Mouse Models of Gastric Cancer

小鼠胃癌模型

• 批准号: 6741827
• 负责人: Timothy Cragin Wang
• 金额: $ 11.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6741827
• 关键词: Helicobacter; bacterial disease; carcinogenesis; chemoprevention; cholecystokinin; disease /disorder model; enzyme activity; gastrins; gene mutation; gene targeting; genetically modified animals; hormone receptor; laboratory mouse; model design /development; neoplasm /cancer genetics; p53 gene /protein; prostaglandin endoperoxide synthase; stomach neoplasms; vascular endothelial growth factors

DESCRIPTION: (Adapted from the investigator's abstract) Helicobacter pylori infection has been strongly linked to both hypergastrinemia and gastric cancer, but the role of elevated serum gastrin levels in progression to malignancy has not been well studied. Previous investigations have suggested that parietal cell loss or gastric atrophy represents a key preneoplastic precursor. Our group has developed a hypergastrinemic transgenic (insulin-gastrin or INS-GAS) mouse model that shows progression over time to gastric atrophy, intestinal metaplasia, dysplasia and gastric cancer. Further analyses of our INS-GAS mouse model, as well as studies in gastrin deficient (GAS-KO) mice, suggest that chronic elevations of amidated gas trin (G- 17) can lead to parietal cell decline, which can be prevented by infusions of incompletely processed glycine-extended gastrin (G-gly). Gastrin may also promote the development of cancer through induction of cyclooxygenase-2 (COX-2), resulting in increased proliferation and upregulation of VEGF. Helicobacterfelis infection of INS-GAS mice leads to a marked acceleration of gastric cancer and early mortality, suggesting a strong synergistic interaction between hypergastrinemia and Helicobacter infection. We propose to explore further the role of gastrin in gastric carcinogenesis. (1) A possible interaction between hypergastrinemia and p53 mutations will be investigated. Alterations in the p53 gene will be investigated in neoplastic lesions, and INS-GAS mice will be crossed with p53 null mice and the response to Helicobacter infection tested. (2). Possible downstream targets (COX2 and VEGF) in gastrin/Helicobacter-dependent gastric cancer will be studied. Selective COX-2 antagonists will be administered to Helicobacter-infected INS-GAS mice, and INS-GAS mice will be crossed to VEGF-GFP transgenic mice to assess VEGF gene expression during cancer progression. (3). The importance of the parietal cell CCK-B/gastrin receptor and Gq signaling pathways will be determined. Highly specific CCK-B receptor antagonists will be administered, and a constitutively active Gq-coupled CCK-B receptor targeted to the parietal cell in transgenic mice. (4). The possible protective effective of glycine-extended gastrin, (G-gly) in the prevention of atrophy/cancer will be studied. Double transgenic mice (INS-GAS x G-gly) or INS-GAS mice receiving infusions of 0-gly will be infected with Helicobacter and progression to atrophy and cancer analyzed. Overall, these studies will explore the mechanisms by which gastrin may influence the parietal cell and susceptibility to gastric neoplasia.

描述：（改编自调查员的摘要）幽门螺杆菌 感染与高胃血症和胃癌密切相关， 但是，血清胃蛋白水平升高在恶性肿瘤中的作用具有 没有得到很好的研究。先前的调查表明，顶 细胞丢失或胃萎缩代表关键的肿瘤前体。我们的 小组已经开发了高胃血症转基因（胰岛素 - 加斯特林或INS-GAS） 小鼠模型显示了随着时间的流逝发展到胃萎缩，肠道的进展 化生，发育不良和胃癌。进一步分析我们的ins-Gas鼠标 模型以及对胃蛋白缺乏（GAS-KO）小鼠的研究表明 胺化气trin（g-17）的慢性升高会导致顶细胞 衰落，可以通过未完全处理的输注来阻止这种情况 甘氨酸延伸的胃癌（G-Gly）。胃癌也可能促进 通过诱导环氧合酶2（COX-2）诱导癌症，导致增加 VEGF的增殖和上调。 Helicobacterfelis感染Ins-Gas 小鼠导致胃癌和早期死亡的显着加速， 提示高胃血症和 螺旋杆菌感染。我们建议进一步探索胃蛋白的作用 胃癌发生。 （1）高胃血症和 将研究p53突变。 p53基因的改变将在肿瘤病变中进行研究，并将 INS-GAS小鼠将与P53无效小鼠交叉，并对 测试了旋律感染。 （2）。可能的下游目标（COX2和VEGF） 将研究在胃蛋白/螺旋杆菌依赖性胃癌中。选择性 COX-2拮抗剂将被施用到感染的Helicobacter Ins-Gas小鼠中， INS-GAS小鼠将被交叉至VEGF-GFP转基因小鼠，以评估VEGF 癌症进展过程中的基因表达。 （3）。顶叶的重要性 将确定细胞CCK-B/胃药受体和GQ信号通路。 将施用高度特异的CCK-B受体拮抗剂，并 靶向顶点细胞的组成型活性GQ耦合的CCK-B受体 在转基因小鼠中。 （4）。甘氨酸延伸的可能有效的保护性 将研究（G-Gly）预防萎缩/癌症的胃蛋白。双倍的 转基因小鼠（INS-GAS X G-GLY）或INS-GAS小鼠接受0-GLY输注 将被螺旋杆菌感染并发展为萎缩和癌症 分析。总体而言，这些研究将探讨胃蛋白的机制 可能影响顶叶细胞和对胃肿瘤的敏感性。