Glucagon family peptide signaling regulates pancreatic endocrine expansion

描述（由申请人提供）：胰腺细胞长期以来被认为只是葡萄糖稳态的调节剂。然而，最近的几项研究表明，胰高血糖素信号在调节胰腺内分泌细胞新生中具有重要作用，无论是在胚胎中还是在成年胰腺的导管祖细胞中。无论是在体外还是体内，抑制胚胎胰腺中胰高血糖素信号传导都会抑制胰岛素阳性细胞的生长。 分化我们推测，胰高血糖素在胚胎胰腺是一个重要的调节分化的其他内分泌谱系，特别是胰岛素细胞。我们现在有初步证据表明，在子宫内用GLP-1激动剂exendin-4或转化的α细胞系进行胚胎治疗可以显著增强内分泌分化，这可能是通过不同的机制实现的，具体取决于治疗时胚胎的年龄。有趣的是，exendin-4治疗的小鼠患上了糖尿病和肥胖症，但其严重程度取决于胚胎治疗时的年龄。在这个提议中，我们希望研究胰高血糖素信号传导对其他类型胰岛细胞发育的影响，以及在正常胰腺发育过程中对胰腺祖细胞的影响。由于胰高血糖素信号传导似乎在招募新的内分泌细胞中发挥关键作用，在本提案中，我们将表征胰高血糖素和GLP 1受体的表达和定位，作为胰腺内分泌祖细胞的潜在标志物。接下来，我们将研究胰高血糖素肽家族如何调节发育过程中的细胞新生和增殖。该提案中的研究将提供新的见解，特别是通过细胞新生。这些发现可能会在多个层面影响糖尿病治疗。

DESCRIPTION (provided by applicant): Pancreatic ¿-cells have long been thought to simply be modulators of glucose homeostasis. However, several recent studies have shown an important role for glucagon signaling in regulating pancreatic endocrine cell neogenesis, both in the embryo and from ductal progenitor cells in the adult pancreas. Inhibition of glucagon signaling in the embryonic pancreas, either in vitro or in vivo, will inhibit insulin-positive cell differentiation. We hypothesize that glucagon in the embryonic pancreas is an important regulator of the differentiation of other endocrine lineages, particularly insulin cells. We now have preliminary evidence showing that in utero embryonic treatment with a GLP-1 agonist exendin-4 or a transformed alpha cell line could significantly enhance endocrine differentiation, possibly through different mechanisms depending on the age of the embryo when the treatment was applied. Interestingly, exendin-4 treated mice developed diabetes and obesity but the severity of that depends on the age when the embryonic treatment was given. In this proposal we wish to study the influence of glucagon signaling on the development of other islet cell types, and on pancreatic progenitor cells during normal pancreas development. Because of the key role that glucagon signaling seems to play in the recruitment of new endocrine cells, in this proposal we will characterize the expression and localization of the receptors for glucagon and GLP1 as a potential marker of pancreatic endocrine progenitor cells. Next, we will examine how the glucagon family of peptides regulates ¿-cell neogenesis and proliferation during development. The studies in this proposal will provide new insights especially through ¿- cell neogenesis. These findings may impact diabetes therapy at multiple levels.