Helicobacter pylori causes gastritis, peptic ulcer disease, gastric carcinoma, and gastric lymphoma, however, only a subset of infected individuals develops disease in the form of ulceration or adenocarcinoma. The mechanisms by which bacterial and/or host factors cause disease are being explored, but exact factors remain incompletely defined. Phagocytic leukocytes recruited to the gastric mucosa during infection become activated, generating reactive oxygen species (ROS) that alter gastric epithelial cell growth and induce apoptosis. In addition, H. pylori infection induces oxidative stress directly in gastric epithelial cells through the generation of ROS and the subsequent activation of a redox-dependent signaling pathway which controls the transcription of genes that regulate cell function, including growth, repair, and death processes. Of particular interest is ROS- induced activation of apurinic/apyrimidinic endonuclease (APE)-1, also known as redox factor (Ref)-1, that can activate transcription factors, including activator protein (AP)-1, NF-kB, and p53. APE-1/Ref-1 is potentially very important in chronic inflammatory conditions, including H. pylori infection, since this molecule may regulate whether damaged mucosa is repaired or vulnerable to the development of neoplasia. Based on progress to date, we propose that H. pylori infection stimulates redox-sensitive signaling through APE-1/Ref-1 that regulates gastric epithelial cell function and survival. This hypothesis will be examined in the following new specific aims:
Aim 1. Evaluate role of APE-1/Ref-1 in gastric epithelial injury during H. pylori infection.
Aim 2. Assess redox-sensitive transcriptional activation of gene expression by APE-1/Ref-1.
Aim 3. Define the role of APE-1/Ref-1 in negative regulation of gene expression. These studies will address the molecular mechanisms whereby APE-1/Ref-1 governs epithelial responses to oxidative stress. This knowledge will improve our understanding of the pathogenesis of epithelial cell damage associated with H. pylori infection and help identify strategies for the prevention and treatment of human gastric disease.

Public Health Relevance

Public Health Significance Over half the world is infected with Helicobacter pylori and it is thought that infection contributes to most cases of gastric cancer, the second most common cause of cancer death worldwide. Thus, understanding how infection may lead to cancer development is an important area for research. It is also apparent that individual human factors known as host factors may also be key in the development of gastric cancer. Some of the host factors being studied relate to inflammatory mediators but other factors are genes that regulate the response to various stresses to the body. One such stress that is important in the development of various cancers is something known as oxidative stress. Our laboratory has shown that H. pylori infection and oxidative stress can each lead to increased levels of a host protein that regulates many cell functions. This protein is vital for normal life and is known as apurinic/apyrimidinic endonuclease-1 (APE -1 for short) for its ability to repair damaged DNA in cells. Another property of this molecule also known as Redox factor -1 (Ref-1) is to regulate how the biochemical machinery within all mammalian cells functions. We are starting to explore how APE- 1/Ref-1 affects the cells that line the human stomach with the goal of understanding why only a subset of patients with H. pylori infection will get ulcers or cancer arising in these lining cells known as the epithelium. Our initial results show that the APE-1/Ref-1 molecule plays a role in determining whether these stomach lining cells proliferate or grow or whether they die. The balance in growth or death of cells is felt to be a key area in understanding how cancers and other gastric diseases develop. The proposed work will play an important role in role in establishing how APE-1/Ref-1 may modulate host responses to infection and consequently influence in whom different H. pylori-associated diseases arise and the mechanisms by which this may happen.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DIG-C (03))
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Hamilton, Frank A
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University of Virginia
Internal Medicine/Medicine
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