Dissecting the establishment and regulation of human pluripotency

剖析人类多能性的建立和调节

• 批准号: 8196106
• 负责人: Alexander Meissner
• 金额: $ 222.23万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196106
• 关键词: Dissecting; establishment; regulation; human; pluripotency

DESCRIPTION (provided by applicant): Induced pluripotent stem (iPS) cells have a tremendous potential for aidvancing our understanding of human development and disease. To help unlock this potential we have organized a program to (A) comprehensively identify the genetic and epigenetic components of the regulatory network that maintains cells in a pluripotent state; (B) characterize culture-induced variation in the activites of these components in pluripotent cells; and (C) characterize temporal variation in their activities during induction of pluripotency with defined factors. To achieve these goals, we have formulated four interdependent projects: Project I (Meissner) will (1) characterize transcriptional coregulators and small non-coding RNAs that modulate the activity of the core pluripotency transcription factors, and (2) define and isolate subpopulations from pluripotent cell cultures to characterize their transcriptional and epigenetic states. Project II (Rinn) will characterize long non-coding RNAs expressed in pluripotent cells and elucidate their role in remodeling the epigenetic landscape during reprogramming. Project III (Mikkelsen) will characterize the cis-regulatory modules that direct activation, maintenace and repression of gene expression in pluripotent cells by recruiting transcription factors and their coregulators to key genomic loci. Project IV (Eggan) will characterize the inheritance patterns and maintenance of inactivated X chromosomes during reprogramming and in pluripotent cell cultures. The four projects rely on complementary use of innovative high-throughput genomic and proteomic technologies to profile high-quality iPS cell lines. The integration of data and insights from each of the projects will generate a comprehensive view of protein-protein, protein-RNA and protein-DNA interactions essential to the maintenace of pluripotency (goal A). This intergrated view will then guide studies of culture- induced and temporal variation in the network (goals B and C). PUBLIC HEALTH RELEVANCE: Induced pluripotent stem cells are a potential revolutionary tool for disease modeling, drug screening and regenerative medicine. This program is organized to fully characterize the molecular properties of these cells, which is essential to ensure that their use in biomedicine is effective and safe.

描述（由申请人提供）：诱导多能干细胞（iPS）具有巨大的潜力，有助于我们了解人类发育和疾病。为了帮助释放这种潜力，我们组织了一个项目，以（A）全面鉴定维持细胞处于多能状态的调控网络的遗传和表观遗传组分;（B）表征多能细胞中这些组分的培养诱导的活性变化;和（C）表征在用定义的因子诱导多能性期间其活性的时间变化。为了实现这些目标，我们制定了四个相互依存的项目： 项目I（Meissner）将（1）表征调节核心多能性转录因子活性的转录辅调节因子和小的非编码RNA，以及（2）从多能性细胞培养物中定义和分离亚群，以表征其转录和表观遗传状态。 项目II（Rinn）将表征多能细胞中表达的长非编码RNA，并阐明它们在重编程过程中重塑表观遗传景观中的作用。 项目III（Mikkelsen）将描述顺式调控模块的特征，这些模块通过将转录因子及其辅助调节因子募集到关键基因组位点来指导多能细胞中基因表达的激活、维持和抑制。 项目IV（Eggan）将描述在重编程和多能细胞培养过程中失活X染色体的遗传模式和维持。 这四个项目依赖于创新的高通量基因组学和蛋白质组学技术的互补使用，以分析高质量的iPS细胞系。每个项目的数据和见解的整合将产生对维持多能性必不可少的蛋白质-蛋白质，蛋白质-RNA和蛋白质-DNA相互作用的全面看法（目标A）。这种整合的观点将指导网络中文化诱导和时间变化的研究（目标B和C）。 公共卫生关系：诱导多能干细胞是疾病建模、药物筛选和再生医学的潜在革命性工具。该计划旨在充分表征这些细胞的分子特性，这对于确保它们在生物医学中的使用是有效和安全的至关重要。