Epitenetic regulation and enhancement of beta cell differentiation

表观调控和β细胞分化的增强

• 批准号: 8143514
• 负责人: ARTHUR D RIGGS
• 金额: $ 49.88万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8143514
• 关键词: Adult; Affect; Autoimmunity; Basic Science; Beta Cell; C-Peptide; California; Cell Differentiation process; Cell Fate Control; Cell physiology; Cells; Cellular biology; Chromatin Structure; Cities; Clinical; Collaborations; Communities; DNA Methylation; Data Set; Development; Disease; Emerging Technologies; Endocrine; Endoderm; Ensure; Epigenetic Process; Fostering; Future; Generations; Glucose; Goals; Histones; Human; Hydrogels; In Vitro; Institution; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Lead; Literature; Methods; Nylons; Organ; Pancreas; Population; Principal Investigator; Proteins; Protocols documentation; Regulation; Replacement Therapy; Research; Research Personnel; Resources; Source; Stem cells; Testing; Transplantation; United States National Academy of Sciences; Work; clinical application; genome-wide; histone modification; human embryonic stem cell; improved; innovation; islet; member; mouse Neurog3 protein; new technology; novel; progenitor; public health relevance; tool; transcription factor

DESCRIPTION (provided by applicant): Human embryonic stem cells (hESCs) may provide an unlimited source of insulin-secreting beta-like cells for cell replacement therapy of type 1 diabetes, a disease in which insulin-secreting beta cells in the pancreatic islets of Langerhans are destroyed by autoimmunity. In spite of the recent progress in deriving early definitive and pancreatic endoderm-like progenitors from hESCs, a robust generation of later functional pancreatic beta-like cells has not yet been achieved in vitro. It is increasingly recognized that profound alterations in chromatin structure, including changes in epigenetic DNA methylation and histone modifications, contribute to the control of cell fate decisions. To harness the capability to efficiently differentiate hESCs in vitro, it is necessary to further define epigenetic signatures during pancreatic development. In this Beta Cell Biology Consortium application, we propose to identify and develop novel research resources and tools to advance our long-term goal of enhancing the yield of clinically-applicable human pancreatic beta-like cells from hESCs in culture for the purpose of cell replacement therapy for type 1 diabetes. Specific Aim 1 is to perform epigenome profiling for DNA methylation and key histone marks on two cell populations: mature adult human beta cells, obtained from cadaverous organs, and human ESC-derived pancreatic endocrine like progenitor cells that express neurogenin 3, a transcription factor necessary for the formation of the endocrine pancreas. We will then compare the epigenetic signature of these two populations, which will lead to identification of epigenetic targets and allow development of strategies to manipulate cell differentiation. Specific Aim 2 is to improve the yield of functional beta like cells from hESCs in vitro. We will use three emerging technologies, i.e., macromolecular hydrogels, protein transduction domains, and polyamides, to deliver or inhibit specific molecules that are known, in the literature, to affect beta cell commitment, maturation and function. If successfully completed, the proposed work will be the first data set describing the epigenetic profiles of different human pancreatic cell populations. The novel technologies to be employed will also be valuable for the community to further explore in the field of beta cell biology. Finally, the proposed work will allow us to assess hESC-derived cells in a novel manner, increasing our understanding about whether these cells may be suitable for future clinical applications. PUBLIC HEALTH RELEVANCE: In spite of the recent progress in deriving early definitive and pancreatic endoderm-like progenitors from human embryonic stem cells (hESCs), a robust generation of later functional pancreatic beta-like cells has not yet been achieved in culture. We propose to identify and develop novel research resources (such as epigenetic signatures of beta cells and progenitors) and tools (such as macromolecular hydrogels, protein transduction domains, and polyamides) to advance our long-term goal of enhancing the yield of clinically-applicable human pancreatic beta-like cells from hESCs in culture for the purpose of cell replacement therapy for type 1 diabetes.

描述（由申请人提供）：人胚胎干细胞（hESC）可以为 1 型糖尿病的细胞替代疗法提供无限来源的胰岛素分泌 β 样细胞，在这种疾病中，朗格汉斯胰岛中的胰岛素分泌 β 细胞被自身免疫破坏。尽管最近在从 hESC 衍生早期定型和胰腺内胚层样祖细胞方面取得了进展，但尚未在体外实现后期功能性胰腺 β 样细胞的强大一代。人们越来越认识到，染色质结构的深刻改变，包括表观遗传 DNA 甲基化和组蛋白修饰的变化，有助于细胞命运决定的控制。为了利用体外有效分化 hESC 的能力，有必要进一步定义胰腺发育过程中的表观遗传特征。在此 Beta 细胞生物学联盟申请中，我们建议识别和开发新的研究资源和工具，以推进我们的长期目标，即提高培养的 hESC 中临床适用的人胰腺 β 样细胞的产量，用于 1 型糖尿病的细胞替代疗法。具体目标 1 是对两个细胞群的 DNA 甲基化和关键组蛋白标记进行表观基因组分析：从尸体器官获得的成熟成人 β 细胞，以及表达神经原素 3 的人 ESC 衍生的胰腺内分泌样祖细胞，神经原素 3 是形成内分泌胰腺所必需的转录因子。然后，我们将比较这两个群体的表观遗传特征，这将导致表观遗传目标的识别，并允许开发操纵细胞分化的策略。具体目标 2 是提高体外 hESC 功能性 β 样细胞的产量。我们将使用三种新兴技术，即大分子水凝胶、蛋白质转导域和聚酰胺，来传递或抑制文献中已知的影响β细胞定型、成熟和功能的特定分子。如果成功完成，拟议的工作将成为第一个描述不同人类胰腺细胞群表观遗传特征的数据集。将采用的新技术对于社区在β细胞生物学领域的进一步探索也很有价值。最后，拟议的工作将使我们能够以一种新的方式评估 hESC 衍生细胞，增加我们对这些细胞是否适合未来临床应用的了解。 公共健康相关性：尽管最近在从人胚胎干细胞 (hESC) 衍生早期定形和胰腺内胚层样祖细胞方面取得了进展，但尚未在培养中实现后期功能性胰腺 β 样细胞的强大一代。我们建议识别和开发新的研究资源（例如β细胞和祖细胞的表观遗传特征）和工具（例如大分子水凝胶、蛋白质转导域和聚酰胺），以推进我们的长期目标，即提高培养的hESC中临床适用的人胰腺β样细胞的产量，用于1型糖尿病的细胞替代疗法。