DIFFERENTIATION OF GRANULOCYTES AND MACROPHAGES

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The colony stimulating factors (CSFs) which regulate the production and activity of granulocytes and macrophages are currently being used in extensive clinical trials on patients with defects in the production or function of these cells or in patients that are immunocompromised or to enhance the rate of hemopoietic recovery after cytotoxic therapies and/or bone marrow transplantation in patients with cancer. The long-term aims of this project are to understand in molecular detail the structures of the CSFs and their cellular receptors, the mechanisms by which CSFs deliver their signals to cells, the regulation of the production and action of CSFs in controlling granulocyte-macrophage populations and the molecular defects that underlie the behavior of malignant myeloid leukemic cells. The present application is to isolate CSF receptors from cells in a soluble form and to reconstruct the binding parameters seen in intact cells. While these studies will be carried out on purified receptors extracted from cells, major attempts will also be made to molecularly clone CSF receptors by screening expression libraries in COS cells with radioactive CSFs and autoradiography. If this is successful it will provide the means to analyze CSF receptor structures in detail and to determine, by receptor transfection studies, the components required for signal transduction. It is also proposed to analyze the development of myeloid leukemia in whole animal models that bear a striking resemblance to the human situation and to determine their responsiveness patterns to CSFs as well as the genetic alterations, that may involve CSF genes, leading to their malignant behavior. Finally, CSF expression and modulation will be examined in normal cells as well as a model of chronic GM-CSF exposure (in GM-CSF transgenic mice) that has relevance to the pathological effects that might be seen with CSF treatment in patients.