The production of blood cells in the human marrow is regulated by a complex network of interacting cells and growth factors. A small number of self-renewing multipotent stem cells give rise to progenitor cells committed to single hematopoietic lineages. These commited progenitor cells in turn proliferate and differentiate to form granulocytes, monocytes, erythrocytes, platelets, and lymphocytes. The regulation of granulocyte production is of particular interest, both because of the tremendous baseline production of granulocytes each day and the extraordinary ability of marrow cells to respond to stress by increasing production of granulocytes up to 10 fold in a few hours. Production of granulocytes both in vitro and in vivo can be stimulated by a group of growth factors termed colony- stimulating factors (CSFs), of which 4 such human factors are known: IL-3, GM-CSF, G-CSF, and M-CSF. It is likely that the supply of these factors to marrow cells determines the net production of granulocytes or monocytes in many situations, including acute infections and possibly in steady-state hematopoiesis. However, very little is known about the cells which supply CSFs or about the factors which regulate CSF gene expression in these cells. It is the goal of this project to investigate the production of CSFs in a variety of human cell types, including monocytes, T cells, endothelial cells, fibroblasts, mesothelial cells, progenitor cells, and marrow stromal cells. Each of these cell types will be stimulated with a variety of cytokines and other factors, and CSF production will be investigated using mRNA detection (Northern blot and in situ hybridization) and by bioassays and immunoassays. Stimuli which induce CSF production will be further characterized by determining which directly induce gene transcription and which factors affect CSF mRNA stability. The information generated by this project will provide an improved understanding of the role of CSFs in myelopoiesis, the types of cells that regulate myelopoiesis, and the basic mechanisms of CSF gene regulation. This information will also be relevant to the understanding of diseases in which there is altered regulation of hematopiesis, including aplastic anemia, AML, myelodysplastic and myeloproliferative syndromes.
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