Gene Regulatory Signals for Beta Cell Development

描述（由申请人提供）： 该提案的目标是推进关于胚胎发育和成年胰岛中胰腺β细胞发育机制的技术和理解，并促进β细胞生物学联盟（BCBC）其他成员将这些进展应用于胰岛再生和干细胞生物学。我建议将两种技术带到BCBC;一种将识别与内分泌发育相关的新的和未预料到的基于转录因子的调控事件，另一种将定义促进内分泌分化和胰腺基质细胞存活的内皮细胞信号传导因子。在我们的第一个目标中，我们将在胰腺发育和衰老的不同阶段产生体内足迹数据和前内分泌转录因子基因的相关信息，以更好地定义管理内分泌祖细胞分化和β细胞再生能力的调节事件。通过向BCBC成员传播数据，合作者可以帮助我们定义新的因子-调控序列相互作用，并使用这些信息来监测、预测和最终干扰干细胞和胰岛再生过程中的β细胞生成。这种方法是对现有遗传学研究的补充，现有遗传学研究给出了终末表型，但没有关于遗传调控机制的信息。在我们的第二个目标中，我们将使用现有的内皮细胞系，并从小鼠胚胎中创建新的内皮细胞系，以鉴定促进内分泌祖细胞分化和胰腺基质细胞存活的内皮信号传导因子。由于内皮细胞和基质细胞都控制胰腺生长，这些研究旨在揭示控制胰岛发育和再生的新信号分子。我们还计划通过研究前内分泌基因对内皮信号的反应，将目标1和2联系起来。通过与BCBC分享我们的技术和信息，我们的基础发展研究将更快地转化为糖尿病的治疗方法

DESCRIPTION (provided by applicant): The goal of this proposal is to advance technologies and understanding about the mechanism of pancreatic beta cell development in embryogenesis and adult islets, and to promote the application of such advances to islet regeneration and stem cell biology by other members of the Beta Cell Biology Consortium (BCBC). I propose to bring two technologies to the BCBC; one will identify new and unanticipated transcription factor-based regulatory events that are relevant to endocrine development, and the other will define endothelial cell signaling factors that promote endocrine differentiation and pancreatic stromal cell survival. In our first Aim, we will generate in vivo footprinting data and related information on proendocrine transcription factor genes at different stages of pancreatic development and aging, to better define regulatory events that govern endocrine progenitor cell differentiation and beta cell regenerative capacity. By disseminating data to members of the BCBC, collaborators can help us define new factor-regulatory sequence interactions and use the information to monitor, predict, and ultimately perturb beta cell generation from stem cells and during islet regeneration. This approach is complementary to existing genetic studies, which give terminal phenotypes but not information about genetic regulatory mechanisms. In our second Aim, we will use existing endothelial cell lines and create new ones from mouse embryos to identify endothelial signaling factors that promote endocrine progenitor differentiation and pancreatic stromal cell survival. Since endothelial cells and stromal cells both control pancreatic growth, these studies are intended to reveal new signaling molecules that control islet development and regeneration. We also plan to link Aims 1 and 2 by investigating transcription factor occupancies at pro-endocrine genes in response to endothelial signals. By sharing technology and information from our work with the BCBC, our basic developmental studies will be more rapidly translated to develop cures for diabetes