WNT新型受体PTPRO调控神经病理性痛的作用机制研究

Protein tyrosine phosphatase receptor type O （PTPRO） is one member of the superfamily of protein tyrosine phosphatase.The balance of tyrosine phosphorylation is important in the regulation of synaptic plasticity of nervous system. Newly recent study showed that WNT1 and WNT3a, the typical agonists of WNT family, could bind the extracellular domain of PTPRO. WNT/frizzled/β-catenin signaling pathway has been proved to play a vital role in the regulation of peripheral neuropathic pain. Whether PTPRO contibutes to WNT/β-catenin signaling pathway in neuropathic pain remains unclear. Our preliminary data showed that PTPRO was upregulated in the DRG after peripheral nerve injury. PTPRO could interact with β-catenin via protein-protein interaction with the technique of co-immunoprecipitation. These results suggested that PTPRO may play a role in the progress of neuropathic pain by the direct interaction with WNT and β-catenin. Combined with multiple studies of behavior, morphology, RNA interference in vivi, electrophysiology and cell culture, the role of PTPRO in WNT/β-catenin pathway modulating neuropathic pain and its underlying mechanisms will be investigated. This study would provide basic data for the research on the mechanisms of neuropathic pain.

O型受体型蛋白酪氨酸磷酸酶(PTPRO)是蛋白酪氨酸磷酸酶超家族的成员，酪氨酸磷酸化对调节神经系统突触可塑性十分重要。神经系统重要的信号通路WNT/frizzled/β-catenin途径在神经病理性痛的调控中发挥关键作用，最新研究发现WNT1和WNT3a分子可直接作用于PTPRO。尚无PTPRO与疼痛相关的报道，前期实验发现：外周神经损伤后背根神经节中的PTPRO表达上调；且PTPRO能与β-catenin直接相互作用，强烈提示PTPRO作为WNT的新型受体，可能参与WNT/β-catenin信号途径调控神经病理性疼痛。本项目将通过行为学、形态学、在体RNA干扰、电生理和细胞培养等技术，对PTPRO与WNT/frizzled/β-catenin通路的相互作用，以及该作用对靶基因、突触可塑性以及神经病理性痛行为的影响进行研究，为神经病理性疼痛机制研究提供资料。

O型受体型蛋白酪氨酸磷酸酶(PTPRO)是蛋白酪氨酸磷酸酶超家族的成员，酪氨酸磷酸化对调节神经系统突触可塑性十分重要。本研究拟探讨作为WNT的新型受体，PTPRO是否参与WNT/β-catenin信号途径调控神经病理性疼痛。结果发现神经损伤后Ptpro在DRG和脊髓背角的表达上调，且与神经病理性痛的发生和发展时程高度吻合；外源性Wnt3a可诱导疼痛行为，且MMP2和ADAM17是WNT/β-catenin信号系统重要的靶基因；已培育特异性敲除PTPRO小鼠，可为PTPRO与神经病理性疼痛相关性提供明确的结论