Regulation of exocrine pancreas formation

胰腺是由内分泌、外分泌和导管上皮组成的复合腺。 在新陈代谢功能和消化活动的调节中起核心作用的隔室。 与这些胰腺间隔相关的功能障碍会导致糖尿病、胰腺炎和 分别是胰腺癌。尽管它们的功能不同，但所有的胰腺细胞类型都出现了 来自前肠内胚层的共同祖先群体。近年来，重要的是 我们对启动形成的环境信号的理解已经取得了进展 腹侧和背侧胰腺原基的分化。此外，Pdx1和Ptf1a具有 被确定为两个关键的监管因素，它们合作决定了 位于这些原基内的胰腺多能祖细胞。最近，FOXA1和Foxa2 被证明对胰腺原基的生长和分化是必不可少的 Pdx1的监管。除了这些因素外，人们对启动的分子调控知之甚少。 来自前肠内胚层的胰腺程序。此外，虽然有大量的 对胰岛规范、分化和发育至关重要的转录因子 外分泌的特性，但对外分泌的规范和发展知之甚少 胰腺。在这里提出的研究中，我们将调查两个GATA因子家族的作用 成员，GATA4和GATA6，在胰腺原基规范的调节和在 胰腺外分泌的发育和分化。我们的初步数据使用有条件的 GATA4和GATA6的敲除等位基因表明它们在这些基因中具有部分冗余的功能 监管流程。此外，我们认为GATA蛋白可能与FoxA协同作用 参与Pdx1和Gata4调节的蛋白质可能与Ptf1a协同调节外分泌- 特定的基因转录。我们打算在早期探索GATA4和GATA6各自的作用 胰腺形成和外分泌分化在以下特定目标中：在特定目标1中，我们将 用条件基因表征GATA介导的胰腺原基形成调控 去除Sox9+和Pdx1+胰腺原基中的GATA基因 血统追踪。在特定的目标2中，我们将研究GATA因子在外分泌中的各自作用 细胞发育。在特定的目标3中，我们将研究Gata4在胰腺中的分子作用- 通过研究Gata4和Ptf1a或Ptf1a之间的遗传和物理相互作用来实现特定基因的表达 Gata4和Foxa2及其各自在胰腺基因调控中的协同作用 表达和发展。我们还将使用全球芯片序列和RNA序列分析来确定 胰腺中受GATA4和/或GATA6调控的一组基因。

The pancreas is a compound gland comprised of endocrine, exocrine and ductal epithelial compartments that play central roles in the regulation of metabolic functions and digestive activities. Dysfunctions associated with these compartments of the pancreas lead to diabetes, pancreatitis and pancreatic cancer, respectively. Despite their diverse functions, all of the pancreatic cell-types arise from a common progenitor population derived from the foregut endoderm. In recent years, significant advances have been made in our understanding of the environmental signals that initiate the formation and differentiation of the ventral and dorsal pancreatic primordia. Furthermore, Pdx1 and Ptf1a have been identified as two key regulatory factors that cooperate to determine the fate specification of the pancreatic multipotent progenitor cells within these primordia. More recently, Foxa1 and Foxa2 have been shown to be essential for the outgrowth and differentiation of the pancreatic primoridia and the regulation of Pdx1. Beyond these factors, little is known about the molecular regulation of the initiation of the pancreatic program from the foregut endoderm. In addition, although a large number of transcription factors that are essential for pancreatic islet specification, differentiation and development have been characterized, little is known about the specification and development of the exocrine pancreas. In the studies proposed here, we will investigate the roles of two Gata factor family members, Gata4 and Gata6, in the regulation of pancreatic primordia specification and in the development and differentiation of the exocrine pancreas. Our preliminary data using conditional knockout alleles of Gata4 and Gata6 suggest they have partially redundant functions in these regulatory processes. Furthermore, we propose that the Gata proteins may cooperate with the FoxA proteins in the regulation of Pdx1, and Gata4 may cooperate with Ptf1a in the regulation of exocrine- specific gene transcription. We intend to explore the respective roles of Gata4 and Gata6 in early pancreas formation and exocrine differentiation in the following specific aims: In Specific aim 1 we will characterize Gata-mediated regulation of pancreatic primordia formation using conditional gene ablation of the Gata genes in the Sox9+ and Pdx1+ pancreatic primordia, combined with genetic lineage tracing. In Specific aim 2 we will investigate the respective roles of the Gata factors in exocrine cell development. In Specific aim 3 we will investigate the molecular role of Gata4 in pancreas- specific gene expression by exploring genetic and physical interactions between Gata4 and Ptf1a or Gata4 and Foxa2 and determining their respective cooperative activities in regulating pancreas gene expression and development. We will also use global ChIP-Seq and RNA-Seq analysis to identify the set of genes regulated by Gata4 and/or Gata6 in the pancreas.