miRNA-448介导STAT5上调在奥沙利铂诱导中枢敏感化和痛觉过敏中的作用及机制

奥沙利铂诱导的痛觉过敏是制约其治疗肿瘤的重要原因，但机制不清，目前尚无有效防治手段。高通量预实验发现奥沙利铂诱导可能调控STAT5 mRNA的miRNA-448显著下调，脊髓背角STAT5蛋白上调，且STAT5 mRNA的水平不改变，然而miRNA-448如何介导STAT5上调，且STAT5如何参与痛觉过敏尚不清楚。我们还发现：鞘内注射STAT5抑制剂ON146040可显著抑制奥沙利铂诱导的脊髓背角Nav1.3表达上调。提示：上调的STAT5可能通过表观遗传学机制促进Nav1.3基因的转录，从而诱导痛觉过敏，相关内容目前并无文献报道。本项目拟在体内和体外实验中：1）明确miRNA-448促进STAT5表达在痛觉过敏中的作用及机制；2）探讨STAT5介导Nav1.3表达上调在痛觉过敏中的作用及机制。本项目研究将为防治化疗药诱导的痛觉过敏提供新的靶点。

Oxaliplatin-induced allodynia is a common side effect limiting the treatment of cancer. Since the mechanism is unclear, there are no effective prevention and treatment measures. miRNAs microarray analysis revealed that oxaliplatin-induced downregulation of miRNA-448 may contribute to increase the STAT5 expression whereas STAT5 mRNA was unaltered. Intrathecal injection of STAT5 inhibitor significantly attenuated oxaliplatin-induced pain. However, the mechanism of miRNA-448 increased the expression of STAT5 and the role of STAT5 in the oxaliplatin-induced neuropathy remained unclear. In the present study, we found that intrathecal injection of STAT5 inhibitor suppressed the oxaliplatin-induced upregulation of Nav1.3. These results indicate that increased STAT5 may through the epigenetic regulation promoted the expression of Nav1.3 mediated oxaliplatin-induced central sensitization and allodynia. This project proposed by in vivo and in vitro experiments: 1) clarify the role of miRNA-448/STAT5 signaling pathway in central sensitization and allodynia induced by oxaliplatin; 2) clarify the epigenetic mechanism underlying STAT5 in the upregulation of Nav1.3. The project will provide new evidence that help to elucidate the mechanism of oxaliplatin-induced pain.