趋化因子CXCL12/CXCR4信号通路在骨癌痛中枢敏化中的脊髓机制研究

The research and treatment of bone cancer pain is a major challenge for pain scientists and physicians in this field. The development of desired therapy methods and drugs depends on exploring the mechanisms of bone cancer painc. Spinal central sensitization is a key mechanism underlying the induction and maintenance of bone cancer pain. Neuronal sensitization and glial activation are theoretical foundation and research hotspot for central sensitization in the spinal cord. Our recent studies suggest that chemokine CXCL12 and its receptor CXCR4 could be involved in neuronal plasticity and glial activation. In this project, we will focus on the contributions of CXCL12/CXCR4 signaling pathway to the biological functions of multiple nerve cells from double aspects (in vitro and in vivo) and double levels (cell and molecule). In order to illuminate the regulating effects of CXCL12/CXCR4 axis on the neuronal plasticity and astrocytic/microglial activation via activating its downstream RhoA/ROCK signaling pathway. And verify the influence of this signaling pathway on pain behavior through specific intervention for related cells and molecules. This study, covering multi-cells function, multi-pathways activation and multi-targets intervention, is not only comprehensive but also profound. Therefore, we aim to reveal the spinal mechanisms of CXCL12/CXCR4-RhoA/ROCK signaling pathway in bone cancer pain regulation, and provide new target for intrathecal drug research and development.

骨癌痛是极具挑战的理论研究和临床课题，理想的治疗手段和药物研发依赖于对其机制的深入认识。脊髓水平中枢敏化是骨癌痛形成的关键环节，神经元敏化与胶质细胞激活是中枢敏化形成的理论基础。我们前期研究提示，趋化因子CXCL12及其受体CXCR4可能组成性地参与神经元敏化与胶质细胞激活。本项目拟以“CXCL12/CXCR4信号通路同时调控多种神经细胞功能”为切入点，从两个方面（离体和在体水平）和两个层次（细胞和分子水平），阐明脊髓CXCL12/CXCR4轴通路介导胞内RhoA/ROCK信号通路对神经元兴奋性，及星型胶质细胞和小胶质细胞激活的调节作用。并通过特异性干预相关细胞和分子，验证该信号通路对骨肿瘤相关疼痛行为的影响。实现“多细胞功能—多通路激活—多靶点干预”的研究纵深。旨在全面揭示CXCL12/CXCR4-RhoA/ROCK 信号通路参与骨癌痛调控的脊髓机制，并为靶向脊髓的药物研发提供新的靶标。

骨癌痛是极具挑战的理论研究和临床课题，理想的治疗手段和药物研发依赖于对其机制的深入认识。脊髓水平中枢敏化是骨癌痛形成的关键环节，神经元敏化与胶质细胞激活是中枢敏化形成的理论基础。本项目拟以“CXCL12/CXCR4信号通路同时调控多种神经细胞功能”为切入点，从两个方面（离体和在体水平）和两个层次（细胞和分子水平），阐明脊髓CXCL12/CXCR4轴通路介导胞内CaMKII/CREB、RhoA/ROCK、ALK5/Smad3信号通路对神经元兴奋性，及星型胶质细胞和小胶质细胞激活的调节作用。实现“多细胞功能—多通路激活—多靶点干预”的研究纵深。揭示CXCL12/CXCR4信号通路参与骨癌痛调控的脊髓机制，并为靶向脊髓的药物研发提供新的靶标。