: 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genes repressed by Blimp-1 and determine if Blimp-1 -dependent transcriptional repression is reversible when Blimp-1 is withdrawn.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.
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