DEVELOPMENT REGULATION OF GASTRIN GENE EXPRESSION

胃泌素基因表达的发育调控

• 批准号: 3080843
• 负责人: Timothy Cragin Wang
• 金额: $ 7.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3080843
• 关键词: cell differentiation; gastrins; gene expression; genetic regulation; genetically modified animals; growth factor; human tissue; laboratory mouse; mammalian embryology; pancreatic islets; protooncogene; regeneration

A number of observations suggest that gastrin may play a role in regulation pancreatic development. Gastrin is transiently expressed in the pancreas during early fetal development corresponding to a time of rapid proliferation of islet cells. In addition, pancreatic gastrin is selectively repressed after birth when the mature, pancreatic islets have little capacity for further proliferation or regeneration. Furthermore, gastrin has recently been shown to act as an autocrine growth factor in vitro for some islet cell lines. The activity of the gastrin promoter in islet cells depends on a cis-acting islet cell specific DNA element similar to the insulin enhancer. Upstream of the insulin enhancer-like element is a silencer element, identical to part of the B-interferon negative regulatory domain, to which a trans-acting repressor binds to inhibition gastrin gene transcription. In vivo competition and DNA transfection studies will be used to demonstrate that the gastrin promoter is activated in islet cells by the same islet cell specific transcription factor which activates the insulin gene. Binding of the insulin transactivator to the insulin enhancer-like element will also be shown using mobility shift assays and methylation interference studies. Gastrin transgenes containing deletions of the insulin enhancer-like domain will be inserted into the germline of mice to determine if this abolishes pancreatic expression during fetal development. Analysis of the developmental expression of gastrin transgenes containing deletions of the B-interferon-like negative element should provide insights into the role of the negative element in mediating the postnatal extinction of pancreatic gastrin expression. Further, the transgenic approach should define the role of gastrin as an islet cell growth factor. The effect of oncogenes and growth factors on repressor activity will also be investigated in order to elucidate the mechanism through which proto- oncogenes regulate islet cell differentiation. Overall, these studies on the regulation of the gastrin promoter provide an approach to analyze the molecular events that regulate islet cell differentiation. Understanding these events may lead to ways of improving islet cell regeneration.

大量的观察表明，胃泌素可能在调节 胰腺发育 胃泌素在胰腺中瞬时表达 在早期胎儿发育期间，对应于快速发育的时间， 胰岛细胞增殖。 此外，胰腺胃泌素是 出生后选择性抑制，当成熟的胰岛 几乎没有进一步增殖或再生的能力。 此外，委员会认为， 胃泌素最近被证明是一种自分泌生长因子， 一些胰岛细胞系体外。 胃泌素启动子的活性在 胰岛细胞依赖于顺式作用的胰岛细胞特异性DNA元件， 胰岛素增强剂 胰岛素增强子样元件的上游是 一个沉默元件，与B-干扰素阴性的部分相同， 调节结构域，反式作用阻遏物与其结合以抑制 胃泌素基因转录。 体内竞争和DNA转染研究将用于 证明了胃泌素启动子在胰岛细胞中被 与激活胰岛素的胰岛细胞特异性转录因子 基因 胰岛素反式激活因子与胰岛素增强子样蛋白的结合 还将使用迁移率变动分析和甲基化来显示元件 干扰研究。 含有缺失的胃泌素转基因 胰岛素增强子样结构域将被插入小鼠的种系中， 确定这是否会在胎儿发育期间消除胰腺表达。 分析含有胃泌素的转基因的发育表达， B-干扰素样阴性元件的缺失应该提供一些见解， 探讨消极因素在调解产后灭绝中的作用 胰腺胃泌素的表达。 此外，转基因方法应 确定胃泌素作为胰岛细胞生长因子的作用。 的影响 癌基因和生长因子对阻遏物活性的影响也将被 为了阐明机制，研究了原- 癌基因调节胰岛细胞分化。 总的来说，这些研究 胃泌素启动子的调控提供了一种分析 调节胰岛细胞分化的分子事件。 理解 这些事件可能导致改善胰岛细胞再生的方法。