The overarching goal of this award is to provide comprehensive training to prepare the principal investigator for an independently-funded research career, focused on Complimentary and Alternative Medicine (CAM) natural products and their effect on clinical outcomes of gastroenterological diseases. I am a Research Instructor with extensive experience in the immunopathogenesis of H. pylori. My near-term goal is to gain additional expertise in analytical biochemistry, an essential tool for performing research with natural products. This award will allow me to meet this goal with formal graduate-level coursework;workshops in separation, analysis, and informatics;and protected time for five years of mentored research. My mentor is Keith T. Wilson, MD, Professor of Medicine, Cancer Biology, and Pathology, Microbiology, and Immunology, who has a well- established track record of high impact mucosal immunology research related to H. pylori and inflammatory bowel disease. Dr. Wilson has successfully mentored graduate students, post-doctoral fellows, and physician- scientists. The strong mentorship, additional training, and environment detailed in this application will position me to reach my ultimate objective of becoming an independent investigator in the field of CAM natural products. This application will facilitate understanding f the molecular mechanisms underlying the action of curcumin in protecting the host from H. pylori infection and associated pathology. H. pylori is a Gram-negative bacterium that causes chronic gastritis, peptic ulcers, and gastric cancer. Gastric adenocarcinoma is the second leading cause of cancer-related death worldwide and H. pylori infection is its strongest known risk factor. However, in some disparate parts of the world research has found very low rates of gastric cancer despite high H. pylori prevalence;these phenomena have been termed the African, Colombian, and Indian enigmas. The African enigma has been attributed to parasitic co-infection in humans and recently our laboratory has demonstrated that the geographical origin of the bacteria may also be a basis for the Colombian enigma. Diet has been postulated as a possible explanation for the Indian enigma. Curcumin, a secondary metabolite of the plant turmeric, is a common food ingredient in India and its consumption (40-200 mg/day) has been linked to decreased incidence of colorectal cancer and Alzheimer's disease. H. pylori infection induces a strong macrophage (Mac)-associated innate immune response and an inappropriate Th1-biased adaptive immune response that contributes to disease pathogenesis. In this application we hypothesize that curcumin polarizes H. pylori activated Macs to a tolerant regulatory phenotype in a NF-kB1 (p105/p50)-dependent manner. Tolerance may lead to persistence of H. pylori, and thus long-term interaction of bacteria and epithelial cells that induces DNA damage and resulting mutations. However, in the application, we will test the hypothesis that curcumin specifically induces apoptosis in gastric epithelial cells with DNA damage and will thus have an overall effect of decreasing cancer risk.

Public Health Relevance

Helicobacter pylori is a Gram-negative bacterium causing chronic gastritis, peptic ulcers, and gastric cancer. Antibiotic treatment can be costly and often fails to eradicate the infection. In the proposed application we seek to define new strategies for amelioration and prevention of Helicobacter pylori-induced diseases with curcumin.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AT007324-02
Application #
8517590
Study Section
Special Emphasis Panel (ZAT1-PK (21))
Program Officer
Duffy, Linda C
Project Start
2012-08-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$122,203
Indirect Cost
$9,052
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Chaturvedi, R; de Sablet, T; Asim, M et al. (2015) Increased Helicobacter pylori-associated gastric cancer risk in the Andean region of Colombia is mediated by spermine oxidase. Oncogene 34:3429-40
Wroblewski, Lydia E; Piazuelo, M Blanca; Chaturvedi, Rupesh et al. (2015) Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells. Gut 64:720-30
Carbo, Adria; Olivares-Villagómez, Danyvid; Hontecillas, Raquel et al. (2014) Systems modeling of the role of interleukin-21 in the maintenance of effector CD4+ T cell responses during chronic Helicobacter pylori infection. MBio 5:e01243-14
Van Kaer, Luc; Algood, Holly M Scott; Singh, Kshipra et al. (2014) CD8??? innate-type lymphocytes in the intestinal epithelium mediate mucosal immunity. Immunity 41:451-64
Chaturvedi, Rupesh; Asim, Mohammad; Piazuelo, M Blanca et al. (2014) Activation of EGFR and ERBB2 by Helicobacter pylori results in survival of gastric epithelial cells with DNA damage. Gastroenterology 146:1739-51.e14
Sierra, Johanna C; Hobbs, Stuart; Chaturvedi, Rupesh et al. (2013) Induction of COX-2 expression by Helicobacter pylori is mediated by activation of epidermal growth factor receptor in gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol 305:G196-203