Molecular Control of Hematopoietic Stem Cell Fate

描述（由申请人提供）： 该项目的总体目标是阐明造血干细胞独特生物学的基本机制。从最广泛的意义上说，该计划汇集了造血和干细胞生物学实验室专家与那些参与研究脊椎动物细胞生长，增殖和分化的关键途径。最近的造血研究已经确定了几种这样的途径的关键贡献，包括由Notch和Wnt受体家族激活的那些，其决定造血前体的自我更新和分化，以及Myc/Max/Mad网络的那些，其作用于Wnt和Notch途径的下游，其在转录水平上起作用以调节造血细胞生长和增殖。我们建议研究这些关键途径的机制：1）影响造血干细胞生长; 2）通过相互作用协调; 3）受泛素连接酶Fbw 7的影响，其功能调节Notch和Myc途径。在干细胞生物学的特定背景下，这些因素的知识的提高可能会提供机会，开发新的方法来指导造血和潜在的其他干细胞类型的自我更新和分化，并可能最终提供方法，以产生适当的细胞用于治疗目的。拟议的项目包括：Notch配体对造血干细胞命运的调节（项目1）; Myc和Mad转录因子在干细胞自我更新和分化中的功能（项目2）; Fbw 7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传导（项目4）。该计划成功的核心是细胞分离和定量移植核心，该核心将提供FACS分离的干细胞群、体内或体外分化的细胞群的表型分析以及定量移植测定，以允许对操作的干细胞群进行计数和功能评估。这一核心将使研究人员能够处理评估正在调查的途径的影响这一关键但耗时且困难的任务。行政核心将促进研究者之间的整体互动，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.