新型肾移植急性排斥标志物lncRNAs的筛选及调控机制研究

Renal transplantation is the main way to treat end-stage renal diseases, and acute rejection is still a major obstacle in long-term allograft survival. The ʻgold standardʼ for clinical diagnosis of acute rejection in patients with kidney transplants is based on histological classification of a graft biopsy. So, it is urgent needed to establish a non-invasive and high specific testing scheme for monitoring survival condition of transplanted kidneys. It was reported that candidate lncRNAs displaying differential expression in acute rejec¬tion biopsy samples, suggesting that expression of lncRNAs was associated with acute rejection. However, expression signatures of lncRNAs in peripheral blood of patients with kidney transplants and the underlying mechanisms were still unclear. Our early study show that, by means of increasing recipients Tregs’ functions, allograft survival was prolonged and acute rejection was alleviated. Meanwhile, it was suggested that lncRNA could affect Tregs related Foxp3 exression. In this study, we will use arraystar gene chip technology to detect dynamic expression spectrum of lncRNA in peripheral blood of patients with transplanted kidney, and then screen biomarker of acute rejection. After that, we will explore relationship between dynamic expression level of lncRNA and Tregs’ functions and Foxp3 expression level in recipients. Impact of LncRNA biomarkers on functions of Tregs and allograft survival will then be analyzed by silencing or overexpressing lncRNAs in Tregs. In order to provide theoretical basis for establishing non-invasive and high specific testing scheme for monitoring survival condition of transplanted kidneys.

肾移植是临床治疗终末期肾脏疾病的重要手段，而急性排斥反应仍是影响移植肾存活率的主要难题。术后监测移植肾生存状态的金标准仍依赖穿刺活检，因此临床亟需非侵入性、高特异性监测移植肾生存状态的检验标志物。研究表明在急性排斥期活检病理切片中多种lncRNA具有动态表达趋势，表明lncRNA与急性排斥反应具有相关性，而关于lncRNA在肾移植患者外周血的表达情况及其调控急性排斥反应的机制尚不清楚。我们前期研究发现应用药物增强移植受体Treg细胞功能可减轻急性排斥反应；而有研究表明lncRNA可通过上调Foxp3表达增强Treg细胞功能。因此我们拟利用基因芯片技术分析肾移植患者外周血lncRNA表达谱，筛选急性排斥反应的生物标志物，然后探讨lncRNA的表达水平对移植受体Treg细胞功能、Foxp3表达及对移植物存活状态的影响。以期为建立非侵入性、高特异性监测急性排斥反应的检验方案奠定理论基础。