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Title page for ETD etd-11122009-131410


Type of Document Dissertation
Author Nagy, Toni Ann
URN etd-11122009-131410
Title Delineation of signaling pathways induced by Helicobacter pylori that regulate host cell survival
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Christopher S. Williams Committee Member
Richard M. Peek, Jr. Committee Member
Timothy L. Cover Committee Member
Wael El-Rifai Committee Member
Keywords
  • Gastric cancer
  • Helicobacter pylori
  • PPARdelta
  • Epithelial turnover
  • Host-bacteria interactions
  • PI3K
Date of Defense 2009-11-02
Availability unrestricted
Abstract
Gastric adenocarcinoma is strongly associated with the presence of H. pylori. Microbial factors of H. pylori and host responses induced by the interactions of H. pylori with gastric epithelial cells play important roles in the development of disease. PI3K and β-catenin/p120 are multifunctional host proteins that coordinate carcinogenic epithelial responses when aberrantly activated, such as in malignant gastric lesions. We demonstrate that H. pylori infection results in upregulation of PI3K-AKT signaling, through stimulation of EGFR. Activation of this pathway reduces rates of epithelial cell death induced by H. pylori and promotes resistance to apoptosis. We also demonstrate that H. pylori infection induces additional host signaling pathways to potentiate a proliferative response in gastric epithelial cells. Specifically, PPARδ, a target of β-catenin transcriptional activation, contributes to increased rates of gastric epithelial cell proliferation in response to H. pylori infection. Based on these findings we hypothesize that an anti-apoptotic response in the presence of increased proliferation increases the risk of retaining mutagenized gastric epithelial cells in the presence of H. pylori induced gastritis. Taken together, these studies have identified effectors that directly mediate host responses related to carcinogenesis. Molecular delineation of such pathways activated by host-microbial interactions will improve our understanding of H. pylori-induced carcinogenesis, allowing for targeted therapies to high-risk individuals, as well as provide insight into other malignancies that arise within the context of pathogen-induced inflammation.
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