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.
|Endele, Max; Loeffler, Dirk; Kokkaliaris, Konstantinos D et al. (2017) CSF-1-induced Src signaling can instruct monocytic lineage choice. Blood 129:1691-1701|
|Caescu, Cristina I; Guo, Xingyi; Tesfa, Lydia et al. (2015) Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21. Blood 125:e1-13|
|Hiroyasu, Shungo; Chinnasamy, Prameladevi; Hou, Rong et al. (2013) Donor and recipient cell surface colony stimulating factor-1 promote neointimal formation in transplant-associated arteriosclerosis. Arterioscler Thromb Vasc Biol 33:87-95|
|Mouchemore, Kellie A; Sampaio, Natalia G; Murrey, Michael W et al. (2013) Specific inhibition of PI3K p110ýý inhibits CSF-1-induced macrophage spreading and invasive capacity. FEBS J 280:5228-36|
|Schlitzer, Andreas; McGovern, Naomi; Teo, Pearline et al. (2013) IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38:970-83|
|Nandi, Sayan; Cioce, Mario; Yeung, Yee-Guide et al. (2013) Receptor-type protein-tyrosine phosphatase ? is a functional receptor for interleukin-34. J Biol Chem 288:21972-86|
|Nandi, Sayan; Gokhan, Solen; Dai, Xu-Ming et al. (2012) The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation. Dev Biol 367:100-13|
|Hoeffel, Guillaume; Wang, Yilin; Greter, Melanie et al. (2012) Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med 209:1167-81|
|Groh, Janos; Weis, Joachim; Zieger, Hanna et al. (2012) Colony-stimulating factor-1 mediates macrophage-related neural damage in a model for Charcot-Marie-Tooth disease type 1X. Brain 135:88-104|
|Yu, Wenfeng; Chen, Jian; Xiong, Ying et al. (2012) Macrophage proliferation is regulated through CSF-1 receptor tyrosines 544, 559, and 807. J Biol Chem 287:13694-704|
Showing the most recent 10 out of 120 publications