Formation of endocrine pancreas progenitors

内分泌胰腺祖细胞的形成

基本信息

批准号：
8143486
负责人：
DORIS A STOFFERS
金额：
$ 73.64万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8143486
关键词：
Adult Affect Beta Cell Binding Biochemical Bioinformatics Cataloging Catalogs Cell Line Cell Lineage Cell Separation Cell Therapy Cells Chromatin Collaborations Competence Complement Complex DNA Sequence Data Data Set Ductal Epithelial Cell Ductal Epithelium Embryo Endocrine Endoderm Enhancers Epigenetic Process Epithelial Cells Epithelium Gene Expression Genes Genetic Goals Histone Code Human Individual Insulin-Dependent Diabetes Mellitus Islets of Langerhans Islets of Langerhans Transplantation Laboratories Light Maps Modeling Molecular Mus Outcome Pancreas Pathway interactions Patients Pattern Phenotype Population Primitive foregut structure Principal Investigator Promoter Regions Regulation Role Sorting - Cell Movement Source Staging Stem cells Transplantation chromatin immunoprecipitation chromatin modification embryonic stem cell genetic analysis homeodomain human embryonic stem cell improved in vivo induced pluripotent stem cell islet pancreas development progenitor public health relevance stem stem cell differentiation synergism transcription factor

项目摘要

DESCRIPTION (provided by applicant): Approaches to cell based therapies for type 1 diabetes have largely focused on the expression of a single or a combination of transcription factors that can drive ( cell specific patterns of gene expression, and most have relied at least in part on Pdx1, a homeodomain transcription factor with critical regulatory roles in early pancreas development and in the mature ( cell, and on Ngn3, a critical pro-endocrine transcription factor whose transient expression characterizes endocrine progenitors. However promising, the efficiency of achieving a ( cell phenotype by any of these approaches remains low, and the fidelity and stability of these efforts have not been fully evaluated. Although endoderm is achieved reproducibly and efficiently, subsequent transitions, such as from pancreatic progenitor to endocrine pancreatic progenitor, are achieved with particularly low efficiency. We recently determined that Pdx1 contributes to specification of endocrine progenitors in mice both by regulating Ngn3 directly in concert with Hnf6 and by participating in a cross-regulatory transcription factor network during early pancreas development. We hypothesize that understanding the epigenetic regulation of the transcription factor Ngn3 and the roles of Pdx1 and Hnf6 in the cross-regulatory transcription factor network of developing ( cells will inform efforts to improve the efficiency, fidelity and stability of the ( cell phenotype achieved through the guided differentiation of non-( cell populations. Therefore, we propose in AIM 1: To examine the genetic and epigenetic regulation of Ngn3 in human pancreas progenitors, in AIM 2: To analyze the genetic and molecular interactions between Pdx1 and Hnf6 in promoting endocrine progenitor specification, and in AIM 3: To define the role of Pdx1 and Hnf6 in the transcriptional network of endocrine pancreas progenitors through global occupancy and gene expression analysis. The overarching long-term goal is to utilize this information gained from these studies to optimize the guided transition of ES and iPS cells, and possibly mature lineages, toward a ( cell fate. PUBLIC HEALTH RELEVANCE: The high hopes for cell based therapy for type 1 diabetes have been tempered by the limited availability and short-term function of human islets for transplantation, leading to intense focus on alternate sources of (?cells. The overarching goal of the proposed studies is to optimize the guided transitions of ES and iPS cells toward a ( cell fate to make potentially patient-specific ( cells available for transplantation.

描述（由申请人提供）：基于细胞的 1 型糖尿病治疗方法主要集中于可驱动基因表达的细胞特异性模式的单个或组合转录因子的表达，并且大多数方法至少部分依赖于Pdx1 是一种同源域转录因子，在早期胰腺发育和成熟细胞中具有关键调节作用；Ngn3 是一种关键的前内分泌转录因子，其瞬时表达是内分泌祖细胞的特征。通过任何这些方法实现细胞表型的效率仍然很低，并且这些努力的保真度和稳定性尚未得到充分评估。尽管内胚层可重复且有效地实现，但随后的转变，例如从胰腺祖细胞到内分泌胰腺祖细胞，我们最近确定 Pdx1 通过与 Hnf6 直接调节 Ngn3 并通过参与一个过程来促进小鼠内分泌祖细胞的规范。早期胰腺发育过程中的交叉调节转录因子网络。我们假设，了解转录因子 Ngn3 的表观遗传调控以及 Pdx1 和 Hnf6 在发育中细胞的交叉调控转录因子网络中的作用，将为提高 ( 细胞表型的效率、保真度和稳定性) 的努力提供信息。引导非(细胞群的分化。因此，我们在 AIM 1 中提出：检查 Ngn3 在人类胰腺祖细胞中的遗传和表观遗传调控，在 AIM 中2：分析 Pdx1 和 Hnf6 在促进内分泌祖细胞规范中的遗传和分子相互作用，以及 AIM 3：通过全局占据和基因表达分析来定义 Pdx1 和 Hnf6 在内分泌胰腺祖细胞转录网络中的作用。长期目标是利用从这些研究中获得的信息来优化 ES 和 iPS 细胞以及可能的成熟谱系的引导转变，以实现（细胞命运。公共健康相关性：对于 1 型糖尿病的细胞治疗寄予厚望，但由于用于移植的人类胰岛的可用性和短期功能有限，因此人们对 (? 细胞) 的替代来源产生了强烈关注。拟议的研究旨在优化 ES 和 iPS 细胞向细胞命运的引导转变，从而使潜在的患者特异性细胞可用于移植。