HO-1基因过表达阻断MLK3/MKK7/JNK信号通路对脊髓损伤保护作用的机制研究

Spinal cord injury (SCI) refers to a disease that will bring severe negative impact to the health. It would result in paraplegia or quadriplegia，incontinence and sensory disturbances. Anyone who suffers from SCI would become a great burden to the family and society. Heme Oxygenase-1 (HO-1) plays an important role in protecting SCI. The expression of HO-1 closely relates to the JNK signaling pathway. So far there's no report about whether HO-1 gene transfection would protect SCI or whether HO-1 gene overexpression has therapeutic effect on SCI by inactivating the MLK3-MKK7-JNK signaling pathway. Based on our previous research, we aims to adjust different HO-1 expressions with lentivirus-mediated gene overexpressions and siRNA technics, so as to study the effect of HO-1 gene overexpression on SCI and explore its molecular mechanisms, which would provide theoretical basis and experimental evidence for the treatment of SCI.

脊髓损伤（Spinal cord injury, SCI）是一种严重损害人类健康的疾患，常导致截瘫或四肢瘫痪、大小便失禁和感觉障碍，给个人、家庭及社会带来沉重的负担。血红素氧合酶-1(Heme Oxygenase-1,HO-1)在SCI中具有重要的神经保护作用，HO-1的表达与JNK信号通路密切相关。迄今，HO-1基因转染是否能够对SCI起神经保护作用？HO-1对SCI的治疗作用是否是通过阻断MLK3/MKK7/JNK信号通路实现的？国内外均未见报道。因此，本项目立足前期研究基础，拟联合慢病毒载体介导的基因过表达技术和siRNA技术来调控HO-1的表达，探讨HO-1基因是否可以通过阻断MLK3/MKK7/JNK信号通路对SCI起保护作用，从而为HO-1用于SCI的治疗提供新思路和新靶点。

血红素氧合酶-1(Heme Oxygenase-1,HO-1)在脊髓损伤（Spinal cord injury, SCI）中具有重要的神经保护作用。本项目观察了HO-1基因转染对大鼠SCI和原代培养大鼠脊髓神经元损伤起神经保护作用；其次，深入探讨了其神经保护机制，发现过表达的HO-1可以通过阻断MLK3/MKK7/JNK信号通路对大鼠SCI和原代培养大鼠脊髓神经元损伤起保护作用；第三，本项目还发现AAV-HO-1通过抑制核苷酸结合寡聚化结构域样受体蛋白1（NOD-like receptor protein-1, NLRP1）表达减轻SCI大鼠脊髓神经元和损伤原代培养脊髓神经元的凋亡，从而发挥神经保护作用；最后，本项目制备白细胞介素1β（interleukin-1β, IL-1β）特异的RNA干扰腺病毒载体（Ad-shIL-1β），发现Ad-shIL-1β能够对SCI大鼠起神经保护作用，并探讨了其作用机制。上述系列研究为SCI的基因治疗研究提供新思路和新靶点。