Establishing roles for the type I interferon/double-stranded RNA response and Helicobacter pylori-specific transcripts in the progression to metaplasia in gastric epithelium

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PROJECT SUMMARY From parent award (K08DK122116-01) This application proposes a five year research career development program that focuses on the host and microbial factors that contribute to gastric metaplasia. The comprehensive approach of exploring the host and bacterial determinants of the metaplastic milieu will enhance our overall understanding of the dynamic interplay that establishes a gastric pre-neoplastic state. The candidate is currently an Assistant Professor of Medicine in the Division of Gastroenterology at the Washington University in St. Louis School of Medicine. This proposal is an extension of the candidate's previous work demonstrating the ability of Helicobacter pylori to exploit metaplastic changes in the host to expand its niche. The proposed experiments will incorporate gastric epithelial biology expertise from the candidate's mentor, Dr. Jason Mills, as well as Helicobacter pylori mutagenesis experience from the candidate's co-mentor, Dr. Rick Peek. Together, the candidate will be uniquely positioned to acquire new skill sets and expand on previously developed techniques that will allow him to carve out a unique niche within the field and transition to an independent physician scientist. Gastric cancer remains one of the leading causes of cancer-related deaths worldwide. Chronic infection with the stomach-adapted bacterium, Helicobacter pylori, represents the most significant risk factor for the progression to gastric cancer. In the setting of chronic inflammation, loss of acid-secreting parietal cells from the gastric corpus stimulates a reorganization of the corpus gland, characterized by an increased proliferation of gastric progenitor cells and a reprogramming of post-mitotic chief cells at the gland base into a population of proliferative metaplastic cells, a process that we have termed paligenosis. We recently demonstrated that Helicobacter pylori exploits these metaplastic glandular changes to expand its colonization of the gastric corpus, which is known to confer added oncogenic risk. This proposal describes a dual approach toward identifying and characterizing the host and microbial factors that contribute to the establishment of the metaplastic milieu. From the host perspective, a microarray analysis identified multiple components of the type I IFN/dsRNA signaling pathway that were upregulated in two distinct models of gastric metaplasia. We will dissect the role of this highly conserved antiviral pathway in the previously uncharacterized context of gastric metaplasia. Similarly, we aim to demonstrate that the accumulation of endogenous dsRNA during paligenosis serves as an intra-cellular signal for the development of gastric metaplasia. From the microbial perspective, a newly developed bacterial RNAseq analysis found Helicobacter pylori-specific transcripts that were differentially expressed in the gastric corpus. Using an established pipeline of in vivo and ex vivo experiments, we will validate and characterize these genes in the context of Helicobacter pylori's colonization of the gastric corpus and establishment of gastric metaplasia. Taken together, this proposal seeks to identify microbial prognostic indicators and areas of potential therapeutic intervention in the development of gastric metaplasia.