7. Nutrient Modulation. Bernadene Magnuson is a new investigator as she has been in an independent position for less than four years. The long- term objective of the proposed research is to enhance our understanding of the role of aging in the modulation of colon cancer development by dietary compounds. We are proposing to examine the effect of aging on the ability of a natural anti-carcinogen, vitamin D3, to inhibit the development of early lesions of colon cancer called aberrant crypt foci (ACF). We have observed differences in the development of ACF in young and old rats. The ACF model in young animals is widely used to evaluate various dietary treatments as potential chemopreventive agents. However, the usefulness of this model for identify nutrient interventions that would be effective in an aging population has not been examined.
The specific aims addressed by the proposed experiment are: (1) identify differences and similarities in development and progression of ACF in treats treated with a chemical carcinogen at young and middle age; (2) examine the relationship between cell proliferation and apoptosis in carcinogen and non-carcinogen treated rats in young and middle aged populations; (3) compare the effects of dietary addition of the natural anti-carcinogen vitamin D3 on development of and progression of chemically induced ACF in young and middle age rats; (4) examine the relative effects of dietary addition of vitamin D3 on colonic cell proliferation and apoptosis in carcinogen and non-carcinogen treated rats in young and middle age rats; and (5) examine the effect of aging and vitamin D3 supplementation on the expression of vitamin D receptor protein and mRNA in ACF and normal colonic mucosa. Young and old rats will be injected with a colon carcinogen, azoxymethane, to induce the development of ACF. Rats will be randomly assigned to a diet with normal or high levels of vitamin D3. After 14 weeks on the diet, the number, size, location and hexosaminidase activity of ACF will be determined. To elucidate potential mechanisms for age-related differences in the development of ACF in young and aged rats, colonic cell proliferation and apoptosis rates will be assessed in carcinogen and non-carcinogen treated rats in both diet groups. Preliminary studies are proposed to evaluate age-related and vitamin D-induced changes in the expression of vitamin D receptor protein and mRNA in ACF and normal colonic mucosa using immunohistochemistry, Western blotting and RT-PCR. The results from this study will provide preliminary data to support long-term and mechanistic studies on the effect of aging on nutritional intervention of colon cancer. Elucidation of the cell mechanisms involved in colon cancer development and progression in older populations will enhance our ability to extrapolate findings from nutritional intervention studies with young animals to target aged populations.
