We have demonstrated that chemoprotective diets containing turmeric (curcumin) and citrus (limonin) bioactives reduce chronic inflammation and colon cancer risk. With respect to cancer biology, recent observations demonstrate that crypt stem cells are the cells-of-origin of intestinal cancer. Since non-coding microRNA-mediated translational repression and changes to chromatin structure may be linked to the development of colon cancer, it is vital that the effect of chemopreventive diets on microRNAs, their messenger RNA (mRNA) targets, and epigenetic modifications on both the histone and DNA levels in intestinal stem cells be determined. However, to date, the effect of dietary botanicals on genome-wide chromatin epigenetic modifications, microRNAs, and mRNA populations in intestinal stem cells, crypts and tumors has not been determined. Therefore, we hypothesize that a chemoprotective diet, containing curcumin and/or the citrus bioactive limonin, will modulate the stem cell transcriptome, resulting in a favorable shift in disease progression.
Aim 1 will use highly novel stem cell specific Lgr5-LacZ and Lgr-EGFP mice to quantify the number and spatio-temporal location of stem cells, DNA damage and targeted apoptosis in the colonic crypt at the initiation and tumor stages of colon carcinogenesis following exposure to diets containing curcumin, limonin, and their mixture.
Aim 2 will use the Lgr5-EGFP mouse to investigate the effect of disease progression on microRNAs and their post-transcriptionally regulated mRNA targets in colonic stem cells, intact colonic crypts and tumors following carcinogen/inflammation or saline (control) exposure.
Aim 3 will generate high-resolution genome- wide """"""""chromatin-state"""""""" maps for (i) intestinal epithelial cell crypts, and (ii) colonic tumors using chromatin immunoprecipitation in order to assess the effect of diet and colitis-associated colon carcinogenesis on epigenetic modifications at both the histone and DNA levels. It is anticipated that novel stem cell signaling networks and markers will emerge from these studies. The proposed studies will promote our understanding of how botanicals impact critical signaling pathways during normal intestinal development and malignant transformation, including self-renewal of stem cells.

Public Health Relevance

The proposed studies will promote our understanding of how dietary chemoprotective natural botanical products, e.g., curcumin, citrus-derived limonin, and their mixture, impact critical signaling pathways during normal intestinal development and malignant transformation, including self-renewal of stem and progenitor cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168312-02
Application #
8330239
Study Section
Special Emphasis Panel (ZAT1-SM (23))
Program Officer
Kim, Young S
Project Start
2011-09-08
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$298,684
Indirect Cost
$90,353
Name
Texas A&M University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
078592789
City
College Station
State
TX
Country
United States
Zip Code
77845
Fan, Yang-Yi; Vaz, Frederic M; Chapkin, Robert S (2016) Dietary fat and fiber interactively modulate apoptosis and mitochondrial bioenergetic profiles in mouse colon in a site-specific manner. Eur J Cancer Prev :
Shah, Manasvi S; Kim, Eunjoo; Davidson, Laurie A et al. (2016) Data describing the effects of dietary bioactive agents on colonic stem cell microRNA and mRNA expression. Data Brief 6:398-404
Hou, Tim Y; Davidson, Laurie A; Kim, Eunjoo et al. (2016) Nutrient-Gene Interaction in Colon Cancer, from the Membrane to Cellular Physiology. Annu Rev Nutr 36:543-70
Shah, Manasvi S; Kim, Eunjoo; Davidson, Laurie A et al. (2016) Comparative effects of diet and carcinogen on microRNA expression in the stem cell niche of the mouse colonic crypt. Biochim Biophys Acta 1862:121-34
Kim, Eunjoo; Davidson, Laurie A; Zoh, Roger S et al. (2016) Homeostatic responses of colonic LGR5+ stem cells following acute in vivo exposure to a genotoxic carcinogen. Carcinogenesis 37:206-14
Kim, Eunjoo; Davidson, Laurie A; Zoh, Roger S et al. (2016) Rapidly cycling Lgr5(+) stem cells are exquisitely sensitive to extrinsic dietary factors that modulate colon cancer risk. Cell Death Dis 7:e2460
Fan, Yang-Yi; Davidson, Laurie A; Chapkin, Robert S (2016) Murine Colonic Organoid Culture System and Downstream Assay Applications. Methods Mol Biol :
DeClercq, V; McMurray, D N; Chapkin, R S (2015) Obesity promotes colonic stem cell expansion during cancer initiation. Cancer Lett 369:336-43
Turk, Harmony F; Chapkin, Robert S (2015) Analysis of epidermal growth factor receptor dimerization by BS³ cross-linking. Methods Mol Biol 1233:25-34
Davidson, Laurie A; Callaway, Evelyn S; Kim, Eunjoo et al. (2015) Targeted Deletion of p53 in Lgr5-Expressing Intestinal Stem Cells Promotes Colon Tumorigenesis in a Preclinical Model of Colitis-Associated Cancer. Cancer Res 75:5392-7

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