DEVELOPMENT REGULATION OF GASTRIN GENE EXPRESSION

许多观察表明，胃泌素可能在调节中起作用。 胰腺发育。胃泌素在胰腺中瞬时表达 在早期胎儿发育中，与快速的时期相对应 胰岛细胞增殖。此外，胰腺胃泌素是 出生后选择性地抑制，当成熟的胰岛有 几乎没有进一步增殖或再生的能力。此外， 胃泌素最近被证明是一种自分泌生长因子，在 对一些胰岛细胞系进行体外培养。胃泌素启动子的活性 胰岛细胞依赖于一种类似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 消音器元件，与部分B-干扰素阴性相同 反式作用抑制子与抑制物结合的调控结构域 胃泌素基因转录。 体内竞争和DNA转基因研究将用于 证明在胰岛细胞中胃泌素启动子被激活 激活胰岛素的相同的胰岛细胞特异性转录因子 吉恩。胰岛素反式激活剂与胰岛素增强剂样物的结合 元素也将使用迁移率变化分析和甲基化来显示 干扰研究。含有胃泌素基因缺失的转基因 胰岛素增强子样结构域将被插入小鼠生殖系以 确定这是否会取消胎儿发育过程中胰腺的表达。 含胃泌素转基因基因的发育表达分析 删除B-干扰素样阴性元件应提供洞察力 论负性元素在调节出生后灭绝中的作用 胰腺胃泌素的表达。此外，转基因方法应该 定义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抑制子活性的影响也将 研究的目的是为了阐明原生生物-- 癌基因调控胰岛细胞分化。总体而言，这些研究是关于 胃泌素启动子的调节提供了一种分析 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。

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.