The long term goals of this project are to understand the events which regulate the production of myeloid lineage cells from hematopoietic stem cells. Normal, non-infected, humans produce about 2 x 10/9 neutrophils per kilogram of body weight simply to replenish basal neutrophil loss each day. This makes the mass of myeloid precursor cells in the marrow one of the most actively proliferating tissues in the body. The events which regulate proliferation of myeloid cells at all levels are precise, complicated, flexible, and subject to may levels of controls. There is increasing evidence that both humoral and cell-associated cytokines provide much of the regulation of myeloid cell proliferation, influence patterns of differentiation, control traffic of mature and immature cells, and influence functions of mature neutrophils, monocytes, eosinophils & basophils. An interplay between groups of growth-promoting cytokines and growth-inhibitory cytokines helps to determine whether stem cells become committed to the myeloid lineage, whether myeloid precursor cells proliferate or become quiescent, how long it takes to generate a neutrophil from a stem cell, and even how long both precursor cells and neutorphils will live. There are a large number of cytokines which are believed to have a regulatory effect on myelopoiesis, at least in inflammatory situation, including G-CSF, GM-CSF, IL-3, IL-1, IL-5, IL-6, SCF, and others. Over the initial five years of this grant (1984-88), our aims were to identify the major cytokines affecting myelopoiesis and determine their major biological properties first in vitro, and then in vivo in human subjects. Over the last five years of the grant (1989-93), our aims were to identify the receptors for the major myeloid growth factors, begin to understand how these cytokines interact physically with their receptors, and identify the initial elements of receptor signaling. Over the next grant period, we propose to investigate in detail how signals travel from cytokine receptors to the nucleus, how positive and negative signals are integrated in hematopoietic cells, and how these different cytokines and their receptors function together in the context of the whole cell, and ultimately the whole animal, to regulate myelopoiesis. To this end, we will be increasingly using techniques which specifically block or augment selected avenues of signal transduction in intact cells, and later in animals, to dissect the functional pathways of signaling which control hematopoietic cell growth and function. It is anticipated that these studies will result in an improved understanding of how myelopoiesis is regulated at a molecular level. These studies should be further useful in understanding how abnormalities of growth regulatory processes contribute to the pathogenesis of a number of human myeloproliferative disorders such as AML, CML, juvenile CML, polycythemia vera, and marrow failure syndromes.
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