B Lymphocyte Induced Maturation Protein

描述（由申请人提供）：B淋巴细胞诱导成熟蛋白-1 （Blimp-1）是一种转录抑制因子，具有独特的特性，能够驱动B细胞分泌免疫球蛋白，不分裂，最终分化的浆细胞表型。在研究这种蛋白的过程中，我们的长期目标是：1)了解Blimp-1在末端B细胞分化过程中的功能；2)利用Blimp-1作为切入点，更好地了解决定生发后中心B细胞命运的调节机制；3)确定涉及末端分化的普遍机制。在目前的资助期内，我们在阐明Blimp-1的结构、调节和作用机制的基本方面以及在B细胞中确定由Blimp-1调节的基因表达程序方面取得了良好进展。我们还创造了基因靶向小鼠，这些小鼠将在成熟的B细胞中产生缺乏Blimp-1的动物。我们计划通过开展包含4个具体目标的深入研究来利用这一进展。1) B细胞中缺乏Blimp-1的小鼠将被用来确定是否/何时需要Blimp-1来承诺浆细胞的命运。将对B细胞的发育和功能进行彻底的分析，并测试Blimp-1突变体或其他转录因子（如XBP-1）补充Blimp-1-/-表型的能力。衰老小鼠将揭示Blimp-1在B细胞中是否具有肿瘤抑制活性。2)生发中心B细胞发育为记忆细胞或浆细胞的短期培养系统将用于研究Blimp-1和其他转录调节因子何时/如何在这些交替的命运中被诱导和发挥作用。我们将识别指示它们表达的信号。3)已建立的方法将用于确定来自IL-6、IL-10和TNF/TNFRs的信号是否/如何激活Blimp-1转录。4) Blimp-1的基因抑制机制可能不同寻常。我们将研究被Blimp-1抑制的靶基因中的DNA和组蛋白是如何被修饰的，并确定当Blimp-1退出时，Blimp-1依赖性转录抑制是否可逆。我们将纯化含有blimp -1的抑制复合物，并鉴定复合物的成分。

DESCRIPTION (provided by the applicant): B Lymphocyte Induced Maturation Protein-1 (Blimp-1) is a transcriptional repressor with the unique property of being able to drive B cells to an immunoglobulin secreting, non-dividing, terminally differentiated plasma cell phenotype. In studying this protein our long-term goals are to: 1) understand how Blimp-1 functions during terminal B cell differentiation, 2) use Blimp-1 as an entry point to gain a better understanding of the regulatory mechanisms responsible for determining post-germinal center B cell fates and 3) identify universal mechanisms involved in terminal differentiation. In the current grant period we have made good progress in elucidating basic aspects of Blimp-1 's structure, regulation and mechanism of action and in identifying gene expression programs regulated by Blimp-1 in B cells. We have also created gene-targeted mice that will give rise to animals lacking Blimp-1 in mature B cells. We plan to exploit this progress by carrying out in-depth studies consisting of 4 specific aims. 1) Mice lacking Blimp-1 in their B cells will be used to determine if/when Blimp-1 is required for commitment to plasma cell fate. A thorough analysis of B cell development and function will be performed and the ability of Blimp-1 mutants or other transcription factors like XBP-1 to complement the Blimp-1-/- phenotype will be tested. Aging the mice will reveal if Blimp-1 has tumor suppressor activity in B cells. 2) Short-term culture systems in which germinal center B cells develop into memory or plasma cells will be used to learn when/how Blimp-1 and other transcriptional regulators are induced and act during commitment to these alternate fates. We will identify signals that direct their expression. 3) Established approaches will be used to determine if/how signals from IL-6, IL-10 and TNF/TNFRs activate Blimp-1 transcription. 4) Blimp-1's mechanism of gene repression may be unusual. We will study how DNA and histones are modified in target genes repressed by Blimp-1 and determine if Blimp-1 -dependent transcriptional repression is reversible when Blimp-1 is withdrawn. We will purify Blimp-1-containing repression complexes and identify the components of the complexes.