits and vegetables and may help reduce cancer risk. The goal of this pre-clinical pilot study is to understand whether pomegranate intake can reduce the level of genome rearrangements. Ogg1/Myh deficient mice will be treated with pomegranate extract (PomX) in their drinking water and genome rearrangements, including point mutations and deletions, will be determined in PomX treated mice and control mice receiving normal drinking water. If PomX reduces genome rearrangements, it will suggest that PomX may act as a cancer preventive agent. This pilot study would provide a justification to examine the long-term chemopreventive effect of PomX. These studies are significant to the mission of the National Institute of Health, because they will (i) advance our understanding of gene-nutrient interactions in the modulation of cancer risk, (ii) investigate the mechanisms of action of dietary antioxidants, and (iii) test a new strategy to prevent cancer in persons at increased genetic risk. This research could be transferred to the clinical setting for prevention of primary and recurrent cancers, especially in OGG1 and MYH mutation carriers. In addition, intake of pomegranate products could be recommended to help reduce cancer throughout the population.