Arp2/3复合物介导的核骨架重排在浆细胞发育中的作用及机制研究

浆细胞是抗体介导排斥（ABMR）的病理效应细胞，PAX5和BLIMP1是其发育中作用相互拮抗的转录因子，两者启动区均可受YY1和C/EBPbeta调控，但转录热点切换的机制不明。Rho GTPase家族中Cdc42和Rac1对B细胞向浆细胞分化具有决定作用，研究组前期研究证实抑制两者共同下游Arp2/3复合物可阻滞分化进程。Arp2/3通过催化肌动蛋白丝的分枝和交联启动细胞骨架重排，核内骨架运动可调节染色质结构和转录因子定位，但是否与浆细胞发育过程中转录热点切换相关未见报道。本项目通过干预浆细胞分化过程中Arp2/3所介导的核骨架重排，从转录因子移位和释放、染色质空间结构改变的双重机制角度，评估其对Pax5和Blimp1基因转录效能的调控，以及对浆细胞发育的影响，并在小鼠肾移植ABMR模型中探索Arp2/3复合物作为ABMR治疗靶点的可行性和有效性。

Plasma cells (PC) are the crucial effect cells of antibody mediated rejection (ABMR) in kidney transplantation. PAX5 and BLIMP1 are the transcription factors which play the essential and antagonistic roles in PC development. The promoter regions of PAX5 and BLIMP1 compatibly combine with YY1 and C/EBPbeta, while the mechanism(s) transcriptional hotspot switching is unknown. In Rho GTPase family, Cdc42 and Rac1 play a decisive role in the B cell differentiation progress into PC, who are both belonged within the Rho GTPase family. Arp2/3 complex is the public downstream of both Cdc42 and Rac1. The suspension of PC maturation has been seen by Arp2/3 complex blocking in our previous study. Arp2/3 complex initiates cytoskeleton rearrangement by catalyzing actin filament branching and cross-linking reactions. Nuclear skeleton rearrangement regulates both chromatin cis and trans dimension interacting structure and transcription factor movements. While whether Arp2/3 complex is related to transcription hotspot switching during plasma cell development is still in veil. In this project, the PAX5 and BLIMP1 transcriptional efficiency and chromosome conformation structure in related loci will be investigated by intervening Arp2/3 complex in PC differentiation process. Furthermore, the mice kidney transplant ABMR model will be employed to evaluate the therapeutic value of Arp2/3 complex blocking in ABMR pathological progress.