mir30d和mir137下调AMPK介导硼替佐米诱导痛觉过敏的作用及机制

Peripheral neuropathy induced by bortezomib treatment is an important clinical problem. Our recent studies found that AMPK agonist significantly attenuated the mechanical allodynia and IL-6 upregulation induced by bortezomib, but the underlying mechanism is not clear. Furthermore, preliminary experiment showed that bortezomib increased the mir137 and mir30d and downregulated the AMPK protein expression, but not affects the level of mRNA. In addition, mir137 mimic significantly decreased the expression of AMPK in HEK293 cells and mir30d inhibitor prevented the spinal LTP. These results implied that upregulation of mir137 or mir30d induced bortezomib via increased AMPK expression enhanced the IL-6 level, caused the central sensitivity and mediated mechanical allodynia. In this project, by in vivo and vitro method, we will explore: 1) The role of AMPK/IL-6 pathway in the central sensitivity and mechanical allodynia induced by bortezomib, 2) The epigenetic mechanism of mir137 or mir30d-mediated AMPK decrease. The objective of the research provides new targets for prevention and treatment of bortezomib-induced pathological pain for clinical.

硼替佐米治疗肿瘤诱发的痛觉过敏是困扰临床的一个重要问题。我们新近发现预先应用AMPK激动剂显著减弱硼替佐米诱导的痛觉过敏和脊髓IL-6上调，然而机制不清。预实验显示：硼替佐米显著下调AMPK蛋白的表达，但不影响mRNA的表达；高通量筛选显示硼替佐米明显脊髓上调mir30d和mir137，且脊髓局部应用mir30d inhibitor阻断脊髓背角LTP。离体实验进一步显示：mir137 mimic转染显著抑制HEK293细胞AMPK表达，提示硼替佐米通过诱导脊髓mir30d/mir137表达，调控AMPK表达，促进IL-6的合成与释放，诱导中枢敏感化，介导痛觉过敏。本项目拟通过体内和体外实验：1)明确AMPK/IL-6通路在硼替佐米诱导中枢敏感化及痛觉过敏中的作用；2)阐明mir30d/mir137调节AMPK的表观遗传学机制。本项目为阐明硼替佐米诱导痛觉过敏的发生机制提供全新的证据。

化疗药物硼替佐米使用诱发的痛觉过敏是困扰临床用药及治疗效果的一个重要问题。我们的研究发现预先脊髓应用AMPK激动剂显著缓解硼替佐米诱导的痛觉过敏和IL-6表达上调，然而机制不清。我们的实验结果显示：硼替佐米显著下调AMPK蛋白的表达，但不影响mRNA的表达；高通量筛选显示硼替佐米明显脊髓上调mir30d和mir137，且脊髓局部应用mir30d inhibitor阻断脊髓背角LTP。离体实验进一步显示：mir137 mimic转染显著抑制HEK293细胞AMPK表达，提示硼替佐米通过诱导脊髓mir30d/mir137表达，调控AMPK表达，促进IL-6的合成与释放，诱导中枢敏感化，介导痛觉过敏。本项目拟通过体内和体外实验：1)明确AMPK/IL-6通路在硼替佐米诱导中枢敏感化及痛觉过敏中的作用；2)阐明mir30d/mir137调节AMPK的表观遗传学机制。本项目为阐明硼替佐米诱导痛觉过敏的发生机制提供全新的证据。