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Formation and maturation of endocrine pancreas progenitors

内分泌胰腺祖细胞的形成和成熟

基本信息

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
项目类别：
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

项目摘要

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.