Cells of the myeloid lineage play critical roles in both innate and adaptive immunity. This application is designed to elucidate the role, molecular mechanism of action and regulation of B Lymphocyte Induced Maturation Protein-1 (Blimp-1) in myeloid lineage cells. Blimp-1 is a zinc finger-containing transcriptional repressor that is known to play a key role in commitment and differentiation of B lymphocytes to plasma cells. However, our recent studies have shown that Blimp-1 is also expressed in monocytes and granulocytes and induced upon macrophage differentiation of promyeloid lines and primary bone marrow progenitors. Furthermore, it is required and sufficient to trigger macrophage differentiation of U937 promonocytes. Therefore, Blimp-1 is likely to be a critical regulator of macrophage differentiation and function and may also be important for the differentiation and/or function of other myeloid lineage cells. The project has three specific aims. First, we will use gene targeting and expression of inhibitory forms of Blimp-1 to determine the ability of myeloid cells to differentiate and function in the absence of Blimp-1. These studies are designed to establish the role of BLIMP-1 in macrophages, granulocytes and myeloid dentritic cells. Second, we will exploit microarray technology to characterize Blimp-1 -dependent programs of gene expression during macrophage and granulocyte differentiation. Further studies will be performed to identify direct targets of Blimp-1 and to compare them among myeloid and B lymphocyte lineages. Finally, the signals and mechanisms responsible for regulation of Blimp-1 expression in myeloid cells will be studied.
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