Regulation of Granulocyte and Macrophage Production

Yeshiva University, New York NY

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): 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 addition, CSF-1 plays an important role in fertility via its direct regulation of testicular macrophages and cells of the female reproductive tract, including decidual cells, trophoblast, oocytes, embryonic cells as well as macrophages. Not surprisingly, therefore, CSF-1 -less mice have a pleiotropic phenotype. In addition, 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 protooncoprotein Cbl, the macrophage F-actin-associated tyrosine-phosphorylated protein (MAYP) and the Dok (RasAGAPp62) family members, Dok-1, Dok-2 and Dok-3 are among many proteins identified by the PI and others 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 structure-function analysis of the CSF-1 R in the regulation of mononuclear phagocyte survival, proliferation and differentiation. 2. To identify novel CSF-1 signaling complexes and elucidate their function. 3. To analyze the role of MAYP in the regulation of mononuclear phagocyte survival, proliferation, differentiation and function. 4. To carry out a structure-function analysis of Cbl in the macrophage. 5. To analyze the roles of Dok-1, 2 and 3 in CSF-1 R signaling.