HB-EGF's Role in Atrophic Gastritis and Gastric Cancer

我们发现胃泌素对结肠的生长很重要，胃泌素缺乏会导致结肠增殖减少，而甘氨酸延长的胃泌素的过度表达会导致结肠增殖增加和结肠粘膜肥大。我们已经进一步证明，胃泌素似乎是介导肠息肉生长的β-连环蛋白/Tcf-4信号通路的下游靶标。胃泌素在胃的发育中也很重要。胃泌素缺乏导致壁细胞数量显著减少，可通过短期输注胃泌素来挽救。然而，随着长期输注，壁细胞萎缩发生。我们已经证明，过表达酰胺化胃泌素的转基因小鼠也有初始增生，随后壁细胞萎缩，小凹增生，并最终浸润性胃癌。当壁细胞萎缩发展时，肝素结合表皮样生长因子（HB-EGF）上调。我们已经表明，胃泌素可以通过PKC依赖性途径直接上调HB-EGF表达。从这些发现中，我们假设胃泌素可以直接影响胃干细胞向壁细胞分化，但随着时间的推移，它会导致壁细胞中HB-EGF的上调，这在负反馈回路中抑制向壁细胞分化，并促进向窝细胞分化。目的是检验这一假设：1。确定参与胃泌素调节HB-EGF启动子的顺式作用调节元件。2.通过建立壁细胞中过表达HB-EGF的转基因小鼠，确定胃壁细胞中HB-EGF表达对胃粘膜分化的作用。

We have found that gastrin is important in the growth of the colon, with gastrin deficiency resulting in decreased colonic proliferation, and over- expression of glycine-extended gastrin resulting in increased colonic proliferation and colonic mucosal hypertrophy. We have further demonstrated that gastrin appears to be a downstream target of the beta- catenin/Tcf-4 signaling pathway that mediates growth of intestinal polyps. Gastrin is also important in the development of the stomach. Gastrin deficiency results in a marked decreased in parietal cell number which can be rescued by short-term infusions of gastrin. With long term infusion however, parietal cell atrophy occurs. We have shown that transgenic mice that overexpress amidated gastrin also have initial hyperplasia, followed by parietal cell atrophy, foveolar hyperplasia, and eventually invasive gastric cancer. At the time when parietal cell atrophy develops, there is an up-regulation of heparin binding epidermal-like growth factor (HB-EGF). We have shown that gastrin can directly up- regulate HB-EGF expression through a PKC-dependent pathway. From these findings we hypothesize that gastrin can directly influence the gastric stem cell to differentiate towards the parietal cell partway, but with time it causes up-regulation of HB-EGF in parietal cells which in a negative feedback loop inhibits differentiation towards parietal cells and promotes differentiation into pit cells. The aims are to test this hypothesis: 1. Determine the cis-acting regulatory elements involved in gastrin's regulation of the HB-EGF promoter. 2. Determine the role of HB-EGF expression in gastric parietal cells on gastric mucosal differentiation by creating transgenic mice that over-expression HB-EGF in parietal cells.