GENETIC MOUSE MODELS TO STUDY GASTRIC PHYSIOLOGY AND DISEASES

Genetic mouse models include introduction of exogenous gene into the mouse genome (the so-called transgenic mouse) and targeted disruption of endogenous gene (knockout mouse). Up to date, ~10% of the known mouse genes have been knocked out, 21 transgenic/ knockout mouse strains have been studied with respect to the gastric physiology and diseases by us during the past 10 years, and the hypothetic model of the mechanisms behind the regulation of acid secretion in normal state has been largely validated. In this project, we will continuously utilize the genetic mouse models to validate our hypothesis that the interaction and/or interplay between endocrine and neural pathways play a crucial role in the regulation of gastric acid secretion, whereas the perturb ation induced by multiple external factors (such as carcinogens, infection, and stress) will result in the development of gastric cancer and peptic ulcer. The project includes 3 parts. 1) Study of compensatory mechanisms in somatostatin receptor subtype 2 knockout and CCK 1 and 2 receptor double knockout mice. 2) Study of gastric cancer in our established mouse models of both wild-type and gastrin transgenic mice infected with H. pylori +/- snus diet. The animals will be subjected to bilateral or unilate ral vagotomy. Comparisons with respect to the cancer development will be made between these two mouse models, between these two types of vagotomy, and between innervation and denervation sides in the unilateral vagotomized mice. We also plan to treat the two mouse models with newly developed gastrin receptor antagonist YF476 at the stage of CIS to see if the tumour invasion can be prevented. 3) We will apply the recognized psychosocial stress model to wild-type, gastrin knockout and gastrin and CCK doubl e knockout mice that are infected with H. pylori The research group is able to complete this project within the timeframe. The data will be published in international peer-reviewed professional journals.