Formation and maturation of endocrine pancreas progenitors

内分泌胰腺祖细胞的形成和成熟

• 批准号: 9056074
• 负责人: Maureen A Gannon
• 金额: $ 56.72万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-22 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056074
• 关键词: Adult; Affect; Attention; Beta Cell; Biochemical; Biological Models; Birth; Cell Count; Cell Line; Cell Lineage; Cell physiology; Cells; Characteristics; Data; Defect; Development; Diabetes Mellitus; Disease; Double Effect; Ductal Epithelial Cell; Embryo; Embryonic Development; Endocrine; Endoderm; Epigenetic Process; Epithelium; Failure; Gene Activation; Gene Expression; Genes; Genetic; Genetic Epistasis; Glucagon; Goals; Heterozygote; Human; Hyperglycemia; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Molecular; Mus; Neonatal; Pancreas; Pancreatic duct; Pathway interactions; Patients; Phenotype; Population; Primitive foregut structure; Regulation; Replacement Therapy; Source; Stem cells; Testing; Tissues; Transgenic Mice; Transplantation; Work; cell type; gain of function; human embryonic stem cell; improved; in vivo; insight; intestinal epithelium; islet; overexpression; pancreas development; premature; progenitor; programs; public health relevance; stem cell differentiation; synergism; transcription factor; transcriptomics; transdifferentiation

 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.

 描述（由申请人提供）：1 型糖尿病患者对胰岛素独立性的厚望因移植的人类胰岛的可用性有限和短期功能而受到影响。因此，通过干细胞的引导分化或其他成熟细胞的转分化来开发β细胞的替代来源，已成为治疗糖尿病的可行前景。实现β细胞表型的低效率使人们将注意力集中在控制胰腺向内分泌祖细胞发育转变的因素上。我们已经确定，在此转变过程中表达的两种转录因子 Pdx1 和 Oc1 的协同作用，通过直接调节原内分泌基因 Ngn3 并参与交叉调节转录网络，有助于小鼠内分泌祖细胞及其后代的形成和成熟。我们假设 Pdx1-Oc1 相互作用在正常发育期间和感受性祖细胞中驱动内分泌胰腺基因程序的诱导。我们通过以下方式测试这一假设：(1) 表征胚胎发育过程中 Pdx1 和 Oc1 之间的遗传相互作用，(2) 确定 Pdx1 和 Oc1 是否为 ß 细胞谱系的基因激活建立了一个允许的表观遗传景观，以及 (3) 确定组合的 Pdx1 和 Oc1 功能获得是否可以促进体内、人胰管细胞和人体内 ß 细胞的形成和功能。 胚胎干细胞。这些研究利用了小鼠和人类模型系统的离体和体内方法。成功完成所提出的目标将揭示 Pdx1 和 Oc1 合作建立内分泌和 ß 细胞谱系的生化、表观遗传和发育作用机制。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 ß 细胞生成新的功能齐全的 ß 细胞。