Arginine Availability and Metabolism in H. pylori-associated Gastric Inflammation and Disease Progression

Veterans Health Administration, Decatur PA

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Helicobacter pylori and its sequelae of peptic ulcer disease and gastric cancer remain substantial health concerns for our Veterans. H. pylori infects half of the world's population, causes peptic ulcers in 10% and gastric cancer in 1-3% of those infected, and it is the third leading cause of cancer death worldwide. American Servicemen/women are exposed to H. pylori in regions where infection rates are very high and strains associated with high cancer risk are prevalent. For disease progression, chronic inflammation and epithelial events are necessary. We have identified mechanisms underlying inflammation and carcinogenesis. This includes induction of futile, dysregulated, innate and adaptive immune responses leading to inflammation; and molecular signatures of carcinogenesis. Antibiotics do not uniformly eradicate the infection, and do not reduce cancer risk if preneoplastic lesions have developed, thus there is a great need to establish strategies for prevention of disease progression. Risk for cancer remains a major issue in Veterans particularly those that are Hispanic, whose numbers are increasing. We have implicated the biogenic polyamines (putrescine, spermidine, and spermine), derived from the rate-limiting enzyme ornithine decarboxylase (ODC), in gastric inflammation and carcinogenesis, and shown that DNA damage is due to induction of spermine oxidase (SMOX), which is downstream of ODC and generates H2O2. We have reported that H. pylori strains from Veterans induced SMOX expression and oxidative DNA damage in vitro and in tissues. Our goal is to find new strategies for intervention. Polyamine generation is downstream of the amino acid L-arginine (L-Arg). We have shown that cellular uptake of L-Arg is regulated by cationic amino acid transporter 2 (CAT2; solute carrier family 7, member 2, or SLC7A2), and is induced by H. pylori infection. We have key new evidence that SLC7A2 is a key player in gastric epithelial cells, and that it is upregulated in gastric cancer. We have recently implicated the cytoskeletal protein Talin-1 in the pathogenesis of infectious colitis, and now show that it may link L-Arg and H. pylori-induced immune dysregulation. Talin-1 is upregulated in macrophages with H. pylori infection, including in gastric cancer. We will further pursue targets for intervention in the L-Arg/polyamine pathway by investigating SMOX and oxidative stress derived from epithelial cells vs. macrophages, and by utilizing a novel inhibitor of SMOX. We hypothesize that arginine availability and metabolism, including polyamine synthesis and oxidation, are key events that lead to H. pylori-associated gastric inflammation, injury, DNA damage, and risk for carcinogenesis. Our specific aims are: 1) To determine the myeloid and epithelial components related to SLC7A2-mediated effects on gastric inflammation and damage. We will utilize H. pylori strains and tissues from Veterans and from subjects at high and low cancer risk, and study cell-specific responses: A) Induction and role of SLC7A2 in gastric epithelial cells, gastric organoids, and gastric tissues; B) Bone marrow chimeras using Slc7a2-/- mice. 2) To determine if Talin-1 is a key regulator of responses to H. pylori infection. We will assess Talin-1 expression and function in vitro and in vivo: A) Talin-1 expression and function in epithelial cells and macrophages, and effect of L-Arg availability; B) Role of Talin-1 n vivo, including studies in human tissues from Veterans, in mice with altered L-Arg availability and with myeloid-specific deletion of Tln1. 3) To determine effects of epithelial cells and immune cells in SMOX- mediated gastric inflammation and carcinogenesis. We will utilize mouse and gerbil models and assess: A) Effects of bone marrow chimeras using Smox-/- mice; B) Effect of a novel SMOX inhibitor on inflammation and carcinogenesis in mice and gerbils. These studies will have a major impact on our understanding of H. pylori immunopathogenesis and progression to gastric carcinogenesis, and will lead to new approaches for risk assessment and treatment.