Transcriptional Regulation of the Immune Response

描述(申请人提供)：在目前的资助期间，我们发现了我们实验室分离的转录因子XBP-1，它是浆细胞分化和抗体产生所必需的。XBP-1是IRE1a(IRE1)的唯一底物，IRE1a是内质网跨膜内切核酸酶和激酶，介导未折叠蛋白反应(UPR)。我们的研究已经建立了浆细胞分化与UPR之间的联系。我们已经提供了证据，证明XBP-1在B细胞和腺泡细胞中具有扩大分泌机制的功能，并且在树突状细胞的存活中起重要作用。此外，XBP-1是蛋白酶体抑制剂治疗多发性骨髓瘤的主要靶点。XBP-1 FLOX/FLOX小鼠品系的可获得性以及在当前资助期产生的IRE/淋巴嵌合体将使我们能够探索IRE1、XBP-1和UPR在前B细胞(IRE1)和浆细胞(XBP-1)分化、在正常和恶性树突状细胞生存和功能、自身免疫性疾病和多发性骨髓瘤中的功能等许多悬而未决的问题。在下一个资助阶段，我们建议1)进一步探讨XBP-1在B细胞承诺中的作用。2)确定IRE1信号通路的新成分。3)研究XBP-1和UPR在正常和恶性树突状细胞(DC)中的作用。4)研究XBP-1在自身免疫性疾病中的作用。5)研究XBP-1在浆细胞肿瘤发生和增殖中的需求。

DESCRIPTION (provided by applicant): In the current funding period, we have discovered that the transcription factor XBP-1, isolated in our laboratory, is required for plasma cell differentiation and antibody production. XBP-1 is the only substrate of IRE1a (IRE1), the ER transmembrane endoribonuclease and kinase that mediates the Unfolded Protein Response (UPR). Our studies have established a link between plasma cell differentiation and the UPR. We have provided evidence that XBP-1 functions to expand the secretory machinery in B cells and acinar cells and is important in dendritic cell survival. Further, XBP-1 is a major target of proteasome inhibitors in the treatment of multiple myeloma. The availability of an XBP-1 flox/flox mouse strain as well as IRE-/- lymphoid chimeras generated in the current funding period will allow us to explore many unanswered questions about the function of IRE1, XBP-1 and the UPR in pre B (IRE1) and plasma cell (XBP-1) differentiation, in normal and malignant dendritic cell survival and function, in autoimmune disease and in multiple myeloma. In the next funding period we propose to 1) Further explore the role of XBP-1 in B cell commitment.2) Identify novel components of the IRE1 signaling pathway. 3) Investigate the function of XBP-1 and the UPR in normal and malignant dendritic cells (DCs). 4) Examine the role of XBP-1 in autoimmune disease.5) Investigate the requirement of XBP-1 for the development and propagation of plasma cell neoplasms.