Regulation of Granulocyte and Macrophage Production

Colony Stimulating Factor-1 (CSF-1) is the primary regulator of the survival, proliferation and differentiation of mononuclear phagocytes, including tissue macrophages and osteoclasts. These cells play critical roles in the development and function of the tissues in which they reside, in inflammatory diseases such as atherosclerosis, obesity, glomerulonephritis and arthritis. CSF-1-regulated macrophages have been shown to enhance tumor progression and metastasis and CSF-1 appears to have important autocrine and/or paracrine roles in neoplasias of the myeloid, lymphoid and female reproductive system. All of the effects of CSF-1 are mediated via the CSF-1 receptor (CSF-1R), a ~165-kDa tyrosine kinase encoded by the c-fms proto-oncogene. The PTPase SHP-1, the protooncoprotein Cbl, the macrophage F-actin-associated tyrosine-phosphorylated protein (MAYP) and the Dok (RasGAPp62) family members, Dok-1, Dok-2 and Dok-3 are among many proteins identified by the PI that are tyrosine phosphorylated in response to CSF-1 and which play important roles in CSF-1 signal transduction. The overall aim of this proposal is to study the mechanism by which CSF-1 transduces its signals for survival, proliferation, differentiation and function of the mononuclear phagocyte. The specific aims are: 1. To carry out a detailed structure-function analysis of the CSF-1 R in the macrophage. 2. To isolate of CSF-1 signaling complexes and elucidate their function. 3. To elucidate the role of MAYP in mononuclear phagocyte proliferation, differentiation and function. 4. To analyze of the role of Doks 1-3 in CSF-1 R signaling. Relevance to public health: Colony stimulating factor-1 (CSF-1) is a hormone that regulates the production and function of a tissue white cell known as the macrophage. CSF-1 and macrophages have been shown to enhance tumor metastasis and to play negative roles in a number of chronic inflammatory diseases, including atherosclerosis, obesity, glomerulonephritis and arthritis. The aims of this grant are to understand how CSF-1 regulates macrophage production and function at the molecular level in order to identify key molecules that can be inhibited in novel therapies for these diseases.