The long term objective of this grant application is to identify, map, sequence and define in molecular terms the biochemical and biophysical changes that mediate the action of the human hormone granulocyte-- macrophage colony-stimulating factor on human neutrophils. This growth factor, which is released by several activated cells such as T lymphocytes, is an important stimulus for the proliferation of erythroid and myelomonocytic stem cells in vitro . In patients with AIDS, it increases the number of neutrophils, eosinophils and monocytes. It is also an important in vivo regulator of granulopoiesis and neutrophil function; it induces significant leukocytosis and shortens the period of neutropenia following bone marrow transplantation. The addition of this growth factor to mature human neutrophils primes these cells to subsequent stimulation by the chemotactic factor fMet-Leu-Phe. Thus, it plays an important role in the host defense. In spite of its importance very little is known about the mechanism of its action. In this work, particular emphasis will be placed upon delineating the differences in the action of GM-CSF and other stimuli on neutrophils in suspension versus attached to surface. Several techniques will be used and they include, among others, protein phosphorylation, superoxide generation, immunoblotting, binding, ADP-ribosylation, generation of phosphatidic acid and production of diacylglycerol.
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