This program is focused in the basic nature of the hematopoietic stem cell with a particular emphasis on the phenotype of that stem cell at different points in cell cycle and after exposure to different cytokines, focusing on both in vitro growth and differentiation and the capacity to engraftment and populate in vivo. Our overall hypothesis is that the basic phenotype of the hematopoietic stem cell may alter dependent upon phase of cell cycle. Responsiveness of the cell to cytokines, expression of adhesion proteins, transcriptional regulatory events in the capacity to engraft and populate in vivo may all directly relate to phase of cell cycle. Stem cells traversing cell cycle and exposed to various stimuli may commit to a specific lineage losing certain primitive phenotypic characteristics or may continue to traverse cell cycle and after the next division once again have the phenotype of a primitive engrafting stem cell. The Program Project consists of four projects around this general theme with three supporting cores. The first project focuses on engraftment potential, the relationship to cell cycle and the potential of establishing conditions to quiesce stem cells or to maintain dormant stem cells in an engraftable state. The second project focuses on the expression of adhesion proteins in both hematopoietic cell lines and explant stem cells in relationship to cell cycle and cytokine exposure. The third and fourth projects continue the these of cell cycle and cytokine phenotypic modulation in hematopoietic cell lines with explant stem cells focusing on the role of histone promoter regulation or the ID family of transcription regulators as determinance of decisions relating to renewal, proliferation or differentiation. These projects are supported by a stem cell core which will provide cells from cell lines and purified stem cells from explant marrow to investigators. This core will also synchronize the cell populations and provide synchronized cells to investigators. The gene expression core will provide expertise in in situ PCR and antisense techniques, assist in establishing retroviral producer lines and provide general support in a variety of molecular genetic approaches for each project. This Program Project promises to provide unique insights into the phenotype of marrow cells engrafting into nonmyeloablated hosts and the nature of that phenotype through different points in cell cycle and/or after exposure to different cytokines.
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