Gene Regulatory Signals for Beta Cell Development

这项提议的目标是促进技术进步和对 胰岛β细胞在胚胎发育和成体胰岛中的发育及其推广应用 贝塔细胞生物学联盟其他成员在胰岛再生和干细胞生物学方面的进展 (英国广播公司)。我建议为BCBC带来两项技术；一项将识别新的和意想不到的 与内分泌发育相关的基于转录因子的调控事件，以及其他将 明确促进内分泌分化的内皮细胞信号转导因子和胰腺基质细胞 生死存亡。在我们的第一个目标中，我们将产生体内足迹数据和有关PRO-2的信息。 内分泌转录因子基因在胰腺发育和衰老的不同阶段 确定控制内分泌祖细胞分化和β细胞再生的调节事件 容量。通过向BCBC成员传播数据，合作者可以帮助我们定义新的因素- 调节序列相互作用，并使用该信息来监控、预测并最终扰乱Beta 干细胞和胰岛再生过程中的细胞生成。这种方法是对现有方法的补充 遗传研究，给出末端表型，但不提供关于遗传调节机制的信息。 在我们的第二个目标中，我们将使用现有的内皮细胞系和从小鼠胚胎中创造出新的内皮细胞系来 识别促进内分泌祖细胞分化和胰腺的内皮信号因子 基质细胞存活。由于内皮细胞和基质细胞都控制着胰腺的生长，这些研究 旨在揭示控制胰岛发育和再生的新信号分子。我们也是 计划通过研究前内分泌基因中转录因子的占有率将目标1和目标2联系起来 对内皮细胞信号的反应。通过分享我们与BCBC合作的技术和信息，我们的 基础发育研究将更快地转化为糖尿病的治疗方法。

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 cellbiology 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 pro- endocrine transcription factor genes at different stages ofpancreatic 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 createnew 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. Wealso plan to link Aims 1and 2by investigating transcription factor occupancies at pro-endocrine genes in response to endothelial signals. Bysharing technology and information from our work with the BCBC, our basic developmental studies will be more rapidly translated to develop cures for diabetes.