This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gastric cancer is one of the most common cancers in the world with a very high mortality rate. The incidence of the disease varies according to geographical areas and is dependent on several factors including gender, ethnicity, socioeconomic status, diet, and genetic factors, among others. Infection with Helicobacter pylori (H. pylori) is the only irrefutable factor associated with the disease. H. pylori infects nearly half of the human population and induces a process of active gastritis that leads to a cascade of inflammatory responses that include the presence of non-atrophic gastritis (NAG), multifocal atrophic gastritis (MAG), intestinal metaplasia, dysplasia, and cancer. Even though it is widely accepted that each one of these stages is phenotypically and functionally linked to the next more advanced stage, little is known about the genetic changes associated with the progression of these gastric lesions. In humans, the infection with H. pylori occurs very early in life and evolves differently in each individual, depending not only on the many factors listed previously, but also on the virulence of the bacteria. After the infection H. pylori reaches the mucus layer of the gastric epithelium and triggers a cascade of inflammatory responses that are associated with the tissue damage and the pathological findings on each gastric inflammatory stage. We consider that a genetic signature of each stage exists long before the appearance of the lesion and could be used as predictor of the aggressiveness of the lesions. Our previous findings suggest that the basal pattern of gene expression of individuals who progress to more advanced gastric lesions is different than the pattern of those who regressed or remained in the same pathological gastric lesion classification. The same is true for the pattern of genes expressed 72 months after the initial diagnosis. However, the differential patterns of gene expression observed in our study show only a one-time measure and do not show the evolution of the genetic patterns after H. pylori infection. We hypothesize that the progression of the gastric inflammatory stages is closely regulated by a time-dependent expression of cytokine genes and is dependent on the genetics of H. pylori. In order to test our hypothesis, we propose the following specific aims: 1. To establish a follow-up study of gastric inflammatory stages in H. pylori-infected mice; 2. To study the gene expression pattern in the gastric mucosa in H. pylori-infected mice in a time dependent manner using wild type and arginase mutant bacteria; 3. To determine the time-dependent effect of the arginase inhibition using nor-NOHA on the development of gastric lesions and gene expression in INS-GAS mice.
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