Gene Regulatory Signals for Beta Cell Development

β 细胞发育的基因调控信号

• 批准号: 7498280
• 负责人: Kenneth Zaret
• 金额: $ 17.1万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498280
• 关键词: Adult; Age; Aging; Animals; Aorta; Beta Cell; Biological Assay; Cell Biology, Other; Cell Communication; Cell Differentiation process; Cell Line; Cell Survival; Cells; Cellular biology; Coculture Techniques; DNA; Data; Development; Development, Other; Diabetes Mellitus; Dorsal; Elements; Embryo; Embryonic Development; Endocrine; Endoderm; Endothelial Cells; Event; Gene Expression; Generations; Genes; Genetic; Goals; Growth; In Vitro; Information Technology; Islets of Langerhans; Laboratories; Link; Mesenchyme; Methods; Monitor; Mus; Natural regeneration; Pancreas; Pancreatic Bud; Pathway interactions; Phase; Phenotype; Population; Reaction; Regulation; Regulator Genes; Regulatory Element; Regulatory Pathway; Reporter; Signal Transduction; Signaling Molecule; Staging; Stem cells; Stromal Cells; Structure of beta Cell of islet; Technology; Tissues; Transcription factor genes; Transgenic Organisms; Translating; Work; aged; base; chromatin immunoprecipitation; in vivo; insight; islet; juvenile animal; member; progenitor; response; stem; tool; transcription factor

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.

该提案的目标是推进技术和了解的机制， 胰腺β细胞在胚胎发生和成年胰岛中的发育，并促进这种 胰岛再生和干细胞生物学的其他成员的β细胞生物学联盟的进展 （BCBC）。我建议将两项技术带到BCBC;一项将识别新的和未预料到的技术 转录因子为基础的调控事件，与内分泌发展有关，另一个将 确定促进内分泌分化和胰腺基质细胞的内皮细胞信号传导因子 生存在我们的第一个目标中，我们将生成体内足迹数据和相关信息， 内分泌转录因子基因在胰腺发育和衰老的不同阶段， 定义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的成员传播数据，合作者可以帮助我们定义新的因素- 调控序列的相互作用，并使用这些信息来监测，预测，并最终干扰β 从干细胞和在胰岛再生期间的细胞生成。这种方法是对现有的 遗传学研究，提供终末表型，但不提供有关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和来自小鼠胚胎的新内皮细胞系， 鉴定促进内分泌祖细胞分化和胰腺炎的内皮信号传导因子 基质细胞存活率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。我们也 通过研究转录因子在前内分泌基因中的作用，将目的1和2联系起来， 对内皮信号的反应。通过与BCBC分享我们的技术和信息， 基础发展研究将更快地转化为糖尿病的治疗方法。