他克莫司广泛应用于器官移植和自身免疫性疾病，但疗效存在明显的个体差异。影响药动学和药效学的基因多态性是疗效差异的主因，前者可以通过血药浓度监测来规避，后者对药效的影响更重要更复杂。在前期研究中我们发现他克莫司的作用靶点钙调神经磷酸酶的调节亚基α亚型基因（PPP3R1）的单核苷酸多态性位点（rs875）存在T>C有效突变，上调 PPP3R1表达，降低他克莫司疗效，该位点正好位于miR-582-5p调控 PPP3R1的靶序列中，并证实其突变导致miR-582-5p脱靶。本项目将进一步从体外和体内两个层面在T细胞和足细胞中验证rs875 T>C突变抑制miR-582-5p下调PPP3R1表达，影响钙调神经磷酸酶活性，从而降低他克莫司疗效。以上基础研究将从基因水平揭示他克莫司疗效个体差异的本质，为下一步临床前瞻性研究该位点对疗效的预测价值提供理论依据，有望借此指导临床用药，实现个体化治疗。

Tacrolimus is widely used in the treatment of allograft rejection and autoimmune diseases. Large interpatient variability is shown in the effect of tacrolimus, the major reason of which is the polymorphisms of genes involved in its pharmacokinetics and pharmacodynamics. To some extent, the effect of genetic variants in proteins involved in drug metabolism and distribution can be avoided because of the therapeutic drug monitoring (TDM). Therefore, to better understand variable tacrolimus drug response, variants of genes encoding for the pharmacologic targets are more important and complex. Previously, we found that a SNP (rs875 T>C) in the gene (PPP3R1) which encodes tacrolimus drug target (calcineurin) was a functional polymorphism. It led to tacrolimus resistance through the upregulation of PPP3R1. The mutation of this SNP, which is located in the miR-582-5p binding site in the 3'UTR of PPP3R1, proved to influence the function of miR-582-5p. In this study, we will investigate whether rs875 (T>C) leads to tacrolimus resistance through the suppression of the downregulation of PPP3R1 by miR-582-5p and the effect on the activity of calcineurin in T cells and podocytes in vitro and in vivo. This research will help us to know the underlying reasons for the variability of tacrolimus drug response. The next prospective clinical study which focuses on the prediction value of this SNP on drug effect is also based on it. We hope that the results can instruct the clinical practice of tacrolimus, realizing the individualized treatment.