Helicobacter pylori infection causes a spectrum of gastric and duodenal pathology ranging from hyperproliferation and adenocarcinoma to severe tissue loss (ulcers). How the bacterium causes these paradoxical disease outcomes is not understood. Recent studies, including those from our laboratory, have shown that Fas apoptotic signaling plays a significant role in the pathogenesis of helicobacter-induced ulcer disease by initiating cell death programs. In addition, preliminary results strongly suggest a direct role for the Fas signaling pathway in modulating gastric mucosal cell proliferation (in addition to cell death) through induction of NF-kB. Nuclear factor activation has been suggested to positively regulate cell proliferation and promote survival, potentially allowing for mutations within abnormally proliferating cells leading to cancer formation. The experiments proposed in this application are aimed at determining the role and mechanism of Fas-induced aberrant gastric epithelial cell proliferation. We w i l l determine the mechanism of modulating Fas signaling towards a proliferative response and the specific roles of well established components of the Fas pathway in eliciting this response. To accomplish these goals, we will engineer gastric mucosal cell lines which transduce proliferative signaling by manipulating Fas Ag expression (constitutively or inducibly). This approach will be followed with gene-knockout strategies to isolate roles of candidate signaling molecules that mediate this response. The information gained in the controlled in vitro setting will be utilized for the development and characterization of in vitro models. Exploitation of newly engineered Fas Ag and Fas L deficient radiation chimera murine models as a more complex, rigorous and clinically relevant in vivo gastric mucosal environment will allow for the study of the importance of Fas proliferative signaling. Mechanisms which allow aberrant proliferation may contribute to carcinogenesis by inhibiting death and promoting cell division in cells which have accumulated genetic defects. Defining the regulation of these pathways will help define the complex relationship helicobacter shares with its host.
| Cai, Xun; Carlson, Jane; Stoicov, Calin et al. (2005) Helicobacter felis eradication restores normal architecture and inhibits gastric cancer progression in C57BL/6 mice. Gastroenterology 128:1937-52 |
