BDNF通过调控细胞自噬介导小胶质细胞-神经元间"对话"以诱发大鼠骨癌痛

We have described the rat model of bone cancer pain. We showed that microglial purinoceptor (P2X4R) and toll-like receptor-4 (TLR4) are "cross-talked" in signal transduction system and might involve in the enhanced nociceptive transmission associated with secretion of BDNF in the dorsal horn level under a rat model of bone cancer pain. However, mechanisms involved in central sensitization of BDNF remain poorly understood. Our preliminary experiments under bone cancer pain demonstrated that BDNF low-affinity receptor p75NTR in the spinal dorsal horn is correlated with over expression of autophagy signal mTOR. Moreover, recent data showed that BDNF/pro-BDNF and the relative balance between their receptors TrkB/p75NTR affinity was essential for maintaining the balance of neuronal survival and death. And TLR4 was a sensor for autophagy associated with innate immunity. Furthermore, co-expression of P2X4 receptor with P2X7 receptor of macrophages enhanced P2X7-mediated inflammation through both facilitation of release of cytokines and suppression of autophagy. Therefore, we hypothesized that the microglial BDNF may be mediated "cross-talk" between microglia-neuron by regulating and controlling cell autophagy to induce hyperalgesia in rats with bone cancer. We believe that the proposed project will primarily demonstrate the neuro-immunological mechanism of bone cancer pain through a brand-new point: based on the "cross-talk" between the balance of innate immunity and the nervous system (balance of system ), BDNF/pro-BDNF and their receptor affinity equilibrium (molecular equilibrium), or autophagic function as a regulated pathway in contradiction balance of neuronal protection (to maintain cell homeostasis ) and neuronal injury (functional homeostasis).

我室前期研究表明BDNF介导小胶质细胞-神经元间"对话"，小胶质细胞上特异性的嘌呤受体P2X4R与免疫受体TLR4作用共同介导BDNF释放及骨癌痛发生，但机制不明。现预实验发现，骨癌痛大鼠BDNF的低亲和力受体p75NTR调节自噬信号mTOR的表达。已知，BDNF /pro-BDNF及其受体TrkB/ p75NTR亲和力的平衡于维持神经元生存/死亡的平衡至关重要；TLR4是自噬与先天免疫关联的传感器；且外周P2X4R激活可抑制抗炎功能相关自噬。故推测，BDNF可通过调控细胞自噬介导小胶质细胞-神经元间"对话"以诱发大鼠骨癌痛。本申请将结合离体和在体实验经由多水平平衡调控角度- - 先天免疫及神经系统平衡（系统平衡），BDNF/pro-BDNF与受体亲和力平衡（分子平衡），自噬与神经元保护及损伤的平衡（功能平衡）- - 探讨BDNF介导骨癌痛发生和发展的神经免疫机制，以为疼痛诊疗提供新的思路。

本课题组前期研究发现，BDNF /pro-BDNF及其受体TrkB/p75NTR亲和力的平衡于维持神经元生存/死亡的平衡至关重要；TLR4是自噬与先天免疫关联的传感器；且外周P2X4R激活可抑制抗炎功能相关自噬。在此基础上本课题组研究进一步发现，骨癌痛大鼠BDNF的低亲和力受体p75NTR调节自噬信号mTOR的表达，BDNF可通过调控细胞自噬介导小胶质细胞-神经元间"对话"以诱发大鼠骨癌痛。截止至2018年12月1日，本课题已发表相关论文11篇,其中10篇均挂基金号。此外，另参与国内国际学术会议并被录用大会演讲或板报展示12篇。以上研究成果本课题通过探讨BDNF介导骨癌痛发生和发展的神经免疫机制，以为疼痛诊疗提供新的思路，从而对该疾病的发生有更为深入的认识，并有望为其诊断和治疗带来突破。