Molecular Control of Hematopoietic Stem Cell Fate

描述(由申请人提供)： 该计划项目的总体目标是阐明控制造血干细胞独特生物学的基本机制。在最广泛的意义上，这个项目汇集了造血学和干细胞生物学方面的实验室专家，以及那些参与研究对脊椎动物细胞生长、增殖和分化至关重要的途径的实验室。最近对造血的研究已经确定了几个这样的通路的关键作用，包括那些由决定造血前体自我更新和分化的Notch和Wnt受体家族激活的通路，以及那些作用于Wnt和Notch通路下游的Myc/Max/Mad网络的通路，它们在转录水平上调节造血细胞的生长和增殖。我们建议研究这些关键途径的机制：1)影响造血干细胞的生长；2)通过相互作用进行协调；3)受泛素连接酶Fbw7的影响，该酶的功能调节Notch和Myc途径。在干细胞生物学的特定背景下，对这些因素的了解的提高可能为开发指导造血干细胞和潜在的其他干细胞类型的自我更新和分化的新方法提供机会，并最终可能提供产生用于治疗目的的适当细胞的方法。建议的项目包括：Notch配体对造血干细胞命运的调控(项目1)；Myc和Mad转录因子在干细胞自我更新和分化中的作用(项目2)；Fbw7泛素连接酶对造血干细胞增殖和分化的协调控制(项目3)；Wnt和Notch信号通路的组合信号(项目4)。该计划成功的核心是细胞分离和定量移植核心，它将为FACS提供分离的干细胞种群、体内或体外分化的细胞种群的表型分析以及定量移植试验，以便对操纵的干细胞种群进行计数和功能评估。这一核心将使调查人员能够处理评估所调查路径的影响这一关键但耗时和困难的任务。行政核心将促进调查人员之间的全面互动，并监督核心服务与研究项目的整合。

DESCRIPTION (provided by applicant): The overall goal of this program project is elucidation of the fundamental mechanisms that govern the unique biology of hematopoietic stem cells. In the broadest sense, this program brings together laboratories expert in hematopoiesis and stem cell biology with those involved in studying pathways critical to vertebrate cell growth, proliferation, and differentiation. Recent studies of hematopoiesis have identified key contributions by several such pathways, including those activated by the Notch and Wnt receptor families which determine self-renewal and differentiation of hematopoietic precursors, and those of the Myc/Max/Mad network, acting downstream of the Wnt and Notch pathways, which function at the transcriptional level to regulate hematopoietic cell growth and proliferation. We propose to study the mechanisms by which these key pathways: 1) affect hematopoietic stem cell growth; 2) are coordinated through interactions with each other; and 3) are impacted by the ubiquitin ligase Fbw7, whose function regulates the Notch and Myc pathways. Improved knowledge of these factors in the specific context of stem cell biology may provide opportunities to develop novel approaches for instructing the self-renewal and differentiation of hematopoietic and potentially other stem cell types, and may ultimately provide methods to generate appropriate cells for therapeutic purposes. Proposed projects include: Regulation of Hematopoietic Stem Cell Fate by Notch Ligands (Project 1); Functions of Myc and Mad Transcription Factors in Stem Cell Self-Renewal and Differentiation (Project 2); Coordinate Control of Hematopoietic Stem Cell Proliferation and Differentiation by the Fbw7 Ubiquitin Ligase (Project 3); and Combinatorial Signaling by Wnt and Notch Signaling Pathways (Project 4). Central to the success of this Program is the Cell Separation and Quantitative Transplantation Core which will provide FACS isolated stem cell populations, phenotypic analyses of cell populations undergoing differentiation in vivo or in vitro and quantitative transplantation assays to allow enumeration and functional assessment of manipulated stem cell populations. This core will enable investigators to tackle the critical but time-consuming and difficult task of assessing effects of the pathways under investigation. Administrative Core will facilitate overall interaction among investigators, and oversee integration of Core services with research projects.