circRNA_Fnbp4靶向miR-342-5p调控突触前膜mGluR5表达在化疗外周神经损伤中的作用机制

Chemotherapy-induced peripheral neuropathy (CIPN) seriously affects the patients’ life quality and restricts anticancer therapy, but its mechanism is still unclear. Our studies demonstrated that paclitaxel increases glutamate release via presynaptic mGluR5, but the upstream of mGluR5 needs to be elucidated. RNA-seq found a new circRNA circ_Fnbp4 whose expression is up-regulated in CIPN rats’dorsal root ganglion, and correlates with mGluR5 expression and pain positively; bioinformatic analysis suggests that circ_Fnbp4’s sequence contains miR-342-5p microRNA response elements; miR-342-5p shows reverse-correlation with circ_Fnbp4 and mGluR5 in expression. Thus we suppose that circ_Fnbp4 upregulates mGluR5 expression in CIPN through targeting miR-342-5p. In this study, the methods of in vitro and in vivo are utilized to explore the mechanisms of circ_Fnbp4/ miR-342-5p/mGluR5 axis in CIPN. Our study will provide evidence for the better understanding of CIPN and developing new path for CIPN treatment.

化疗外周神经病变（CIPN）严重影响患者生活质量，制约治疗，其机制未明。申请人首次报道紫杉醇通过突触前膜mGluR5增加谷氨酸释放，而mGluR5调控机制尚不清楚。经RNA测序发现新环状RNA circ_Fnbp4在CIPN大鼠背根神经节特异高表达；qPCR验证其与mGluR5表达和疼痛正相关；生信分析显示circ_Fnbp4序列含miR-342-5p反应元件；而miR-342-5p表达与circ_Fnbp4负相关并靶向抑制mGluR5表达。据此，我们提出“circ_Fnbp4靶向miR-342-5p调控mGluR5促进CIPN”的科学假设。本项目拟通过一系列的体内外研究，深入探究并揭示circ_Fnbp4/miR-342-5p/mGluR5轴在CIPN发生发展中的作用及其机制，为将来临床靶向circ_Fnbp4缓解CIPN的可行性提供实验研究的基础，具有重要的理论意义及临床价值。

化疗外周神经病变（CIPN）严重影响患者生活质量，制约治疗，其机制未明。本研究通过对3对CIPN组与空白对照组大鼠的脊髓背角组织进行测序，获得circRNA、lncRNA、miRNA和mRNA的表达差异情况，22个lncRNA和7个circRNA被预测参与lncRNA-miRNA-mRNA和circRNA–miRNA–mRNA的ceRNA机制。其中miR-15b-5p, miR-206-3p, miR-223-3p和miR-363-3p上调最明显，Mpz下调最明显。Mpz是一种编码I型跨膜糖蛋白的蛋白编码基因，它可以作为一种对周围神经系统中致密髓磷脂形成至关重要的嗜同性粘附分子。RT-qPCR验证了Mpz在CIPN组的特异性低表达，过表达Mpz可显著缓解CIPN组小鼠的疼痛。为进一步明确机制，我们利用单细胞数据发现Mpz特异在施万细胞上表达。本研究为诠释CIPN的分子机制和寻找靶向治疗提供科学依据。

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