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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

基本信息

批准号：
8244607
负责人：
JIaqian Wu-Huber
金额：
$ 2.42万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2011-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8244607
关键词：
Integrated Analysis Hematopoietic Precursor Self

项目摘要

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）：我是耶鲁大学Michael Snyder博士实验室的Ruth L. Kirschstein国家研究服务奖博士后。我之前的培训重点是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。在未来的职业发展中，我将在造血学、功能基因组学、蛋白质组学、大规模数据整合和网络建设等方面获得实验和计算层面的深入训练。耶鲁大学基因组学和蛋白质组学中心优秀的培训环境，加上我的共同导师Sherman Weissman博士和顾问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展开独立的学术研究生涯。我的五年研究计划的目标是通过整合基因组学和蛋白质组学方法，以小鼠EML（红系、髓系和淋巴细胞）多电位造血前体细胞为主要模型，对细胞自我更新和分化产生一种新颖而全面的观点。EML细胞是大规模研究早期造血分化分子调控的理想细胞。EML细胞产生自我更新的CD34+前体细胞和部分分化的非更新的CD34-细胞。大量EML细胞可以在没有解剖生态位的情况下在体外生长和分化。基于我对差异基因表达谱和转录因子结合Chip-chip的初步研究，我假设在转录调控网络中存在关键调控因子（如：TCF7， RUNX1和GATA2），决定了EML细胞自我更新和分化的选择。具体而言，我建议利用基因表达和蛋白质组学数据，在全球范围内确定控制这些过程的关键转录调控因子，以指导转录调控工作。结合靶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控。随后，我将把我们的基因组学、蛋白质组学、磷酸化的数据和文献整合到转录因子结合网络中，进一步构建一个全球性的相互作用网络。最后，我将确认在人类造血前体细胞中的关键发现。相关性（见说明）：这些EML细胞的研究将证明干细胞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，在体外复制和分化造血干细胞。因此，本研究对白血病的公共卫生和治疗具有重要的价值。