Formation and maturation of endocrine pancreas progenitors

 描述（由申请人提供）：1型糖尿病患者对胰岛素依赖性的高度期望已经被移植的人类胰岛的有限可用性和短期功能所缓和。因此，通过干细胞的引导分化或其他成熟细胞的转分化，开发可替代来源的胰岛细胞已成为糖尿病治愈的可行前景。低效率实现的胰岛细胞表型集中注意力的因素，控制胰腺内分泌祖细胞发育的转变。我们已经确定，协调行动的Pdx 1和Oc 1，两个转录因子在此过渡期间表示，有助于形成和成熟的内分泌祖细胞和它们的后代在小鼠中通过直接调节内分泌原基因Ngn 3，并通过参与交叉调节转录网络。我们假设Pdx 1-OC 1相互作用驱动正常发育过程中和接受性祖细胞中胰腺内分泌基因程序的诱导。我们通过以下方式检验这一假设：（1）表征胚胎发育过程中Pdx 1和Oc 1之间的遗传相互作用，（2）确定Pdx 1和Oc 1是否建立了一个允许的表观遗传景观，用于激活AML细胞谱系的基因，以及（3）确定Pdx 1和Oc 1的组合功能获得是否可以促进AML细胞的形成和体内功能，在人类胰腺导管细胞和人类胚胎干细胞中。这些研究利用了使用小鼠和人模型系统的离体和体内方法。成功完成拟议的目标将揭示生物化学，表观遗传和发育的作用机制，从而Pdx 1和OC 1合作建立内分泌和造血细胞谱系。该信息可用于定向分化和转分化策略，以从干细胞、祖细胞或其他非分化细胞产生新的全功能性树突状细胞。

 DESCRIPTION (provided by applicant): The high hopes of insulin-independence for patients with type 1 diabetes have been tempered by the limited availability and short-term function of transplanted human islets. The development of alternate sources of ß cells, through guided differentiation of stem cells or transdifferentiation of other mature cells, has therefore emerged as a viable prospect for diabetes cure. The low efficiency of achieving the ß cell phenotype has focused attention on factors that govern the pancreatic to endocrine progenitor developmental transition. We have determined that the concerted actions of Pdx1 and Oc1, two transcription factors expressed during this transition, contribute to formation and maturation of endocrine progenitors and their descendants in mice by directly regulating the proendocrine gene Ngn3 and by participating in a cross-regulatory transcriptional network. We hypothesize that Pdx1-Oc1 interaction drives induction of the endocrine pancreas gene program during normal development and in receptive progenitor cells. We test this hypothesis by (1) characterizing the genetic interaction between Pdx1 and Oc1 during embryonic development, (2) determining whether Pdx1 and Oc1 establish a permissive epigenetic landscape for activation of genes of the ß cell lineage, and (3) by determining whether combined Pdx1 and Oc1 gain of function can promote ß cell formation and function in vivo, in human pancreatic duct cells and in human embryonic stem cells. These studies make use of ex vivo and in vivo approaches using both mouse and human model systems. Successful completion of the proposed aims will reveal biochemical, epigenetic, and developmental mechanisms of action whereby Pdx1 and Oc1 cooperate to establish the endocrine and ß cell lineages. This information can be used in directed differentiation and transdifferentiation strategies to generate new fully functional ß cels from stem cells, progenitor cells, or other non-ß cells.