TRANSCRIP FACTORS IN THE FORMATION OF PANCREATIC ISLETS

糖尿病是一种复杂的疾病，影响高达5%的人类 人口其主要临床症状是异常高水平的 血糖控制葡萄糖稳态的调节激素 是从胰岛细胞中提取的 这项拨款提案的长期目标是了解 胰岛细胞碱性螺旋-环-螺旋转录因子 发展在过去的几年里，取得了重大进展， 识别对胰岛重要的基因（尤其是转录因子） 发展结果表明，Pdx 1、Pax 4、Pax 6、Is 11和BETA 2/neuroD在大鼠脑内表达， 是正常胰岛生长所必需的重要转录因子 发展β 2是一种bHLH转录因子，在我们的研究中分离出来。 实验室和被证明是重要的胰岛素基因调控。 该基因的突变破坏了正常的胰岛形态发生， 两种类型的肠内分泌细胞的形成：分泌素和 胆囊收缩素生成细胞。这些动物会患上严重的糖尿病， 出生后3-5天内死亡。这些结果表明， BETA2基因在肠内分泌细胞的细胞命运决定中的作用以及在 胰岛发育另一个重要的bHLH因子，神经原蛋白3，已经被 最近分离并显示以重叠方式表达的是 胰岛中的BETA 2。我们的初步数据还显示 它调节BETA 2启动子的活性，因此很可能 神经生成素3位于BETA2基因的上游， 发展在这个建议中，我们提出实验来确定 调控BETA2基因表达的上游信号， 回答有关神经生成素3在胰腺中作用的问题 发展这项研究的结果，加上我们已经知道的， 应该可以帮助我们定义各种基本螺旋环之间的相互作用， 螺旋和其它转录因子在胰岛发育中的作用。

Diabetes mellitus is a complex disease which affects up to 5% of the human population. Its primary clinical symptom is abnormally high levels of plasma glucose. The regulatory hormones that control glucose homeostasis are derived from the pancreatic islet cells. The long term goal of this grant proposal is to understand the role of basic helix-loop-helix transcription factors (bHLH) in islet cell development. In the last few years major progress has been achieved toward identifying genes (especially transcription factors) important for islet development. It was shown that Pdx1, Pax4, Pax6, Is11 and BETA2/neuroD were important transcription factors necessary for the proper islet development. Beta2 is a bHLH transcription factor that was isolated in our laboratory and was shown to be important for the insulin gene regulation. Mutation of this gene disrupts proper islet morphogenesis and eliminates the formation of two types of enteroendocrine cells: secretin and cholecystokinin producing cells. The animals develop severe diabetes and die within 3-5 days after birth. These results establish the importance of BETA2 gene in cell fate determination of enteroendocrine cells and in the islet development. Another important bHLH factor, neurogenin 3, has been isolated recently and shown to be expressed in an overlapping manner is that of BETA2 in pancreatic islet. Our preliminary data also indicated that it regulates the activity of the BETA2 promoter, thus it is likely that neurogenin 3 is upstream of the BETA2 gene in controlling the islet development. In this proposal we propose experiments to determine the upstream signals that regulate the expression of the BETA2 gene and to answer questions regarding the role neurogenin 3 plays in pancreas development. Results from this study, together with what we already know, should help us in defining the interplay between various basic helix-loop- helix and other transcription factors in pancreatic islet development.