USAG-1增强调节性B细胞抑制功能及其在肾移植AMR防治中的机制研究

抗体介导的排斥反应（AMR）是临床慢性移植肾失功的主因，调节性B细胞（Breg）有助于抵抗AMR发生，但如何定向增强Breg抑制功能尚未明确。我们运用转录组测序发现子宫致敏相关基因-1（USAG-1）可能通过USAG-1/Wnt3a/BMI1/KLF4通路增强Breg抑制功能；USAG-1激动剂可显著增强Breg抑制功能进而抑制滤泡辅助性T细胞（Tfh）功能。因此推测，上调USAG-1可增强Breg功能进而抑制Tfh辅助抗体产生功能最终防治AMR。本研究拟基于患者样本和转基因小鼠肾移植AMR模型，从临床、动物到细胞分子水平明确Breg中USAG-1表达与AMR相关性，证实USAG-1可增强Breg抑制功能，进而研究USAG-1影响Breg抑制功能的机制，并评估上调USAG-1对AMR的防治效果。预期成果有望阐明USAG-1增强Breg抑制功能的分子调控网，并找到防治肾移植AMR的潜在靶点。

Antibody-mediated rejection (AMR) is the main cause of clinically chronic kidney allograft dysfunction. Regulatory B cells (Breg) can prevent the occurrence of AMR after kidney transplantation, but the activation mechanism of Breg function is not clear and still need to be further investigated. Through transcriptome sequencing, we found that uterine sensitization-associated gene-1 (USAG-1) may promote the immunosuppressive cytokines secretion of Breg through the USAG-1/Wnt3a/BMI1/KLF4 pathway. As the agonist of USAG-1 can upregulate Breg function to inhibit the follicular helper T cell (Tfh) activation which is crucial for the antibody secretion. USAG-1 agonist might be a prevention and cure for AMR. Based on the clinical specimens data and in vivo AMR model using transgenic mice, we will illustrate the correlation between USAG-1 level in Breg and AMR, confirm USAG-1 role on enhancing the inhibitory function of Breg, explore the molecular mechanism of USAG-1-mediated Breg inhibition, and evaluate the effect of upregulation of USAG-1 on controling of AMR from clinical, animal to cell molecular level. Anticipated results will elucidate the molecular regulatory network of USAG-1-mediated Breg inhibition, and find a potential target for controling of AMR after kidney transplantation.