Grant Abstract: Chemoprotective effects of natural products on colonic adult stem cells

Grant Number: 5R01CA168312-05
PI Name: Chapkin
Project Title: Chemoprotective effects of natural products on colonic adult stem cells

Abstract: The parent grant of our NCI sponsored study (CA168312) focuses on how the colonic stem cell population responds to environmental factors such as diet, chronic inflammation, and carcinogen exposure. The original specific aims include: Specific Aim 1: 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 chemoprotective diets. Specific Aim 2: To investigate the effects of disease progression on microRNAs and their post-transcriptionally regulated mRNA targets by evaluating both coding and non-coding transcripts in colonic stem cells following carcinogen/inflammation or saline (control) exposure. Specific Aim 3: Generate high-resolution genome-wide “chromatin-state” maps for (i) intestinal epithelial cell crypts, and (ii) colonic adenocarcinomas using chromatin immunoprecipitation in order to assess the effect of diet and carcinogenesis on epigenetic modifications at both the histone and DNA levels. Exciting data from our on-going experiments indicate that dietary fish oil and curcumin combination increase DNA damage-induced colonocyte apoptosis compared to control (corn oil) diet at the initiation stage of tumorigenesis. We conclude that the fish oil and curcumin combination maximally protects against carcinogenesis by enhancing the deletion of damaged stem cells at the initiation stage of tumorigenesis. This supplemental grant will support complementary experiments designed to test the effect of dietary fish oil and curcumin combination in a novel mouse model in which intestinal Lgr5+ stem cell resistance to DNA damage has been compromised due to the Lgr5+ targeted deletion of p53 signaling pathways. Importantly, adult stem cells in this model are primed to become cancer stem cells. To date, the effect of diet on cancer stem cells, deviant stem cells with cancer-causing misbehavior, has not been investigated. Findings using this model will provide a better understanding of the molecular mechanisms leading to sensitivity or resistance to n- 3 PUFA and curcumin in terms of colon tumor risk.

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