Integrated Analysis of Hematopoietic Precursor Self-renewal and Differentiation

造血前体自我更新与分化的综合分析

• 批准号: 7661972
• 负责人: JIaqian Wu-Huber
• 金额: $ 9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661972
• 关键词: Acetylation; Advisory Committees; Binding; Binding Sites; Biology; CD34 gene; CD34+ precursor; Cells; Data; Environment; Erythroid; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genomics; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; In Vitro; Instruction; Literature; Lymphocyte; Maps; Mentors; Modeling; Modification; Molecular; Molecular Genetics; Mus; Myelogenous; National Research Service Awards; Nuclear Translocation; Organ; Phosphorylation; Postdoctoral Fellow; Process; Property; Proteins; Proteome; Proteomics; Public Health; RUNX1 gene; Research; Stem cells; Testing; Therapeutic; Tissue-Specific Gene Expression; Training; Transcriptional Regulation; Universities; Work; base; career; career development; data integration; functional genomics; genome-wide; hematopoietic stem cell fate; improved; insight; leukemia; novel; precursor cell; repaired; self-renewal; stem cell biology; therapy design; tissue regeneration; transcription factor

DESCRIPTION (provided by applicant): I am a Ruth L. Kirschstein National Research Service Award postdoctoral fellow in Dr. Michael Snyder's lab at Yale University. My previous training focused on molecular genetics and genomics, specifically genome-wide transcriptional mapping and novel gene characterization. During the proposed career development I will obtain in-depth training in hematopoiesis, functional genomics, proteomics, large-scale data integration and network construction on both experimental and computational levels. The excellent training environment in the Yale Center for Genomics and Proteomics in combination with my co-mentor Dr. Sherman Weissman and advisory committee's expertise in hematopoietic stem cell biology is uniquely suited for me to launch an independent academic research career in cell self-renewal and differentiation. The goal of my five-year research plan is to generate a novel and comprehensive view of cell self-renewal and differentiation by using integrated genomic and proteomic approaches and murine EML (Erythroid, Myeloid, and Lymphocytic) multipotential hematopoietic precursor cells as a primary model. EML cells are ideal for studying the molecular control of early hematopoietic differentiation at a large scale. EML cells give rise to the self-renewing CD34+ precursor cells and partially differentiated non-renewing CD34- cells. Large quantities of EML cells can be grown and differentiated in vitro in the absence of an anatomical niche. Based on my preliminary study of differential gene expression profiling, and of transcription factor binding using Chip-chip, I hypothesize that there are key regulators (such as: TCF7, RUNX1 and GATA2) in transcriptional regulatory networks that determine the choice between EML cell self-renewal and differentiation. Specifically, I propose to globally identify the key transcriptional regulators controlling these processes by using gene expression and proteomic data to guide the transcriptional regulation work. The binding targets and transcription factors will be assembled into regulatory networks, and I will identify target hubs and test for master regulators. Subsequently I will integrate our genomic, proteomic, phosphorylation data and literature into the transcription factor binding networks and further develop a global interaction network. Finally I will confirm key findings in human hematopoietic precursor cells. RELEVANCE (See instructions): These studies in EML cells will demonstrate fundamental properties of self-renewal and differentiation mechanisms available to stem cells which hold great promise in repairing or regenerating damaged tissues and organs. Molecular understanding gained through this study will hopefully improve our ability to direct hematopoietic stem cell fate by, for example, replicating and differentiating HSCs in vitro. Therefore, this study is highly valuable for public health and therapeutic purposes for leukemia.

描述（由申请人提供）：我是露丝L。耶鲁大学Michael Snyder博士实验室的Kirschstein国家研究服务奖博士后研究员。我以前的培训集中在分子遗传学和基因组学，特别是全基因组转录作图和新基因表征。在拟议的职业发展期间，我将在造血，功能基因组学，蛋白质组学，大规模数据集成和实验和计算水平的网络建设方面获得深入的培训。耶鲁大学基因组学和蛋白质组学中心的优秀培训环境，加上我的共同导师谢尔曼·韦斯曼博士和咨询委员会在造血干细胞生物学方面的专业知识，非常适合我在细胞自我更新和分化方面开展独立的学术研究。我的五年研究计划的目标是通过使用整合的基因组和蛋白质组学方法和小鼠EML（红细胞，髓细胞和淋巴细胞）多潜能造血前体细胞作为主要模型，产生细胞自我更新和分化的新的和全面的观点。EML细胞是大规模研究早期造血分化的分子调控的理想细胞。EML细胞产生自我更新的CD 34+前体细胞和部分分化的非更新CD 34-细胞。大量的EML细胞可以在没有解剖学小生境的情况下在体外生长和分化。基于我对差异基因表达谱的初步研究，以及使用Chip-chip对转录因子结合的初步研究，我假设在转录调控网络中有关键调控因子（如：TCF 7，RUNX 1和GATA 2）决定EML细胞自我更新和分化之间的选择。具体来说，我建议全球范围内确定关键的转录调控控制这些过程中使用基因表达和蛋白质组数据来指导转录调控工作。结合目标和转录因子将组装成调控网络，我将确定目标枢纽和测试主调节器。随后，我将整合我们的基因组，蛋白质组学，磷酸化数据和文献到转录因子结合网络，并进一步发展一个全球性的相互作用网络。最后，我将确认人类造血前体细胞的关键发现。相关性（参见说明）：EML细胞中的这些研究将证明干细胞可获得的自我更新和分化机制的基本特性，这些干细胞在修复或再生受损组织和器官方面具有很大的前景。通过这项研究获得的分子理解将有望提高我们指导造血干细胞命运的能力，例如，在体外复制和分化HSC。因此，本研究对公共卫生和白血病治疗目的具有很高的价值。