(taken from application) Gastrin is a peptide hormone important in acid regulation and in the growth of the parietal and enterochromaffin-like cells of the oxyntic mucosa of the adult stomach. The role of gastrin in the development of the gastrointestinal tract and as a growth factor for the pancreas and colon is less clear. Recent studies have shown an in vitro trophic effect of less-processed forms of gastrin on pancreatic, colonic, and fibroblast cell lines, even in the absence of the CC-B/gastrin receptor, the only known gastrin receptor. This suggests that gastrin may have growth factor properties in tissues which lack the CC-B/gastrin receptor, such as the colon. We will use the techniques of targeted gene disruption and the transgenic approach of gene overexpression to better study the in vivo role of gastrin on the growth and development of the gastrointestinal tract. We have already created gastrin deficient mice, as well as mice which overexpress progastrin and mice which overexpress glycine-extended progastrin. We will analyze the gastrin deficient mice for abnormalities in development by histology and immunohistochemistry. Defects in acid regulation will be assessed through feeding studies. Effects on colonic proliferation will be assessed by BrdU labeling in gastrin-deficient, and gastrin over-expressing mice. Finally, the role of gastrin as a growth factor for colon cancer will be studied using the methylazoxymethanol model of colon cancer in the gastrin deficient and gastrin overexpressing mice.
