JAK/STAT信号通过调节脊髓突触重塑机制介导骨癌痛的发生与维持

Bone cancer pain (BCP) is the most common complications in patients suffering from primary bone cancer or metastatic bone cancer. Because the specific mechanisms underlying BCP remain elusive, it is inadequately addressed by currently available treatment. Spinal central sensitization induced by synaptic reorganization is required for the induction and maintenance of BCP. JAK/ STAT pathway plays a key role in mediating the development of dendritic spine and synaptic reorgnization. Our preliminary experiment indicated that spinal STAT3 was activated and colocalized with neurons in BCP rats. Our previous results (J Neurochem、Exp Neurol) showed that the spinal astrocytes and microglia mediated BCP. JAK/STAT promoted the activation and proliferation of astrocytes and microglia induced by various nociceptive information. Meanwhile, glial cells contribute to the synaptic plasticity simultaneously. So we hypothesis that JAK/STAT works directly on neurons, and promotes the activation and proliferation of glial cells, both of which contributing to the induction and maintenance of BCP through spinal synaptic reorgnization. Our project will provide evidence to support this hypothesis by using gene silencing, molecular biology,immunohistochemistry, electrophysiology, behaviors and neurophamacology technology in BCP rats, which will provide new theory support for the development of new drug treating BCP.

骨癌痛（BCP）是原发性骨癌和癌症骨转移常见的并发症，因其发病机制未明，目前缺乏有效治疗手段。突触重塑导致脊髓中枢敏感化是BCP发生与维持的核心环节。研究表明JAK/STAT可调节树突棘发生和突触重塑；预实验提示BCP引起脊髓STAT3活化且与神经元共表达。我们发表于J Neuochem、Exp Neurol等杂志的结果提示脊髓的星形胶质细胞、小胶质细胞可参与介导BCP；另外JAK/STAT介导各种伤害性信息引起的上述胶质细胞活化与增殖；而上述胶质细胞参与突触可塑性调节。因此我们提出假说：JAK/ STAT可直接作用于神经元，通过脊髓突触重塑机制调节BCP；且可通过促进胶质细胞活化与增殖，间接通过胶质细胞参与脊髓突触重塑调节，从而介导BCP的发生与维持。本项目拟先建立BCP大鼠模型，运用基因沉默、生化、组化、电生理学、行为学与神经药理等方法相结合验证假说，为研发治疗BCP新药提供理论依据。

骨癌痛（BCP）是原发性骨癌和癌症骨转移常见的并发症，因其发病机制未明，目前缺乏有效治疗手段。突触重塑导致脊髓中枢敏感化是BCP发生与维持的核心环节。研究表明JAK/STAT可调节树突棘发生和突触重塑；我们发表于J Neuochem、Exp Neurol等杂志的结果提示脊髓的星形胶质细胞、小胶质细胞可参与介导BCP；另外JAK/STAT介导各种伤害性信息引起的上述胶质细胞活化与增殖；而上述胶质细胞参与突触可塑性调节。因此我们提出假说：JAK/STAT可直接作用于神经元，通过脊髓突触重塑机制调节BCP；且可通过促进胶质细胞活化与增殖，间接通过胶质细胞参与脊髓突触重塑调节，从而介导BCP的发生与维持。本项目先建立BCP大鼠模型，运用基因沉默、生化、组化、电生理学、行为学与神经药理等方法相结合验证了假说，为研发治疗BCP新药提供理论依据。