Structures of Protein Complexes Regulating Transcription in Enbryonic Stem Cells

调节胚胎干细胞转录的蛋白质复合物的结构

• 批准号: 7982305
• 负责人: ROBERT J FLETTERICK
• 金额: $ 120.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982305
• 关键词: Biochemical; Biochemistry; Bioinformatics; Biophysics; Cardiovascular Diseases; Cell Fate Control; Cells; Clinical; Complex; Data; Development; Disease; Drug Delivery Systems; Embryo; Genetic Transcription; Goals; Hospitals; Image; Institutes; Knowledge; Malignant Neoplasms; Methodist Church; Methods; Modeling; Molecular; Participant; Pathogenesis; Protein Structure Initiative; Regenerative Medicine; Research; Research Institute; Research Personnel; Site; Stem Cell Research; Stem cells; Structure; Tissues; X-Ray Crystallography; anticancer research; design; embryonic stem cell; induced pluripotent stem cell; novel; pluripotency; programs; protein complex; public health relevance; research study; self-renewal; three dimensional structure; tool

DESCRIPTION (provided by applicant): The major goal of this proposal is to reveal molecular mechanisms underlying formation and function of critical transcriptional assemblies essential to embryonic stem (ES) cells and cells with induced pluripotency (induced pluripotent stem (iPS) cells). Using bioinformatics and high throughput experimental methods, we will prepare defined domains of critical transcriptional factors controlling cell pluripotency and analyze them in their functional associations. Thousands of assemblies will be evaluated by biochemical and biophysical methods to identify the critical ones to be targeted by X-ray crystallography. We aim for determination of three-dimensional structures for about 100 stable multi-component transcriptional assemblies. Each of them will represent a partial image of complicated transcriptional machinery controlling the specific transcriptional landscape of pluripotent cells. We expect that thoughtful analyses of these structures will enable us to establish the proper connections between these partial images and reconstruct a general model for function of critical participants of this transcriptional machinery. We will justify this model and the observed regulatory interactions within identified transcriptional complexes in mutational and functional studies using iPS cells. The experiments are to be done at multiple sites: The Methodist Hospital Research Institute (Houston), Department of Biochemistry and Biophysics at UCSF, the Gladstone Institute of Cardiovascular Disease (UCSF) and X-ray crystallography by the PSI labs. The proposed structural and functional studies will propel our general knowledge of the basic mechanisms controlling cell fate, including those underlying self renewal, differentiation and pathogenesis of cancer. The results of this research will also provide more efficient molecular tools allowing precise control over cell programming and reprogramming. The accumulated structural and functional data would be immediately available to biochemical and clinical researchers, and therefore, would have a major impact on stem cell research as well as regenerative medicine. PUBLIC HEALTH RELEVANCE: The proposed studies on embryonic and reprogrammed stem cells will reveal parts of the complex mechanisms controlling cell fate, including those underlying self renewal, differentiation, and development of cancer. The results of our research will provide more efficient molecular tools allowing precise control over cell programming and reprogramming. The images and concepts that we produce will have immediate impact on regenerative medicine as well as stem cell and cancer research.

描述（由申请人提供）：该提案的主要目标是揭示具有诱导多能性（诱导多能茎（IPS）细胞）的临界转录组件（ES）细胞（ES）细胞（ES）细胞（ES）细胞（ES）细胞（ES）细胞所必需的关键转录组件的基础机制。使用生物信息学和高吞吐量实验方法，我们将准备控制细胞多能性的关键转录因子的定义域，并在其功能关联中分析它们。数千个组装将通过生化和生物物理方法评估，以识别X射线晶体学针对目标的关键方法。我们的目标是确定 大约100个稳定的多组分转录组件的三维结构。它们每个都将代表控制多能细胞特定转录景观的复杂转录机械的部分图像。我们希望对这些结构进行周到的分析将使我们能够在这些部分图像之间建立适当的连接，并重建该转录机械关键参与者功能的一般模型。我们将在使用IPS细胞的突变和功能研究中，在已鉴定的转录复合物中观察到的调节相互作用是合理的。这些实验应在多个地点进行：卫理公会医院研究所（休斯顿），UCSF生物化学和生物物理学系，PSI实验室的Gladstone心血管疾病研究所（UCSF）和X射线晶体学研究所。提出的结构和功能研究将推动我们对控制细胞命运的基本机制的一般知识，包括那些基本的自我更新，分化和发病机理的基本机制。这项研究的结果还将提供更有效的分子工具，从而可以精确控制细胞编程和重编程。累积的结构和功能数据将立即用于生化和临床研究人员，因此将对干细胞研究以及再生医学产生重大影响。 公共卫生相关性：关于胚胎和重编程干细胞的拟议研究将揭示控制细胞命运的复杂机制的一部分，包括那些基本的自我更新，分化和癌症发展的人。我们的研究结果将提供更有效的分子工具，从而可以精确控制细胞编程和重编程。我们产生的图像和概念将对再生医学以及干细胞和癌症研究产生直接影响。