DETERMINANTS OF SELF-RENEWAL, DIFFERENTIATION, AND REPROGRAMMING OF HESCS

HECS 自我更新、分化和重新编程的决定因素

• 批准号: 8173148
• 负责人: James Alexander Thomson
• 金额: $ 4.13万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173148
• 关键词: Cell Nucleus; Cells; Commit; Computer Retrieval of Information on Scientific Projects Database; Development; Epigenetic Process; Event; Funding; Genes; Grant; Histone Code; Histone H3; Individual; Institution; Left; Link; Maps; Mass Spectrum Analysis; Mediating; Memory; Myelogenous; Myeloid Cells; Outcome; Post-Translational Protein Processing; Process; Proliferating; Regenerative Medicine; Reporting; Research; Research Personnel; Resources; Role; Source; Specific qualifier value; Techniques; Time; Transact; Transplantation; United States National Institutes of Health; Variant; cell type; embryonic stem cell; histone modification; human embryonic stem cell; novel; nuclear reprogramming; pluripotency; promoter; self-renewal

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: Human ES cells are special because they can grow without limit and can give rise to all other cell types. Here we will try to understand why human ES cells have this remarkable developmental potential, and develop conditions to convert a cell with a more limited potential to an ES cell. Such reprogramming has implications for transplantation and regenerative medicine. Understanding how human embryonic stem (ES) cells can proliferate without limit and yet retain the ability to differentiate to any cell type is the theme that links the three individual projects of this proposal. Project 1 will identify novel histone modifications in human ES cells using a new mass spectrometry technique that allows an unprecedented ability to identify and map posttranslational protein modifications. Histone modifications in human ES cells will be identified globally, at promoters, and at select genes directly regulated by critical pluripotency factors. We will also examine the role of histone H3 variants in establishing long-term epigenetic memory. These studies will determine whether there is a novel histone code in pluripotent cells and determine how histone modifications change dynamically during differentiation. Project 2 examines the critical events that occur in the window of time during which human ES cells commit to exit the pluripotent state upon BMP-induced differentiation. This project will provide an increased understanding of the processes that commit human ES cells to exit the pluripotent state and specify different lineage outcomes. Project 3 will identify combinations of ES cell-specific genes that can reprogram differentiated cells to a pluripotent state. We have previously reported that when myeloid cells are fused with human ES cells, the myeloid nucleus is reprogrammed to an ES cell state, indicating that transacting factors in ES cells are sufficient to mediate nuclear reprogramming. Our preliminary results suggest that over expressing combinations of human ES cell-enriched genes can reprogram myeloid cells, and this project will optimize this reprogramming. The combination of these projects will provide an increased understanding of the pluripotent state and the basic processes by which a cell can leave or return to that state. Such an understanding will be important to transplantation and regenerative medicine.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 目的：人类ES细胞特殊，因为它们可以不受限制地生长，并且会引起所有其他细胞类型。在这里，我们将尝试理解为什么人ES细胞具有这种显着的发育潜力，并发展条件以转化具有更有限潜力的细胞对ES细胞。这种重编程对移植和再生医学具有影响。 了解人类胚胎茎（ES）细胞如何在没有限制的情况下增殖，但保持与任何细胞类型的能力是联系该提案的三个单独项目的主题。项目1将使用一种新的质谱技术鉴定人类ES细胞中的新型组蛋白修饰，该技术允许识别和绘制翻译后蛋白质修饰的前所未有的能力。将在全球，启动子和直接受关键多能因素调节的精选基因上鉴定人ES细胞中的组蛋白修饰。我们还将研究组蛋白H3变体在建立长期表观遗传记忆中的作用。这些研究将确定多能细胞中是否存在新型组蛋白代码，并确定组蛋白在分化过程中如何动态变化。项目2研究了人类ES细胞致力于在BMP诱导的分化后退出多能状态的时间窗口中发生的关键事件。该项目将对使人类ES细胞退出多能状态并指定不同的谱系结果的过程有更多的了解。项目3将确定可以将分化细胞重新编程为多能状态的ES细胞特异性基因的组合。我们先前已经报道说，当将髓样细胞与人ES细胞融合时，将髓样核重编程为ES细胞态，表明ES细胞中的交易因子足以介导核重编码。我们的初步结果表明，富含人ES细胞富集基因的过度表达组合可以重编程髓样细胞，该项目将优化该重编程。这些项目的结合将提供对多能状态以及细胞可以离开或返回该状态的基本过程的更多了解。这种理解对于移植和再生医学将很重要。