Effects of aging and folate on colonic carcinogenesis

描述(由申请人提供)：高龄和叶酸摄入不足都是结肠癌的重要危险因素。在初步研究中，我们观察到衰老和叶酸枯竭改变了啮齿动物结肠中的一碳代谢，增加了尿嘧啶误结合到DMA中，从而产生了染色体和DNA变异和致癌的易感性。基于同样的原因，我们观察到，补充水平的叶酸可以防止结肠衰老引起的异常生化和分子效应的出现。我们还发现几个关键基因的表达在衰老和叶酸耗竭时发生了变化。因此，我们假设，衰老和叶酸供应不足所产生的DNA中尿嘧啶含量的增加会增加染色体和基因组DNA的损伤，影响关键基因的表达，从而促进结肠癌的发生。然而，减少结肠DNA中的尿嘧啶将逆转衰老和叶酸耗竭的致癌作用我们的长期目标是找到一种有效的结肠癌化学预防策略。这项提案中概述的研究旨在确定决定衰老和叶酸状态如何影响结肠癌发生的分子和细胞机制。这项建议的具体目的是确定这种分子异常是否促进了结肠癌的发生，以及叶酸补充或任何其他减少尿嘧啶误掺的方式是否可以减弱这种分子变化，并最终阻止癌症的发展。我们建议使用正常衰老小鼠模型、结肠癌小鼠模型和转基因小鼠模型进行动物研究，后者模仿一种常见的遗传条件，即将叶酸更多地转移到核苷酸合成。通过定义衰老和叶酸调节癌症的分子途径，我们将更好地了解构成高风险的营养状况，从而能够确定叶酸作为化学预防药物有效使用的确切方式。

DESCRIPTION (provided by applicant): Elder age and inadequate folate intake are each strongly implicated as important risk factors for colon cancer. In a preliminary study we observed that aging and folate depletion alter one-carbon metabolism in the rodent colon, increasing uracil misincorporation into DMA, thereby creating a predisposition to chromosomal and DNA aberrancy and carcinogenesis. By the same token we observed that dietary folate at supplemental levels prevents the appearance of the abnormal biochemical and molecular effects of aging in the colon. We also found altered expression of several critical genes in response to aging and folate depletion. We, therefore, hypothesize that the increased uracil content in DNA produced by aging and inadequate folate availability increases chromosomal and genomic DNA damage, affects expression of critical genes and consequently enhances colonic carcinogenesis. However, reduction of uracil in colonic DNA will reverse the pro-carcinogenic effects of aging and folate depletion Our long-term goal is to find an effective strategy for the chemoprevention of colon cancer. The studies outlined in this proposal are aimed at defining molecular and cellular mechanisms that determine how aging and folate status affect colonic carcinogenesis. The specific aim of this proposal is to determine whether such molecular anomalies enhance colonic carcinogenesis and whether folate supplementation or any other modalities to reduce uracil misincorporation attenuates such molecular changes and finally prevents cancer development. We propose animal studies using a normal aging mouse model, a mouse model of colon cancer and a genetically-modified mouse model, the latter mimicking a common genetic condition that diverts folate more to nucleotide synthesis. By defining molecular pathways towards cancer modulated by aging and folate, we will have a better understanding of the nutritional circumstances which constitute high risk and thereby will be able to define the precise manner in which folate can be used effectively as chemopreventive agents.