Role and Regulation of BLIMP-1 in Myeloid Cells

描述(申请人提供)：髓系细胞发挥关键作用 在先天免疫和获得性免疫中的作用。此应用程序旨在 阐明B的作用、作用的分子机制及其调控 髓系细胞中的淋巴细胞诱导成熟蛋白-1(Blimp-1)。 BLIMP-1是一种含有锌指的转录抑制因子，已知 在B淋巴细胞对血浆的承诺和分化中起关键作用 细胞。然而，我们最近的研究表明，Blimp-1也在 单核细胞和粒细胞对巨噬细胞分化的诱导作用 早幼粒系和原代骨髓祖细胞。此外，它是 需要并足以触发U937的巨噬细胞分化 原单核细胞。因此，Blimp-1很可能是一个关键的调节因子 巨噬细胞的分化和功能，可能对 其他髓系细胞的分化和/或功能。 该项目有三个具体目标。首先，我们将使用基因打靶和 Blimp-1抑制形式的表达对判断髓系细胞功能的作用 在没有Blimp-1的情况下细胞分化和功能。这些研究 旨在确定blimp-1在巨噬细胞、粒细胞和 髓系树突状细胞。第二，我们将利用微阵列技术来 巨噬细胞Blimp-1依赖的基因表达程序的特征 粒细胞分化。将进行进一步的研究，以确定 Blimp-1的直接靶点及其在髓系和B淋巴细胞中的比较 血统。最后，负责监管的信号和机制 BLIMP-1在髓系细胞中的表达将被研究。

DESCRIPTION (provided by applicant): 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.