MOLECULAR BIOLOGY OF HEMOPOIETIC STEM CELLS

本项目的目标是研究造血干细胞的分子生物学，重点是分析在干细胞增殖、分化和定型中起重要作用的干细胞基因。该计划项目包括四个项目和四个核心单元。项目1的研究人员已经克隆和测序了数千个在干细胞和早期祖细胞中表达的基因，他们现在提出开发策略，允许对这些基因进行功能分析。将测定逆转录病毒转导的胎儿干细胞的自我更新、定型、增殖潜力，并鉴定需要二聚化才能发挥功能的干细胞调节剂。项目2利用最近开发的二聚化技术来探讨干细胞自我更新和分化的问题。他们将表征参与干细胞扩增的GCSF受体的mpl特征，并测试这些受体的瞬时激活是否影响干细胞发育命运。项目3的目标是定义循环造血（CH）的分子基础，这是一种代表哺乳动物发育时钟原型的条件。该项目的研究人员已经将CH基因定位在19号染色体的900 Kb区域，并提出了克隆该基因、确定其功能和探测其产生CH表型的机制的策略。项目4的目标是克隆基因，这些基因的突变产生家族性白血病，其特征是具有惊人的预期程度。产生家族性白血病和血小板异常综合征的基因已被定位在21号染色体的3 Mb区域，而另一个引起家族性白血病和血小板异常的基因已被定位在16号染色体上。这四个项目由四个核心单位提供支助。核心单元A是项目的行政核心。核心单元B-遗传作图单元-将协助项目3和4绘制周期性造血和家族性白血病基因。核心单元D是转基因/敲除小鼠设施。我们希望我们的研究将为干细胞生物学和哺乳动物发育时钟生物学提供重要见解。

The goal of this program project is to investigate the molecular biology of hemopoietic stem cells with emphasis on the analysis of stem cell genes that play an important role in stem cell proliferation, differentiation, and commitment. The program project consists of four projects and four core units. The investigators of Project 1 have cloned and sequenced several thousand genes which express in stem cells and early progenitors and they now propose to develop strategies which will permit the functional analysis of these genes. Retrovirally transduced fetal stem cells will be assayed for self-renewal, commitment, proliferative potential, and stem cell regulators which require dimerization for function will be identified. Project 2 exploits a recently developed dimerization technology to probe questions of stem cell self renewal and differentiation. They will characterize features of mpl of GCSF receptors that are involved in stem cell expansion and test whether transient activation of these receptors influence stem cell developmental fate. The goal of project 3 is to define the molecular basis of cyclic hematopoiesis (CH), a condition that represents a prototype of a mammalian developmental clock. The investigators of this project have mapped the CH gene on a 900 Kb region of chromosome 19 and propose strategies to clone the gene, determine its function, and probe the mechanisms whereby it produces the CH phenotype. The goal of Project 4 is to clone genes the mutation of which produce familial leukemia characterized by a striking degree of anticipation. A gene producing a syndrome of familial leukemia and platelet abnormalities has been mapped on 3 Mb region of chromosome 21 while another gene causing familial leukemia and platelet abnormalities has been mapped on chromosome 16. The four projects are supported by four core units. Core unit A is the administrative core of the program project. Core unit B-a genetic mapping unit-will assist projects 3 and 4 in the mapping of the cyclic hematopoiesis and familial leukemia genes. Core unit D is a transgenic/knockout mice facility. We expect that our studies will provide major insights into stem cell biology and the biology of mammalian developmental clocks.