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

描述(由申请人提供)： 大量癌症与遗传易感基因有关，特别是DNA修复。例如，OGG1和MYH基因的改变与结直肠癌、肺癌、肾癌和膀胱癌的风险增加有关。同样，Ogg1/MyH基因缺陷的小鼠也容易患上肿瘤。OGG1和MYH基因参与DNA氧化损伤的修复。氧化DNA损伤会导致我们基因组中有害的重排，从而导致癌症。因此，抗氧化剂可能会降低DNA氧化损伤和重排的水平，从而预防癌症。与其他水果和蔬菜相比，石榴含有非常高水平的抗氧化剂，可能有助于降低癌症风险。这项临床前先导性研究的目标是了解石榴摄入是否可以降低基因组重排的水平。Ogg1/Myh缺陷小鼠将在饮用水中加入石榴提取物(POMX)，并将在接受POMX处理的小鼠和接受正常饮用水的对照小鼠中检测基因组重排，包括点突变和缺失。如果POMX减少基因组重排，这将表明POMX可能起到癌症预防的作用。这项初步研究将为检验POMX的长期化学预防作用提供依据。这些研究对国家健康研究所的使命意义重大，因为它们将(I)促进我们对基因-营养相互作用在调节癌症风险方面的理解，(Ii)研究饮食抗氧化剂的作用机制，以及(Iii)测试一种预防遗传风险增加的人患癌症的新策略。这项研究可以转移到预防原发和复发癌症的临床环境中，特别是在OGG1和MYH突变携带者中。此外，可以建议摄入石榴产品，以帮助降低人群中的癌症。

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.