Gene Regulatory Signals for Beta Cell Development

描述(由申请人提供)： 这项建议的目的是促进对胚胎发育和成人胰岛中胰岛β细胞发育机制的技术和理解，并促进这些进展在胰岛再生和干细胞生物学中的应用，由贝塔细胞生物学联盟(BCBC)的其他成员。我建议将两项技术引入BCBC；一项将识别与内分泌发育相关的新的和意想不到的基于转录因子的调控事件，另一项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因子。在我们的第一个目标中，我们将在体内生成关于胰腺发育和衰老不同阶段的前内分泌转录因子基因的足迹数据和相关信息，以更好地定义调控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、预测并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研究的补充，现有的遗传研究给出了末端表型，但没有提供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，以确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因子。由于内皮细胞和基质细胞都控制胰腺的生长，这些研究旨在揭示控制胰岛发育和再生的新的信号分子。我们还计划将AIMS 1和AIMS 2联系起来，通过研究转录因子在前内分泌基因对内皮信号的反应中的占有率。通过分享我们与BCBC合作的技术和信息，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