Spasmolytic polypeptide (SP/TFF2) is a member of the trefoil factor family specifically expressed in gastric mucous neck cells, a poorly understood stomach cell lineage that is believed to represent the cell of origin for gastric adenocarcinoma. Previous studies have shown that SP-expressing cells are upregulated at sites of gastric injury, and that SP may play a role in mucosal repair. Work from this laboratory employing a H. felis-mouse model has demonstrated a close relationship between SP-expressing cells and the proliferative precursor lineage, and the investigator has shown that Helicobacter-dependent amplification of the SP-expressing cells is paralleled by a decline in parietal cells, followed later by the development of gastric cancer. This group has generated an SP knockout mouse, and their hypothesis regarding a role for SP in gastric differentiation has been strengthened by preliminary findings in these mice of increased parietal cell number. Transient transfection studies in AGS gastric cancer cells of SP promoter-luciferase constructs have led to the identification of trefoil/growth factor response elements, as well as gastric cell-specific basal enhancers. Taken together, these observations have suggested the hypotheses that: the SP gene represents a marker for proliferating precursor (stem) cells in the gastric mucosa: that it is regulated by trefoil peptides and Helicobacter pylori through a specific cis-acting element: and that SP functions in mucosal regeneration and repair through modulation of gastric epithelial differentiation. They propose to study the function and regulation of SP through the following aims: (1) determine the molecular basis of gastric cell-specific SP gene expression. They will characterize the trefoil response element and cell specific elements in the human and murine SP promoters, and explore possible regulation of SP expression by H. pylori in vitro. (2) Characterize gastric cell-specific promoter elements through in vivo expression in transgenic mice. They will generate mSP-GFP and mSP-beta-Gal transgenic lines and analyze changes in transgene expression in response to Helicobacter in gastric cancer mouse models. (3) Investigate the function of SP utilizing the SP deficient mice generated through targeted gene disruption. Changes in gastric differentiation will be quantitated, and the SP deficient mice tested in both NSAID and H. felis models. Overall, these studies will utilize gastric cancer models to explore the function and regulation of SP, and may provide further insight into the biology of mucous neck cells.
