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.
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