Friday, April 19, 2024
4/19/2024
Project Summary/Abstract Helicobacter pylori is a highly prevalent pathogen, with 50% of the world’s population infected. All H. pylori infections at minimum cause gastric inflammation. A fraction of those infected will eventually develop gastric or duodenal ulcer disease, atrophy, or gastric adenocarcinoma or MALT lymphoma. Gastric cancer is one of the leading causes of cancer death worldwide, and eradication of the infection leads to prevention or even regression of gastric cancer. Treatment is becoming more difficult because of widespread antibiotic resistance. It is not definitively known who will go on to develop advanced disease, although many different bacterial and host factors have been implicated. The focus of this research proposal is to study mechanisms related to novel host/bacterial connections that potentially lead to gastric injury. H. pylori is known to cause epithelial injury, and preliminary data suggest that the bacteria induce downregulation of the Na,K-ATPase, which is involved with critical transport functions via establishment of an inward sodium gradient and with cell adhsion. Decreased Na,K-ATPase activity in gastric epithelial cells leads to reduced barrier function and gastric injury. Downregulation of the transporter by H. pylori targets newly formed pumps and trafficking from the ER. The mechanism will be further investigated by studying post-translational modifications potentially induced by the bacteria, by looking at the physiologic consequences of decreased pump expression on gastric cells, and by further characterizing the mechanism of pump degradation. H. pylori bacterial factors also play an important role in induction of gastric injury. From the bacterial standpoint, the role of direct H. pylori adhesion in Na,K-ATPase downregulation will be delineated. Dependence on the virulance factor CagA and the CagPAI type 4 secretion system (T4SS) will be determined. The role of gastric injury via Na,K-ATPase downregulation in induction of signaling pathways from stomal cells will be studied in an enteroid-stromal co-culture model. A NanoString platform will be used to examine gene changes in bacteria and host simultaneously in order to expand the targets studied in barrier dysruption and ultimately initiation of oncogenesis. Coordinated signaling systems induced by bacteria and host that impact decrease in Na,K-ATPase will be delineated, specifically as related to the CagPAI T4SS; known pathways will be explored and novel pathways will be identified via innovative mass spectometry techniques. Completion of this work will help determine why and how H. pylori specifically targets the Na,K-ATPase, identify effector molecules aside from CagA that enter cells via CagPAI to affect Na,K-ATPase levels, and delineate how bacterial factors modified by host proteins induce signaling cascades, leading to the changes in transporter levels. The goal of this work is to gain new insight into the mechanism of gastric injury by H. pylori, which will lead to novel therapeutic protective and treatment options.
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