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.
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.
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