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

HB-EGF 在萎缩性胃炎和胃癌中的作用

• 批准号: 6401490
• 负责人: THEODORE J KOH
• 金额: $ 7.82万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-15 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6401490
• 关键词: achlorhydria; carcinogenesis; cell differentiation; epidermal growth factor; gastric mucosa; gastrins; gastritis; gel mobility shift assay; genetic regulatory element; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; stomach neoplasms; tissue /cell culture; transcription factor; transfection

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.

我们发现胃泌素在结肠的生长中很重要，胃泌素缺乏导致结肠增殖减少，而过表达甘氨酸延伸胃泌素导致结肠增殖增加和结肠粘膜肥大。我们进一步证明，胃泌素似乎是介导肠息肉生长的β - catenin/Tcf-4信号通路的下游靶点。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明显减少，可以通过短期内注射胃泌素来挽救。然而，长期输注会导致顶叶细胞萎缩。我们已经证明，过表达修饰胃泌素的转基因小鼠也会出现最初的增生，随后出现壁细胞萎缩、小窝增生，最终发生浸润性胃癌。在壁细胞萎缩发生时，肝素结合表皮样生长因子（HB-EGF）表达上调。我们已经证明胃泌素可以通过pkc依赖性途径直接上调HB-EGF的表达。根据这些发现，我们推测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，胃泌素会引起壁细胞HB-EGF的上调，从而在负反馈回路中抑制细胞向壁细胞分化，促进细胞向坑细胞分化。目的是验证这一假设：确定胃泌素对HB-EGF启动子的调控中涉及的顺式调控元件。2. 通过构建胃壁细胞过表达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。