Molecular mechanisms regulating developmental maturation of pancreatic ductal cells

功能器官是通过将不同功能的细胞排列成三维结构，使器官有效地发挥其在体内的作用而产生的。在某些器官中，在胚胎发育过程中，器官的整体结构形成的同时，也产生了不同的特化细胞类型。尽管最近在阐明调节细胞分化或建立器官结构的分子机制方面取得了进展，但要完全理解这些过程中的每一个过程以及两者之间的联系仍然是一个遥远的目标。在诸如肺和胰腺这样的器官中，高度分支的树形结构有助于增加表面积和可压缩在小区域内的功能单元的数量。此外，分枝树作为一个管道，将细胞产物从器官的周围运送到目的地。因此，分支网络的功能和结构对整个器官的功能至关重要。胰腺的分支网络由导管细胞组成。迄今为止，我们对在发育过程中调节这种细胞群生长和分化的基因程序知之甚少。我们最近开发了遗传工具来特异性地分离或操纵胰腺导管细胞在其发育过程中。通过这些工具，我们确定了候选基因，这些基因对胚胎祖细胞分化为成熟的功能胰管具有潜在的重要作用。在本提案中，我们将利用这些候选基因来检查导管细胞在发育过程中何时被指定。此外，我们将使用我开发的强大的遗传工具来直接测试这些候选基因对导管细胞分化或成熟是否重要。综上所述，本研究项目将为细胞分化与器官结构和功能的建立之间的联系提供新的见解。

Functional organs are created by arranging cells with different function into 3D structures allowing the organ to efficiently carry out its role in the body. In some organs, the creation of distinct specialized cell types occurs at the same time that the overall structure of the organ is created during embryonic development. Despite recent progress in elucidating the molecular mechanisms regulating cellular differentiation or establishing organ structure, a complete understanding of each of these processes and the links between the two remains a distant goal. In organs, such as the lung and pancreas, a highly branched tree structure serves to increase the surface area and number of functional units that can be packed into a small area. In addition, the branched tree serves as a conduit to deliver cellular products from the periphery of the organ to their destination. Thus, the function and structure of the branched network is critical for the function of the overall organ. The branching network in the pancreas is comprised of ductal cells. To date, we know very little about the gene programs regulating the growth and differentiation of this cell population during development. We recently developed genetic tools to specifically isolate or manipulate pancreatic ductal cells during their development. With these tools, we identified candidate genes potentially important for the differentiation of embryonic progenitor cells into mature, functioning pancreatic ducts. In this proposal, we will utilize these candidate genes to examine when ductal cells are specified during development. In addition, we will use the powerful genetic tools I developed to directly test whether these candidate genes are important for ductal cell differentiation or maturation. In sum, the proposed research program will provide new insight into the links between cellular differentiation and the establishment of organ structure and function.