基质金属蛋白酶16调控神经病理性疼痛的机制研究

Matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular endopeptidases. Previous evidence demonstrated that MMP2 played a critical role in the regulation of neuropathic pain. MMP2 was secrected as a pro-enzyme. The activation of proMMP2 requires other enzymes, especially membrane-type members of the MMP family. The membrane-type MMPs are including MMP14, MMP15, MMP16, MMP17, MMP24, & MMP25. Our preliminary data showed that the expression level of MMP16 was significantly upregulated in DRG neurons after peripheral nerve injury and the upregulation lasted for a long time. Comparatively, the expression of other membrane-type MMPs was not changed. Suppression of MMP16 upregulation by in vivo RNA interference could attenuate neuropathic pain behavior remarkably. Intrathecal injection with exogenous MMP16 catalytic domain could induce a neuropathic pain-like behavior. Abovementioned data indicated strongly that MMP16 could be required and necessary in regulating neuropathic pain induced by peripheral nerve injury. In our present project, we would investigate the function of MMP16 in neuropathic pain, and explore the underlying mechanisms. Our work would supply the basic data for the exploration of new drug targets to treat neuropathic pain.

基质金属蛋白酶(MMP)是一类锌离子依赖的细胞外肽链内切酶。新近研究显示其家族成员MMP2在调控神经病理性疼痛的过程中起重要作用。MMP2属分泌型的MMP，其激活主要依赖于同家族的膜型MMP，包括MMP14、-15、-16、-17、-24和-25。我们最新的研究显示：大鼠坐骨神经损伤可导致MMP16在背根神经节神经元中长时程表达上调，而其它膜型MMP的表达未受影响；采用在体RNA干扰技术抑制MMP16的表达可显著缓解外周神经损伤诱导的神经病理性疼痛；椎管内注射外源性的MMP16酶活性片段可在正常成年大鼠诱导类似神经病理性疼痛的行为学表现。上述结果提示MMP16在调控神经病理性疼痛的过程中起重要作用。本项目将通过行为学、形态学、在体RNA干扰、电生理和原代细胞培养等技术方法，研究MMP16调控神经病理性疼痛的作用及其机制，为寻找神经病理性痛新的药物治疗靶点提供实验依据。

基质金属蛋白酶(MMP)是一类锌离子依赖的细胞外肽链内切酶。有研究显示其家族成员MMP2在调控神经病理性疼痛的过程中起重要作用。MMP2属分泌型的MMP，其激活主要依赖于同家族的膜型MMP，包括MMP14、-15、-16、-17、-24和-25。我们的研究结果显示：大鼠坐骨神经损伤可导致MMP16在背根神经节(DRG)神经元中长时程表达上调，而其它膜型MMP的表达未受影响；采用在体RNA干扰技术抑制MMP16的表达可显著缓解外周神经损伤诱导的神经病理性疼痛；椎管内注射外源性的MMP16酶活性片段可在正常成年大鼠诱导类似神经病理性疼痛的行为学表现。通过条件式敲除DRG神经元中的MMP16，可显著减缓外周神经损伤(SNI模型)导致的机械性痛敏。为了研究MMP16表达调控的机制，我们对SNI模型14天的小鼠DRG神经元进行了单细胞RNA测序，结果发现MMP16和一些基因同归属于一个基因模块，这个模块的代表性基因包括ATF3，这个模块中基因多数属于外周神经损伤后表达上调的基因，这一结果提示这些基因可能受到相同或相似的基因表达调控。上述结果提示MMP16在调控神经病理性疼痛的过程中起重要作用。对MMP16调控机制的研究将有助于揭示神经病理性疼痛的作用及其机制，为寻找神经病理性痛新的药物治疗靶点提供实验依据。