Effects of aging and folate on colonic carcinogenesis

描述（由申请人提供）：年龄较大和叶酸摄入不足都是结肠癌的重要危险因素。在一项初步研究中，我们观察到衰老和叶酸消耗改变了啮齿动物结肠中的一碳代谢，增加了尿嘧啶错误掺入DMA，从而产生了染色体和DNA异常和致癌的倾向。出于同样的原因，我们观察到补充水平的膳食叶酸可以防止结肠中老化的异常生化和分子效应的出现。我们还发现了几个关键基因的表达改变，以应对衰老和叶酸消耗。因此，我们假设，增加尿嘧啶含量的DNA产生的老化和叶酸供应不足增加染色体和基因组DNA损伤，影响关键基因的表达，从而增强结肠癌的发生。然而，结肠DNA中尿嘧啶的减少将逆转衰老和叶酸消耗的促癌作用。我们的长期目标是找到一种有效的结肠癌化学预防策略。本提案中概述的研究旨在确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。该提案的具体目的是确定此类分子异常是否会增强结肠致癌作用，以及补充叶酸或任何其他减少尿嘧啶错误掺入的方式是否会减弱此类分子变化并最终预防癌症的发生。我们建议使用正常衰老小鼠模型，结肠癌小鼠模型和遗传修饰小鼠模型进行动物研究，后者模仿一种常见的遗传条件，将叶酸更多地转移到核苷酸合成。通过定义由衰老和叶酸调节的癌症分子途径，我们将更好地了解构成高风险的营养环境，从而能够定义叶酸可有效用作化学预防剂的精确方式。

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.