糖尿病神经病理性疼痛发病早期CD55功能下调的作用和机制研究

The pathogenesis of painful diabetic peripheral neuropathy（PDPN） is a research focus in the related fields. Our previous study demonstrated that abnormal activation of complement system plays an important role in the incidence of early PDPN, but how to start the initial process remains unclear. The existing literature shows that dysfunction of CD55 is most likely to start the uncontrolled cascade reaction of complements in nervous system and as a regulating enzyme for CD55, the activity of GPI-PLD can be directly influenced by the environment in diabetic. Our hypothesis is that abnormal levels of insulin and blood glucose induced the functional down-regulation of complement regulatory protein CD55 in astrocytes in dorsal horn of the spinal cord and epilemma by direct or indirect GPI-PLD paths, accompanied with the stimulating of immune complex deposition and/or other factors, the cascade reaction of complement system activation developed and became out of control，thus caused nerve damage and pathological pain. We plan to make the diabetic mouse model with streptozotocin intraperitoneal injection in C57BL/6J mice, C3 gene knockout mice and CD55 gene knockout mice, then use multiple methods such as controlling the activity of GPI-PLD by the techniques of gene over expression and gene silencing, supplying exogenous CD55 and complement C3, intervening technique of anti-Ig antibody and CD55 gene monoclonal antibody treatment and thus get the results of the effect and mechanism of functional down-regulation of CD55 on the initial stage of painful diabetic peripheral neuropathy by the methods of multi path comparison. The study aims to explore the key molecules and process of the initial part of abnormal activation of complement in dorsal horn of the spinal cord and epilemma in PDPN mice，clarify the upstream mechanism of the pathogenesis of PDPN and provide a new idea for clinical prevention and treatment of PDPN.

糖尿病疼痛性周围神经病变（PDPN）发病机制不明，临床控制困难。我们的前期研究证实了补体异常激活与PDPN早期发病关系密切，但其上游启动机制不明。资料显示CD55功能异常最有可能启动神经系统补体失控性级联反应，而其调节酶GPI-PLD活性可直接受糖尿病内环境影响。假设血糖和胰岛素信号异常直接或通过GPI-PLD间接诱导了脊髓背角星形胶质细胞和神经鞘膜CD55功能下调，引发补体系统异常激活而导致神经损害和病理性疼痛。拟腹腔注射STZ制作野生小鼠及C3、CD55基因敲除小鼠糖尿病神经痛模型，用基因过表达/基因沉默技术控制星形胶质细胞GPI-PLD表达及应用外源性CD55、补体C3、抗Ig抗体、CD55基因单克隆抗体等手段干预，研究糖尿病内环境下CD55活性下调的机制及其在补体异常激活启动环节的作用。旨在探索PDPN发病早期启动脊髓神经系统补体异常激活的关键分子和过程，为PDPN防治提供新思路。

糖尿病疼痛性周围神经病变（PDPN）发病机制不明，临床控制困难。我们的前期研究证实了补体异常激活与PDPN早期发病关系密切，但其上游启动机制不明。资料显示CD55功能异常最有可能启动神经系统补体失控性级联反应，而其调节酶GPI-PLD活性可直接受糖尿病内环境影响。假设血糖和胰岛素信号异常直接或通过GPI-PLD间接诱导了脊髓背角星形胶质细胞和神经鞘膜CD55功能下调，引发补体系统异常激活而导致神经损害和病理性疼痛。拟腹腔注射STZ制作野生小鼠及C3、CD55基因敲除小鼠糖尿病神经痛模型，用基因过表达/基因沉默技术控制星形胶质细胞GPI-PLD表达及应用外源性CD55、补体C3、抗Ig抗体、CD55基因单克隆抗体等手段干预，研究糖尿病内环境下CD55活性下调的机制及其在补体异常激活启动环节的作用。旨在探索PDPN发病早期启动脊髓神经系统补体异常激活的关键分子和过程，为PDPN防治提供新思路。