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

• 批准号: 7994417
• 负责人: Maike Sander
• 金额: $ 115.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994417
• 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; Pancreas; Pathway interactions; Patients; Pennsylvania; Physiological; Principal Investigator; Protocols documentation; Recording of previous events; Replacement Therapy; Research Personnel; Resources; Risk; Screening procedure; Spain; Specific qualifier value; Staging; Stem cells; Testing; Tissues; Transplantation; United States National Institutes of Health; Universities; Work; base; beta cell replacement; combinatorial; 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; stem; stem cell biology; transcription factor

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. PUBLIC HEALTH RELEVANCE: Since the first pioneering work on islet transplantation, it has become clear that a cell-based approach for the treatment of diabetes mellitus can have significant benefits in terms of insulin independence and a reduced risk of hypoglycemia. By exploring novel startegies for deriving insulin-producing beta-cells from human embryonic stem cells for cell transplantation, this proposal seeks to develop cell therapies for diabetes.

描述（由申请人提供）：本提案的总体目标是制定从人胚胎干 (hES) 细胞或患者来源的诱导多能干 (iPS) 细胞中衍生葡萄糖响应性胰岛素生成细胞的策略。为了实现这一目标，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 区分干细胞/祖细胞，用于糖尿病的细胞替代疗法。为了实现我们的目标，我们组建了一个由五位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。通过对各种原代胚胎和成人细胞和组织中关键组蛋白修饰的全基因组图谱，我们将定义表观遗传特征，这些特征定义 胰腺祖细胞及其内分泌后代。这些知识将用于指导改进现有的 hES 细胞体外分化方案，将其分化为胰腺祖细胞，并最终分化为葡萄糖反应性产生胰岛素的 p 细胞。我们提案的关键是一种新颖的细胞微阵列技术，该技术允许对细胞外基质成分、因子和/或 分子途径，以支持沿着从 hES 细胞到成熟 (-cell) 的逐步分化路径有效生成每个中间前体。表观遗传特征将用作终点，以评估体外生成的 hES 细胞衍生细胞与体内胰腺对应细胞的相似程度。最终将测试 hES 细胞衍生 (-cells) 纠正血糖升高的能力 移植到糖尿病小鼠模型后的水平。 公众健康相关性：自从胰岛移植的首次开创性工作以来，已经清楚的是，基于细胞的糖尿病治疗方法在胰岛素独立性和降低低血糖风险方面具有显着的益处。通过探索从人类胚胎干细胞中提取产生胰岛素的β细胞进行细胞移植的新策略，该提案旨在开发糖尿病的细胞疗法。