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职业迁徙
个人简介
The major focus of my laboratory has been to define the biological roles of colony stimulating factor-1 (CSF-1) and its receptor (CSF-1R) using biochemical, cell biological and mouse genetic approaches. We have identified both the growth factor and its receptor and elucidated the developmental and physiological roles of CSF-1, the CSF-1 isoforms and the CSF-1R, showing that they regulate the production of macrophages, osteoclasts, microglia, Langerhans cells, Paneth cells, the survival and differentiation of neural progenitor cells and play an important role in the development of leukemia and of several inflammatory diseases. We have shown that CSF-1 and the CSF-1R, via their regulation of tumor-associated macrophages enhance solid tumor progression. We have developed novel biochemical and genetic approaches to CSF-1R signal transduction to analyze CSF-1R structure/function, identifying and elucidating the function of several downstream signaling molecules, most recently, PSTPIP2, a negative feedback regulator of macrophage and osteoclast differentiation, in which we have described a mutation that leads to an autoinflammatory disease in mice. We have also elucidated the signaling pathway by which the CSF-1R regulates the suppression of the macrophage (M1) phenotype and enhances the trophic or repair (M2) phenotype. Current research in this area is focused on PSTPIP2 action.
Apart from our studies on CSF-1 and the CSF-1R in development and disease, we have pioneered studies of the Shark tyrosine kinase in Drosophila, elucidating the pathways Shark regulates during the processes of embryonic dorsal closure (epithelial sheet movement) and of recognition and engulfment of dying cells.
Our most recent studies have shown: 1) that a novel ligand for the CSF-1R, interleukin-34 (IL-34), similarly activates the CSF-1R, but has a different tissue and cellular expression pattern from CSF-1, 2) complete dependence of microglial development and maintenance on the CSF-1R, 3) that via the CSF-1R, CSF-1 and IL-34 directly suppress neural progenitor cell (NPC) self-renewal and enhance NPC survival and differentiation, 4) that IL-34, but not CSF-1, also acts via an additional receptor, protein tyrosine phosphatase zeta, which is also expressed on NPC, but not on microglia, 5) that the Csf1r+/- mouse is a model of an adult onset dementia known as adult onset leukodystrophy with axonal spheroids and pigmented glia (ALSP) that encompasses two other diseases, hereditary diffusleukoencephalopathy with axonal spheroids (HDLS) and familial pigmented orthochromatic leukodystrophy(POLD) and that is now termed CSF-1 receptor-related leukoencephalopathy (CRL), 6) that mouse CRL is a primary microgliopathy in which elevated cerebral GM-CSF and G-CSF levels enhance CRL development. Current research in this area is focused on the mechanisms underlying the development of CRL.
研究兴趣
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bioRxiv : the preprint server for biology (2024)
biorxiv(2024)
crossref(2023)
Frontiers in Cellular Neuroscience (2023): 1275935
crossref(2023)
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作者统计
#Papers: 427
#Citation: 51956
H-Index: 109
G-Index: 225
Sociability: 7
Diversity: 4
Activity: 35
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