我们前期的研究已经证实,KCNQ/M钾通道在DRG神经元的下调可以引起神经元的超兴奋性和骨癌痛。研究表明,转录抑制因子REST对许多神经元的基因表达起着重要的负性调控作用。我们的研究发现,在骨癌大鼠的DRG中,KCNQ2和KCNQ3的mRNA水平显著降低而REST的表达却显著增加,提示上调的REST可能通过对KCNQ 的转录抑制而引起骨癌痛。有研究报道IGF-I可以上调REST的表达。我们的研究也发现IGF-I在骨癌大鼠的DRG中升高且与骨癌痛的发生有关。本项目拟通过以下研究来进一步明确KCNQ/M通道在骨癌大鼠下调的分子机制及其在骨癌痛中的作用：1)REST对KCNQ转录抑制的分子机制及其在骨癌痛中的作用；2)IGF-I对REST的上调作用及其信号通路；3)由IGF-I上调REST所介导的KCNQ转录抑制在骨癌痛中的作用。该研究将有助于阐明骨癌痛的发病机理,为骨癌痛的药物治疗提供新靶点。

Our previous studies have documented that the down-regulated KCNQ/M channels in cancer rat DRG neurons contributed to the hyperexcitability of the nociceptive DRG neurons and to the cancer-induced bone pain. It is well accepted that the transcription factor REST functions as a repressor for the regulation of neural-specific gene expression. In our pilot study, we have found that in cancer rat DRGs, the mRNA levels of KCNQ2 and KCNQ3 decreased significantly, whereas the expression of REST mRNA and protein increased dramatically, indicating that the up-regulated REST likely resulted in the bone cancer pain via the transcription repression to KCNQ genes expression. In a recent study, the authors have found that IGF-I can elevate the REST expression. Our preliminary experimental results also showed that the expression of IGF-I and its receptor IGF-IR increased markedly in cancer rat DRGs, and the elevated IGF-I likely caused the bone cancer pain through its receptor IGF-IR. On the basis of these findings, we plan to investigate the mechanisms underlying the down-regulated KCNQ/M channels in cancer rat DRG neurons as well as their roles in the bone cancer pain. We will carry out the following studies to validate: (1) the transcriptional repression of KCNQ genes by REST and its contribution to the development of bone cancer pain, and the mechanisms underlying the transcriptional repression of KCNQ genes by REST; (2) Up-regulation of REST by IGF-I and its potential signaling pathway(s); (3) roles of the transcriptional repression of KCNQ genes by IGF-I-upregulated REST in the development of peripheral sensitization and the bone cancer pain. This study will be beneficial to elucidate the pathogenic mechanisms of bone cancer pain, and provide new target for the treatment of bone cancer pain.