GI Mucosal Barrier in Health and Surgical Disease

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DESCRIPTION (provided by applicant): The overall aim of the proposed work is to understand how Helicobacter pylori (HP) infection causes mucosal damage in the stomach, with special emphasis on the fundic region of the stomach. The investigators plan to study how HP infection impairs tight junction integrity and wound repair after injury (restitution) to result in increased mucosal permeability. HP-induced mucosal damage of the stomach is important because it is a major initiating factor in the pathogenesis of HP disease, including inflammation, atrophy of fundic epithelial cells including parietal and chief cells, metaplasia, and progression to gastric cancer. Because HP infection has far-reaching implications in terms of benign and malignant disease, mechanisms that underlie the initiation of mucosal damage, repair after damage, and protection against damage are important and timely. Three hypotheses will be tested. 1) HP infection increases mucosal permeability because either HP or inflammatory cells decrease tight junction integrity. This hypothesis will be tested by investigating how HP sonicates or cytokines secreted during a type 1 T-helper (Th1) response affect the phosphorylation and membrane association of proteins associated with the tight junction. 2) HP infection increases mucosal permeability because ammonia, a cytotoxin produced during HP infection, inhibits restitution. This hypothesis will be tested by investigating the effects of ammonia on activity of the H+/lactate transporter, MCT1, and on basolateral K+-channel activity. 3) L-glutamine (Gln) supplementation decreases mucosal permeability by inhibiting the Th1 response and cytokine-induced decreases in tight junction integrity that occur during HP infection. This hypothesis will be tested by determining whether L-Gln supplementation inhibits the Th1 cytokine response to preserve tight junction integrity in a mouse model of disease. The proposed investigations follow a logical sequence from previous studies in this laboratory, which have provided a structural framework for our knowledge of mucosal injury, protection against injury, and rapid epithelial repair (restitution) as they relate to maintenance of the gastric mucosal barrier in health and surgical disease.