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.
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