IkB家族成员Bcl-3调控B细胞命运决定的机制研究

多种信号调控B细胞命运决定，其中BCR和NF-kB信号尤为重要。但对B细胞命运决定的机制还不甚明了。我们前期研究显示IkB家族成员Bcl-3能促进滤泡B（FOB）细胞发育，但负向调控B细胞向边缘区B（MZB）细胞发育。本研究将利用Bcl-3基因敲除小鼠和细胞特异性Bcl-3转基因小鼠进一步证实 Bcl-3在B细胞命运决定中的重要作用，从BCR信号、BCR诱导的细胞死亡及B细胞阴性选择等方面研究Bcl-3调控B细胞命运决定的机制，发现决定B细胞命运决定的关键因子，探索Bcl-3介导的表观遗传调控在该过程的作用机制，明晰Bcl-3在系统性红斑狼疮病理发生过程中作用机制。本项目将有助于阐明B细胞命运决定，B细胞选择及B细胞介导的自身免疫性疾病的病理生理过程的作用机制。

Many signalings are invovled in B cell fate decision, among which BCR and NF-kB signaling are critical. The mechanisms underlying MZB cell-fate decision remain unclear.Our previous study reveals that an atypical IkB family member Bcl-3 promotes follicular B cells development and negatively regulates the marginal zone B cell commitment. Based on these findings this project will employ Bcl-3 knockout mice and its B cell-specific transgenic mice to further confirm Bcl-3 function in B cell-fate decision. We will exmine the roles of Bcl-3 in BCR signaling, BCR-induced cell death and negative selection of B cells, and consequently understand the Bcl-3-mediated epigenetic regulation in B cell fate decision. After establishing mouse models of autoimmune diseases we will investigate whether and how Bcl-3 regulates the pathogenesis of autoimmune diseases such as SLE. This project will help shed light on B cell-fate decision and the mechanisms by which dysfunction of B cells contributes to pathogenesis of autoimmune diseases.