Transcriptional Regulatory Networks in Living Cells

活细胞中的转录调控网络

• 批准号: 8824724
• 负责人: RICHARD YOUNG
• 金额: $ 31.14万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-02 至 2014-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824724
• 关键词: Biological Assay; Cell Maintenance; Cells; ChIP-seq; Chromatin; Computing Methodologies; Coupled; Data Analyses; Development; Embryo; Foundations; Gene Expression; Gene Targeting; Genes; Genetic Screening; Genomics; Goals; Health; Human; Knowledge; Lead; Life; Maintenance; Maps; Medical; Methods; Modeling; Mus; Play; Pluripotent Stem Cells; RNA; Regenerative Medicine; Regulator Genes; Research; Sequence Analysis; Signal Pathway; Signal Transduction; Signaling Protein; Somatic Cell; Technology; Testing; Therapeutic; chromatin immunoprecipitation; embryonic stem cell; genome-wide; human embryonic stem cell; improved; induced pluripotent stem cell; innovation; insight; novel; pluripotency; programs; research study; self-renewal; small hairpin RNA; stem; transcription factor

DESCRIPTION (provided by applicant): Embryonic stem (ES) and induced pluripotent stem (iPS) cells hold enormous potential for diverse medical applications, limited primarily by our methods to direct the activities of these cells toward specific therapeutic goals. A more complete understanding of the regulatory circuitry of pluripotent stem cells would almost certainly provide insights useful to overcome this limitation. We propose to expand knowledge of the transcriptional regulatory circuitry of murine and human embryonic stem (ES) cells by identifying novel ES cell transcription factors, chromatin regulators and signaling proteins and by determining how they function together to control the gene expression program responsible for pluripotency and self-renewal. Furthermore, we propose to use improved understanding of the control of ES cell state to develop more powerful methods for cellular reprogramming to generate iPS cells. To accomplish these goals, the specific aims of the proposal are: 1) Combine and further develop powerful experimental and analytical technologies that can identify novel regulators of ES cell state and determine their genome-wide occupancy and function; 2) Identify novel transcription factors, chromatin regulators and signaling proteins that play key roles in murine and human ES cell identity; 3) Determine how novel transcription factors, chromatin regulators and signaling proteins contribute to pluripotency and self-renewal in murine and human ES cells; and 4) Use cellular reprogramming assays to gain insights into the control of cell state and to develop more powerful methods for cellular reprogramming. Improved understanding of transcriptional regulatory circuitry from these studies will lead to new insights into the control of ES cell state, reveal how key regulators control the gene expression program of ES cells, facilitate efforts to manipulate cell fates for regenerative medicine, and provide the foundation for further mapping regulatory circuitry in human and other vertebrate cells.

描述（由申请人提供）：胚胎茎（ES）和诱导的多能茎（IPS）细胞对各种医疗应用具有巨大的潜力，主要受我们的方法限制，主要受我们的方法将这些细胞的活性引导到特定的治疗目标。对多能干细胞的调节电路的更完整了解几乎可以肯定会提供有用的见解，可用于克服这一限制。我们建议通过鉴定新型ES细胞转录因子，染色质调节剂和信号蛋白，并确定它们如何共同发挥作用以控制负责多能性和自我更新的基因表达程序，从而扩展对鼠和人类胚胎（ES）细胞转录调节电路的知识。此外，我们建议使用对ES细胞状态控制的改进理解，以开发出更强大的细胞重编程方法来生成IPS细胞。为了实现这些目标，该提案的具体目的是：1）结合并进一步开发出强大的实验和分析技术，这些技术可以识别ES细胞状态的新型调节剂并确定其全基因组的占用和功能； 2）确定在鼠和人ES细胞身份中起关键作用的新型转录因子，染色质调节剂和信号蛋白； 3）确定新颖的转录因子，染色质调节剂和信号蛋白如何有助于鼠和人ES细胞的多能性和自我更新； 4）使用细胞重编程测定法获得对细胞状态控制的见解，并开发出更强大的细胞重编程方法。这些研究对转录调节电路的了解得以提高，将导致对ES细胞状态的控制的新见解，揭示关键调节器如何控制ES细胞的基因表达程序，促进为操纵细胞命运的再生医学的努力，并为人类和其他脊椎动物和其他脊椎动物和其他脊椎动物和其他脊椎动物的进一步映射调节电路提供基础。