This is a competing revision application for R01 DK071590 in response to Notice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications in the Project Summary/Abstract Component of the American Recovery and Reinvestment Act of 2009 (ARRA), Public Law 111-5. Gastric cancer develops from preneoplastic metaplsias. Our present grant is focused on identifying and the mechanisms responsible for induction of metaplasia and characterizing possible markers of induced metaplasia in mouse models of acute and chronic parietal cell loss. The overall aim of these investigations is not only to understand the process of metaplastic conversion in mice but also to identify biomarkers of metaplasia that might have utility in screening human patients for risk of cancer. We have recently initiated a collaboration with colleagues at Seoul National University, the largest volume gastric cancer surgical hospital in the world. In collaboration with members of the Surgery and Pathology department, we have obtained a cohort of samples from normal gastric fundus and from fundus containing metaplasias in patients with well-differentiated adenocarcinomas. All of the frozen samples have been transferred successfully from Korea to the United States and we have performed laser capture microdissection of normal chief cells as well as spasmolytic polypeptide expressing metaplasia (SPEM) and intestinal metaplasia (IM), the latter two from the same patient samples. RNA isolation and microarray studies on 6 normal and 6 metaplastic samples have established both the quality of the samples and their utility in identifying characteristic markers. These results show that we are now ready expand our studies to direct analysis of metaplastic lineages from humans. Therefore, in this Supplemental Revision proposal we will seek to 1) complete microarray analysis on the complete cohorts of 12 normal and 12 cancer metaplasia samples. Second, we will examine microRNA expression profiles for microdissected lineages from the 12 normal and metaplastic samples. Third, we will utilize recently developed technology to assess protein profiles in 12 normal and metaplastic samples from paraffin blocks of the gastric resections. Finally, we will seek to validate key identified markers using tissue arrays of gastric cancer and metaplasia. We hope that these studies, inconjunction with the mouse studies already under way will identify novel biomarkers that my serve as indicators of gastric preneoplasia in humans.
Gastric cancer is the second highest cause of cancer related death worldwide. These studies address the characteristics of pre-cancerous metaplasias. Our long-term goal is to find biomarkers of metaplasia that could be used for screening of those at risk for cancer in large populations.
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