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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025834-04
Application #
7797519
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Murthy, Mahadev
Project Start
2007-03-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$251,399
Indirect Cost
Name
Tufts University
Department
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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Tammen, Stephanie A; Friso, Simonetta; Choi, Sang-Woon (2012) Epigenetics: The link between nature and nurture. Mol Aspects Med :
Park, Lara K; Friso, Simonetta; Choi, Sang-Woon (2012) Nutritional influences on epigenetics and age-related disease. Proc Nutr Soc 71:75-83
Kim, Kyong-Chol; Jang, Hyeran; Sauer, Julia et al. (2011) Folate supplementation differently affects uracil content in DNA in the mouse colon and liver. Br J Nutr 105:688-93
Mason, Joel B (2011) Unraveling the complex relationship between folate and cancer risk. Biofactors 37:253-60
Sauer, Julia; Jang, Hyeran; Zimmerly, Ella M et al. (2010) Ageing, chronic alcohol consumption and folate are determinants of genomic DNA methylation, p16 promoter methylation and the expression of p16 in the mouse colon. Br J Nutr 104:24-30
Sauer, Julia; Mason, Joel B; Choi, Sang-Woon (2009) Too much folate: a risk factor for cancer and cardiovascular disease? Curr Opin Clin Nutr Metab Care 12:30-6
Kim, Kyong-chol; Friso, Simonetta; Choi, Sang-Woon (2009) DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging. J Nutr Biochem 20:917-26
Sohn, Kyoung-Jin; Jang, Hyeran; Campan, Mihaela et al. (2009) The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification. Int J Cancer 124:1999-2005

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