CXCL9/CXCR3介导的脊髓神经元-胶质细胞CROSS TALK在骨癌痛中的机制研究

Nearly 70% of cancer patients with advanced disease develop bone metastases that can lead to serious bone pain. The molecular mechanism of cancer induced bone pain (CIBP) is the hottest research spot nowadays. Evidence shows that neuron–glia cross talk play a crucial role in CIBP. Chemokines involved in the CIBP by mediated this cross-talk. Our previous work showed that the CXCL9/ CXCR3 up-regulate significantly in the rat spinal cord. Furthermore, some research illustrated that activation of glia by activate glia-expressed P2X7 receptors contribute to CIBP. We hypothesized that glia release CXCL9 which will conjugated the CXCR3 receptor on neuron, and then activate electrical activity of neuron by downstream signaling pathway. And, simultaneously actives neurons to release of ATP which act on P2X7 receptors in glial cells, making glial cells further activate and release CXCL9, which finally formed a feedback loop neuronal-glia crosstalk. Our group based on preliminary studies, using transgenic animals to build bone cancer pain model, via electrophysiology, molecular biology , gene regulation technology and other methods to confirm the above hypothesis. In order to help CIBP research and present a new target for potential pain relief drug development and future treatment options.

晚期癌症患者发生骨转移后约70%会出现慢性疼痛。骨癌痛分子生物学机制已成为当今研究热点，近期发现神经元-胶质细胞Crosstalk在骨癌痛机制中起着重要作用：趋化因子通过介导此Crosstalk参与慢性疼痛的发生。课题组前期研究发现骨癌痛小鼠脊髓组织CXCL9/CXCR3表达明显上调。同时有研究表明胶质细胞P2X7受体被激活后，可通过活化胶质细胞参与骨癌痛的产生。我们据此提出假说：在骨癌痛的发生过程中，胶质细胞释放CXCL9作用于神经元上的受体CXCR3，通过下游信号激活神经元电活动产生骨癌痛，同时激活的神经元释放ATP作用于胶质细胞P2X7受体，使胶质细胞进一步激活并释放CXCL9，形成神经元-胶质细胞Crosstalk环路。课题组拟在前期研究基础之上，利用转基因动物建立骨癌痛模型，采用电生理学、分子生物学及基因调控技术等方法证实上述假说，以期为骨癌痛的深入研究及靶向药物研发提供新方向。

晚期癌症患者发生骨转移后约70%会出现慢性疼痛。骨癌痛分子生物学机制已成为当今研究热点，近期发现神经元-胶质细胞Crosstalk在骨癌痛机制中起着重要作用：趋化因子通过介导此Crosstalk参与慢性疼痛的发生。课题组前期研究发现骨癌痛小鼠脊髓组织CXCL9/CXCR3表达明显上调。同时有研究表明胶质细胞P2X7受体被激活后，可通过活化胶质细胞参与骨癌痛的产生。本项目研究结果发现，在骨癌痛的发生过程中，胶质细胞释放CXCL9作用于神经元上的受体CXCR3，通过下游信号激活神经元电活动产生骨癌痛，同时激活的神经元释放ATP作用于胶质细胞P2X7受体，使胶质细胞进一步激活并释放CXCL9，形成神经元-胶质细胞Crosstalk环路。此外，我们还发现，骨癌痛情况下，Akt和ERK磷酸化水平均显著增加，分别给予Akt和ERK的抑制剂可以显著缓解骨癌痛，这说明Akt和ERK的激活在骨癌痛的发生与发展中起到至关重要的作用。本项目的研究成果为骨癌痛的治疗提供理论新的药物靶点。