镜像痛敏发生相关的Tenascins-Beta亚基-Nav1.7互作机制

The mechanism of mirror-image pain is still far from clear. Voltage-gated sodium channels decide the intrinsic excitory properties of neurons and thus play key roles in pain induction, transmission and maintenance. However, the endogenous control of sodium channel-involved pain remains unclear for lacking of subunit-specific drugs. Recently, our preliminary results indicated that perineuronal net extracellular matrix, especially Tenascins (Tenascin R and Tenascin C), the major components of perineuronal net, mediated pain relative sodium channels directly or indirectly through beta subunits. In the present project, with the advantages of our newly-established mirror-image pain model mimicking experimental scorpion sting, the dynamic distribution, expression, functional gating modulation of Nav1.7, β subunits (β1, β2, β3 and β4) and Tenascins (Tenascin R and Tenascin C) would be assayed by animal behavioral pharmacology, patch clamp electrical physiology, immunofluroscence, western blot, living cell image, photogenetic tracing, cell plasmid transfection at molecular, cellular, integral animal levels. The results would unveil the functional and structural regulation of mirror image pain-involved sodium channel Nav1.7 by the molecular interactive combination with β subunits and tenascins. The elucidation of modulating relationships of Tenascins-β subunits-sodium channels during mirror-image pain would promote our understanding of sodium channels-involved pain mechanisms, and thus provide some new scientific and practical distinct strategy for the diagnosis, therapy and drug discovery of clinical pain.

镜像痛敏发生、发展和维持的机制仍不甚清楚。电压门控钠通道亚型选择性分布决定神经元内在特性，介导镜像痛敏发生。前期预实验新发现，神经元周围网络胞外基质主要组分Tenascins通过β亚基或直接调控钠通道的表达和门控特性。基此，本项目拟以项目组新近构建的实验性蝎蛰诱致镜像痛敏动物模型，综合应用动物行为学、药理学、电生理学、免疫印迹、细胞转染、光遗传示踪等技术手段，在分子、细胞和整体动物等层面，比较检测钠通道Nav1.7、β亚基（β1、β2、β3和β4）、Tenascins（Tenascin-C和Tenascin-R）在镜像痛敏发生、发展和维持中的动态组合表达变化特征，探明Tenascins-β亚基- Nav1.7与镜像痛敏发生相关的分子互作组合调控机制，以丰富内源性神经元周围网络胞外基质调控疼痛相关钠通道机制的新理解，为钠通道亚型相关疼痛诊治新策略和镇痛新药物发现提供科学和实验依据。

镜像痛敏发生、发展和维持的机制仍不甚清楚。电压门控钠通道亚型选择性分布决定神经元内在特性，介导镜像痛敏发生。本项目通过比较检测钠通道Nav1.7、β亚基（β1、β2、β3和β4）、Tenascins（Tenascin-C和Tenascin-R）在镜像痛敏发生、发展和维持中的动态组合表达变化特征，明确了胞外基质组分Tenascins与钠通道β亚基参与了由BmK I诱发的镜像痛敏的发生与发展。Tenascins与β亚基在脊髓与DRG双侧中的差异表达以及其在DRG不同类型细胞中的差异分布是诱发损伤对侧产生镜像痛敏的重要原因。Tenascins与β亚基的协同作用会影响Nav1.7等钠离子通道的激活状态，介导疼痛信号的镜像传递。Tenascin-R与β亚基及Nav1.7的可能作用结合位点是第208位的Lys、234位的Arg、235位的Asp以及249位的Glu。依托本项目发表学术论文11篇，获批发明专利1项，申报发明专利4项，培养硕士研究生18人。本项目研究结果丰富了内源性神经元周围网络胞外基质调控疼痛相关钠通道机制的新理解，为钠通道亚型相关疼痛诊治及镇痛新药物的新策略、新靶标提供科学和实验依据。

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