GUT PEPTIDE EXPRESSION IN THE ENDOCRINE PANCREAS

胰岛的内分泌细胞是从胰腺的 多能内胚层细胞向内分泌干细胞定向分化的芽 （nesidioblasts），其在终末分化成 成熟胰岛细胞 除了胰岛素和胰高血糖素， 细胞也瞬时表达在成年胰岛中不活跃的基因， 允许胎儿成胰岛细胞生长。 其中一种瞬时表达的 基因，胃泌素，是一些胰岛细胞系的自分泌生长因子。 胰岛细胞中胃泌素启动子的活性取决于胰岛细胞的分化程度。 类似于胰岛素增强子的特异性顺式作用DNA元件，DNA 转染研究的目的是显示胃泌素启动子在细胞内被激活， 胰岛细胞通过相同的细胞特异性转录因子（反式激活因子） 从而激活胰岛素基因 这将通过分析来证实。 利用DNA酶足迹法和甲基化研究体外DNA/蛋白质相互作用 干扰研究 含有缺失的胃泌素转基因 将胰岛素增强子结构域插入小鼠的生殖系中， 如果该缺失消除了胃泌素转基因的胰腺表达 在体内胎儿发育期间。 出生后胰岛细胞的终末分化导致两种细胞的丧失， 增殖能力和胃泌素基因表达的消失。 胰岛 细胞表达一种特异性转录抑制因子， 如果胃泌素启动子与胰岛素相邻， 增强子样阳性元件。 胃泌素cDNA的克隆 阻遏物将通过使用 胃泌素阴性元件作为DNA探针。 细胞信号 调节胃泌素阻遏物活性将被分析，以阐明潜在的 胰岛发育中胃泌素基因表达的调控机制。 分析含有促胃液素基因的缺失的胃泌素转基因的表达， 消极因素的目的是证明这个消极因素介导了 胰腺胃泌素基因表达的出生后消退， 导致出生后胰岛细胞生长停止。 这些研究 胃泌素启动子的调控旨在分析 在胰腺发育过程中调节胰岛生长。 了解这些 事件可能导致改善I型糖尿病患者胰岛细胞再生的方法， 糖尿病

The endocrine cells of the pancreatic islets develop from the pancreatic bud by commitment of pluripotent endodermal cells to endocrine stem cells (nesidioblasts) which proliferate before terminally differentiating into mature islet cells. In addition to insulin and glucagon, developing islet cells also transiently express genes not active in adult islets which permit growth of fetal nesidioblasts. One of these transiently expressed genes, gastrin, is an autocrine growth factor for some islet cell lines. Activity of the gastrin promoter in islet cells depends on an islet specific, cis-acting DNA element similar to the insulin enhancer, DNA transfection studies aim to show that the gastrin promoter is activated in islet cells by the same cell specific transcription factor (transactivator) which activates the insulin gene. This will be confirmed by analysing DNA/protein interactions in vitro using DNAase footprinting and methylation interference studies. Gastrin transgenes containing deletions of the insulin enhancer domain will be inserted into the germline of mice to see if this deletion abolishes pancreatic expression of the gastrin transgene during fetal development in vivo. Terminal differentiation of islet cells after birth results in both loss of proliferative capacity and extinction of gastrin gene expression. Islet cells express a specific transcriptional repressor which binds to a negative DNA element if the gastrin promoter adjacent to the insulin enhancer-like positive element. Cloning of the cDNA encoding the gastrin repressor will be initiated by screening an islet cDNA library using the gastrin negative element as a DNA probe. The cellular signals which regulate gastrin repressor activity will be analysed to elucidate potential mechanisms controlling gastrin gene expression in islet development. Analysing the expression of gastrin transgenes containing deletions of the negative element aim to demonstrate that this negative element mediates the postnatal extinction of pancreatic gastrin gene expression which in turn contributes the postnatal cessation of islet cell growth. These studies on the regulation of gastrin promoter aim to analyse the molecular events that regulate islet growth during pancreatic development. Understanding these events may lead to ways of improving islet cell regeneration in type I diabetes.