USP25调控新月体肾炎早期Th17细胞分化的机制研究

glomerulonephritis (CGN) has a rapid onset and leads to rapidly progressive renal injury and poor prognosis. Th17 cell-mediated immune response mainly participates in the early stage of CGN, leads to more granulocyte infiltration, and cause massive proteinuria. IL-17 is the siganature cytokine of the Th17 cell, and IL-17-mediated signaling and inflammation can be regulated negatively by the ubiquitin-specific protease USP25. So we hypothesize that USP25 can ameliorate early lesions of CGN by inhibiting Th17 cell-mediated immune response. This project will study the regulation effect of Th17 differentiation in the early stage of CGN by exploring the relationship between USP25 and transcription factors in Th17 cell differentiation, using the gene regulation to change the expression of USP25, and further explore the specific mechanism of the regulation in Th17 cell differentiation by USP25. We will study the mechanisms of Th17 differentiation in the early stage of CGN from the gene regulation, which contributes to the crucial factors in activation of the immune responses in CGN and provides the basis for early intervention in immune responses and the amelioration of pathological damages.

新月体肾炎 (CGN) 起病急骤，肾功能急剧恶化，预后差。病变早期以Th17细胞介导的免疫反应为主，导致较多粒细胞浸润，引起大量蛋白尿。IL-17是Th17细胞特征性的炎症因子，泛素特异性蛋白酶25 (USP25) 能抑制IL-17介导的信号通路及炎症反应，由此，我们推测USP25能抑制Th17细胞介导的免疫反应从而减轻新月体肾炎的早期病变，通过探讨CGN早期USP25与Th17细胞分化的相关转录因子之间的关系，利用基因调控技术，调节USP25的表达水平，研究其在CGN早期对Th17细胞分化的调控作用，并进一步探讨USP25调控Th17细胞分化的具体机制。通过对CGN早期Th17细胞分化机制的研究，探讨CGN免疫反应活化的关键因素，为早期干预免疫反应，减轻病理损害提供理论依据。

新月体肾炎 (CGN) 临床表现以急进性肾炎综合征为主，在短期内出现少尿、无尿，肾功能急剧恶化，预后差。目前已明确CGN的病理进程，但对其发病机制的研究仍有待深入。病变早期以Th17细胞介导的免疫反应为主，导致Th17细胞快速增多、较多粒细胞浸润、新月体和大量蛋白管型形成，血肌酐和尿素氮迅速升高。Th17细胞特征性的炎症因子IL-17A及Th17细胞相关趋化因子CCL-2、CCL-20在脾脏和肾脏中均表达增多，与此同时，泛素特异性蛋白酶25 (USP25) 的表达则呈下降趋势。因此，我们利用MACS分离CD4+ T细胞，定向诱导Th17分化，发现分化后的Th17细胞表达USP25下降，且细胞荧光染色显示USP25表达于细胞核表面。另外，获取小鼠全长USP25 cDNA，构建USP25慢病毒载体，于定向分化前转染Th17细胞，发现Th17细胞增殖能力下降，分化比例减少，特征性转录因子RORγt表达下降。由此，我们推测USP25能抑制转录因子RORγt的表达从而抑制Th17细胞的功能，减轻由Th17细胞介导的免疫反应，为下一步有关新月体肾炎等Th17相关的自身免疫性疾病的临床治疗研究提供了新的药物靶点。