树突膜特异性表达的syndecan-2通过调节actin细胞骨架聚集参与神经病理性痛的机制研究

The production of dendritic spines, increasing number and up-regulated function of receptors on its membrane, as well as the activation of its internal signal pathways, all lead to central sensitization and neuropathic pain, while the actin cytoskeleton plays a certain role in all the processes above mentioned. Syndecan-2 (SDC2) is distributed on the membrane of dendritic spines with specificity, and can regulate actin and play a synergistic role with receptors such as EphB. We then proposed the hypothesis that under the modulation of EphB and heparanase(regulatory enzyme of SDC2), SDC2 could participate in the remodeling of the synapse and neuropathic pain by regulating the actin of dendritic spines. In this study, first, when the expression of SDC2 was specifically inhibited by its siRNA or shRNA, its impacts on spontaneous pain and induced pain in chronic nerve ligation model and on expression of the SDC2-neurofibromin-cAMP-PKA-Ena/VASP-F-actin signal pathway were observed to investigate the regulatory role of SDC2 on kinds of pain; second, with drug intervention on heparanase and/ or EphB, the expression of SDC2 was observed to learn the relationship between heparanase/EphB and SDC2. The interference of SDC2 could precisely treat neuropathic pain as a drastic measure, so SDC2 was believe to be a potential therapeutic target for neuropathic pain.

新树突棘的发生，其膜上受体的数量增多、功能的活跃以及其中信号通路的活化导致中枢敏化和神经病理性痛，而细胞骨架actin在以上过程中都发挥一定的作用。Syndecan-2（SDC2）特异性地分布在树突膜上，具有调节actin的作用，可与EphB等受体协同。我们提出假说，SDC2分子在EphB和其调节酶heparanase 的作用下通过调节树突棘的actin而参与突触重塑和神经病理性痛。本课题首先以siRNA或shRNA特异性抑制SDC2的表达并观察其对慢性神经结扎引起的诱发痛和自发痛的影响以及对neurofibromin-cAMP-PKA-Ena/VASP-F-actin信号通路的影响，藉此来探讨SDC2调控疼痛的作用；其次干预heparanase和/或EphB并观察SDC2的表达来探讨两者与SDC2的关系。干扰SDC2可以“釜底抽薪”的策略精准地治疗神经病理性痛，是个潜在的优良的治疗靶点。

本课题目的在于通过多种技术手段证明syndecan2（SDC2）及其上下游信号分子在神经病理性痛过程中具有重要的作用。首先，SDC2在神经病理性痛过程中在脊髓背角表达增加，并且作为可以激活SDC2的硫酸乙酰肝素酶（Heparanase）也同样在脊髓背角表达增加，而与SDC2同样在神经元上表达的syndecan3则没有变化。进一步，鞘内注射OGT2115和SDC2的shhRNA可以缓解神经损伤引起的热痛敏和机械痛敏。以上结果提示Heparanase-SDC2为核心的信号通路可能会在神经病理性痛过程中起到一定的作用，为最终阐明神经病理性痛的机制奠定基础。

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