狼疮性肾炎（LN）严重威害人类健康，其主要发病机制是调节性T细胞（Treg）稳态失衡后发生表型漂移，免疫耐受破坏引发病理损伤。因此，基于提升Treg功能的免疫调控疗法有望成为治疗新手段。我们前期工作发现去泛素化酶USP21可通过抑制Foxp3泛素化维持Treg稳态，而LN患者外周血Treg中USP21表达下降。因此我们提出假设：USP21可能通过调控Treg稳态参与LN病理过程。本项目拟采用已建立的Treg特异性USP21敲除鼠制作LN模型，结合临床样本，首先明确USP21去泛素化修饰Foxp3，维持Treg稳态在LN发病中的作用；进而研究抑炎因子白血病抑制因子（LIF）通过促进USP21转录，对抗Treg向Th17发生表型漂移的机制；最后探讨新型纳米载体能否提高LIF在LN的疗效。该研究有望为LN的免疫治疗提供新的理论依据和治疗靶点，改善LN患者的临床愈后。

Lupus nephritis (LN) is a life-threatening disease. One of the key pathologic changes of LN is the imbalance of regulatory T cells (Tregs) induced immune tolerance damagment. Therefore, novel immunotherapy which targeted on Treg might be a potential treatment option for LN. Our previous investigation demonstrated that ubiquitin-specific protease (USP21) could regulate the expression of Foxp3 via inhibiting its ubiquitination, in consequence, stabilizing the Foxp3+Tregs. And the level of USP21 in Treg cells from LN patients’ peripheral blood is lower than healthy control. Therefore, we hypothesize that USP21 may participate the LN pathology by regulating the homeostasis of Treg. In this project, we intends to use the estabilished Treg-specific USP21 knockout mice (USP21fl/flFoxp3cre) to induce LN model, together with the clinical samples. We’ll first to investigate the USP21 de-ubiquitination modification of Foxp3 in the pathogenesis of LN; and then study the role of proinflammatory cytokine leukemia inhibitory factor (LIF) promotion of USP21 transcription in inhibition of the phenotype shifting from Treg to Th17 cells. Finaly, we’ll explore if the new nano-carrier can improve the efficacy of LIF in the treatment of LN. Our project will provide new therapeutic evidence and molecular targets of LN, and hence obtaining more clinical benefits.