Coordinated regulation of signaling events for insulin biosynthesis and secretion

总结： 该项目的目标是破译控制细胞凋亡的分子信号机制。 胰岛素的生物合成和分泌，当前的重点是解剖功能 Shp 2酪氨酸磷酸酶在协调细胞中的信号级联中的作用。虽然 胰腺细胞衰竭是所有形式糖尿病的关键组成部分， 细胞功能障碍的基础知之甚少。这主要是因为， 对于介导葡萄糖和胰岛素信号的细胞质成分知之甚少， - 细胞。Shp 2是具有两个SH 2结构域的细胞质酪氨酸磷酸酶， 参与调节和协调信号通路。特别是，Shp 2具有 在体外显示促进胰岛素刺激的Erk激活，尽管 Shp 2功能在胰岛素信号传导中的生理学意义尚不清楚。近几 研究中，我们成功地创建了一个条件性Shp 2敲除等位基因，Shp 2flox， 这使我们能够研究特定细胞类型中的特定Shp 2功能， 体内组织。我们已经产生了突变小鼠，在成熟的细胞中或在成熟的细胞中缺失Shp 2。 Pdx 1+胰腺前体细胞，并将表征这些新的小鼠模型， 测试工作假设，即Shp 2的行为，以协调和控制的强度， 几个信号通路在协调胰岛素的生物合成和分泌的细胞。 作为体内基因靶向方法的补充，我们还将使用siRNA- 介导的基因敲除技术，以破译分子信号传导机制 在牢房里。我们的具体目标是：1）确定Shp 2在细胞中的生理作用， 功能和葡萄糖稳态; 2）剖析Shp 2的分子机制 在细胞中的作用;和3）研究Shp 2在胰腺发育中的功能， - 细胞再生成功完成拟议的实验将填补一个空白， 在我们对细胞中胞质信号事件的协调调节的知识中， 甚至可能导致一种新的模式，调节葡萄糖中的细胞功能 内稳态以及2型糖尿病的发病机制。

Summary: The goal of this project is to decipher molecular signaling mechanisms for control of insulin biosynthesis and secretion, and the immediate focus is on dissecting the function of Shp2 tyrosine phosphatase in orchestrating signaling cascades in ¿ cells. Although pancreatic ¿ cell failure is a critical component in all forms of diabetes, the molecular basis underlying ¿ cell dysfunction is poorly understood. This is mainly because that little is known for the cytoplasmic components mediating glucose and insulin signals in ¿-cells. Shp2 is a cytoplasmic tyrosine phosphatase with two SH2 domains that is implicated in regulation and coordination of signaling pathways. In particular, Shp2 has been shown to promote insulin-stimulated Erk activation in vitro, although the physiological significance of Shp2 function in insulin signaling is unclear. In recent studies, we have successfully created a conditional Shp2 knockout allele, Shp2flox, in mice, which allows us to investigate specific Shp2 functions in a specific cell type or tissue in vivo. We have generated mutant mice with Shp2 deleted in mature ¿-cells or in Pdx1+ pancreatic precursor cells, and will characterize these novel mouse models to test the working hypothesis that Shp2 acts to coordinate and control the strength of several signaling pathways in orchestrating insulin biosynthesis and secretion in ¿-cells. In complement with the gene targeting approach in vivo, we will also use siRNA- mediated gene knockdown technique to decipher the molecular signaling mechanisms in ¿ cells. Our specific aims are: 1) to determine the physiological role of Shp2 in ¿-cell function and glucose homeostasis; 2) to dissect the molecular mechanism for Shp2 action in ¿-cells; and 3) to investigate the Shp2 function in pancreatic development and ¿-cell regeneration. Successful completion of the proposed experiments will fill in a gap in our knowledge for coordinated regulation of cytoplasmic signaling events in ¿-cells, and may even lead to a new paradigm on regulation of ¿-cell functions in glucose homeostasis and also in pathogenesis of type 2 diabetes.