Molecular mechanisms regulating developmental maturation of pancreatic ductal cells

功能性器官是通过将具有不同功能的细胞排列成3D结构来创建的，使器官能够有效地在体内发挥作用。在某些器官中，不同的特化细胞类型的产生与器官的整体结构在胚胎发育期间产生的同时发生。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，但对这些过程中的每一个以及两者之间的联系的完全理解仍然是一个遥远的目标。在器官中，如肺和胰腺，高度分支的树状结构用于增加表面积和可以包装成小面积的功能单元的数量。此外，分支树作为一个管道，将细胞产物从器官的外围输送到目的地。因此，分支网络的功能和结构对于整个器官的功能至关重要。胰腺中的分支网络由导管细胞组成。到目前为止，我们对发育过程中调节细胞群体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，专门分离或操纵胰腺导管细胞在他们的发展。利用这些工具，我们确定了对胚胎祖细胞分化为成熟的、功能性的胰管可能重要的候选基因。在这个建议中，我们将利用这些候选基因来检查何时指定导管细胞在发展过程中。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是否对导管细胞分化或成熟很重要。总之，拟议的研究计划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.