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Research Project: Defining Mechanims by which Select Nutrients Determine Cancer Risk

Location: Jean Mayer Human Nutrition Research Center On Aging

Project Number: 8050-51000-096-01-S
Project Type: Non-Assistance Cooperative Agreement

Start Date: May 1, 2014
End Date: Apr 30, 2019

Objective:
LAB NAME: Vitamins and Carcinogenesis 1: Define the role that intake, or nutrient status, of each of the one-carbon nutrients plays in determining the risk of common cancers and to examine select environmental and genetic factors that further modify the effects of 1-carbon nutrients. Through the use of cell culture, animal models and human studies, determine the cell-signaling pathways(s) through which the effects of 1-carbon nutrients is exerted, and elucidate genetic and epigenetic mechanisms by which this occurs. In animal models, also examine how parental intake of these nutrients influences cancer risk in offspring. 1.1: Determine the effect of maternal B vitamin intake on tumorigenesis in offspring. 1.2: Determine the effect of paternal B vitamin intake on tumorigenesis in offspring. 2: Define the cellular pathways by which obesity, and related factors, enhance cancer risk and explore means of attenuating that risk. By use of cell culture studies, animal models, and human studies, focus on how the chronic, low-grade inflammation produced by obesity incites molecular processes that lead to cancer. 2.1: Define the effects of obesity-induced elevations of colonic IL-1ß on Wnt and NF'B activation in the colonic mucosa of mice. 2.2: Determine the effect of genetic and immunologic blockade of IL-1ß on obesity-induced tumorigenesis. 2.3: Determine the effects of an orally-available inhibitor of Akt on obesity-promoted tumorigenesis in AOM-treated mice. 2.4: Determine whether obesity in humans raises pro-inflammatory cytokine levels in the colonic mucosa and whether the elevation in cytokines is accompanied by activation of mucosal Wnt and NF'B.

Approach:
LAB NAME: Vitamins and Carcinogenesis Alterations in dietary and nutritional habits have an important role to play in cancer prevention. The nutrients involved in 1-carbon metabolism (methionine, choline, and the B-vitamins, folate, B2, B6, and B12), as well as obesity have drawn considerable attention in this regard and are the focus of this laboratory. Our mission is to examine the complex roles that obesity and these 1-carbon nutrients play in modifying cellular pathways that lead to human carcinogenesis and thereby define means by which nutrition can be used to reduce the risk of developing cancer. The program of research emphasizes how dietary intake interacts with the genetic background to modify molecular and signaling pathways which alter the development of cancer, and to examine how other exogenous factors, such as alcohol consumption, also play a role. The laboratory focuses on colorectal and breast cancer, and utilizes cell culture studies, animal models, and human studies to accomplish our research goals.