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Epigenetic strategies for the in vitro generation of replacement beta cells

体外生成替代β细胞的表观遗传策略

基本信息

批准号：
8696967
负责人：
Maike Sander
金额：
$ 115.41万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2010-09-17 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8696967
关键词：
Adopted Adult Area Beta Cell Blood Glucose California Cell Differentiation process Cell Line Cell Therapy Cell Transplantation Cells Cellular biology Characteristics Chromatin Structure Clinics and Hospitals Collaborations Competence Computational Biology Core Facility Cues Data Data Analyses Development Developmental Biology Diabetes Mellitus Diabetic mouse Embryo Endocrine Endoderm Epigenetic Process Event Extracellular Matrix Funding Generations Genes Genomics Glucose Goals Hip region structure Histone Code Histones Human Hypoglycemia Immunodeficient Mouse In Vitro Insulin Islets of Langerhans Transplantation Knowledge Laboratories Maps Microarray Analysis Molecular Molecular Profiling Mus National Institute of Diabetes and Digestive and Kidney Diseases Pancreas Pathway interactions Patients Pennsylvania Physiological Principal Investigator Protocols documentation Recording of previous events Replacement Therapy Research Personnel Resources Risk Sequence Analysis Spain Specific qualifier value Staging Stem cells Testing Tissues Transplantation United States National Institutes of Health Universities Work base beta cell replacement combinatorial epigenome genome wide association study genome-wide histone modification human embryonic stem cell human tissue improved in vivo indexing induced pluripotent stem cell mRNA Expression mouse model multidisciplinary nerve stem cell novel progenitor programs public health relevance research study screening stem stem cell biology transcription factor

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to develop strategies for deriving glucose-responsive insulin-producing (-cells from human embryonic stem (hES) cells or patient-derived induced pluripotent stem (iPS) cells. With this objective our proposal will advance one of the focus areas of the NIH-NIDDK Beta Cell Biology Consortium, which is "to use cues from pancreatic development to directly differentiate (-cells from stem/progenitor cells for use in cell-replacement therapies for diabetes". To achieve our objectives we have assembled a consortium of five investigators, which includes experts in (-cell and stem cell biology as well as genomics. By genome-wide mapping of key histone modifications in a variety of primary embryonic and adult human cells and tissues, we will define epigenetic signatures that define pancreatic progenitors and their endocrine descendants. This knowledge will be used to guide efforts for improving preexisting in vitro differentiation protocols of hES cells into pancreatic progenitors and eventually glucose-responsive insulin-producing p-cells. Key to our proposal is a novel cellular microarray technology that allows for combinatorial screening of extracellular matrix components, factors and/or molecular pathways for their ability to support efficient generation of each intermediary precursor along the step-wise differentiation path from hES cell to mature (-cell. The epigenetic signatures will be used as endpoints to assess how closely the in vitro-generated, hES cell-derived cells resemble their in vivo pancreatic counterparts. hES cell-derived (-cells will eventually be tested for their ability to correct elevated blood glucose levels upon transplantation into diabetic mouse models.

描述(由申请人提供)：这项建议的总体目标是开发从人类胚胎干细胞(HES)或患者来源的诱导多能干细胞(IPS)中获得葡萄糖反应性胰岛素产生细胞的策略。基于这一目标，我们的提案将推进NIH-NIDDK Beta细胞生物学联盟的重点领域之一，即“利用胰腺发育的线索直接从干细胞/祖细胞中分离出用于糖尿病细胞替代疗法的细胞”。为了实现我们的目标，我们组建了一个由五名研究人员组成的联盟，其中包括(细胞和干细胞生物学以及基因组学方面的专家)。通过对各种原始胚胎和成人细胞和组织中关键的组蛋白修饰的全基因组作图，我们将定义定义胰腺祖细胞及其内分泌后代的表观遗传学特征。这些知识将被用来指导改进HES细胞的体外分化方案，使其分化为胰岛前体细胞，并最终转化为葡萄糖反应性胰岛素产生的P细胞。我们建议的关键是一种新的细胞微阵列技术，该技术允许组合筛选细胞外基质成分、因子和/或分子通路，以支持从HES细胞到成熟(-细胞)的逐步分化路径上有效地产生每个中间前体。表观遗传学特征将被用作终点，以评估体外产生的HES细胞来源的细胞与体内胰腺对应细胞的相似程度。在移植到糖尿病小鼠模型后，HES细胞来源的(-细胞)最终将接受测试，以确定它们纠正血糖升高的能力。