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。它的主要临床症状是异常高水平的 血糖。控制血糖动态平衡的调节激素 来源于胰岛细胞。 这项赠款提案的长期目标是了解 胰岛细胞中碱性螺旋-环-螺旋转录因子 发展。在过去的几年中，在以下方面取得了重大进展 识别对胰岛重要的基因(特别是转录因子) 发展。结果表明，Pdx1、Pax4、Pax6、Is11和Beta2/Neurod 是正常的胰岛所必需的重要转录因子 发展。Beta2是一种bhlh转录因子，它是在我们的 实验证明，它对胰岛素基因的调节很重要。 该基因的突变会破坏正常的胰岛形态发生，并消除 肠内分泌细胞的形成有两种：促胰液素和 产生缩胆囊素的细胞。这些动物会患上严重的糖尿病 出生后3-5天内死亡。这些结果证实了 β2基因在决定肠内分泌细胞命运中的作用 小岛的发展。另一种重要的bHLH因子，神经原蛋白3，一直是 最近分离的并显示以重叠方式表达的是 胰岛组织中β2的表达。我们的初步数据也表明 它调节Beta2启动子的活性，因此很可能 神经原3在控制胰岛的Beta2基因的上游 发展。在这项提案中，我们提出了实验来确定 调控Beta2基因表达的上游信号和 回答有关神经原蛋白3在胰腺中的作用的问题 发展。这项研究的结果，加上我们已经知道的， 应该有助于我们定义各种基本螺旋-环之间的相互作用- 螺旋等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.