血清IgG自身免疫复合物参与糖尿病神经病理性疼痛形成机制

People with diabetes are more likely to prolonged chronic pain, which may impact to life quality of diabetic patients and waste medical resources seriously.Advanced glycation end products(AGEs) are irreversible products in diabetic non-enzymatic glycation reaction. In vivo, AGE, LDL and IgG immunoglobulin can combine to form autoimmune complexes (AGE-LDL-IC). The AGE-LDL-IC may damage vessels, retina and nerve. To increase concentration of the AGE-LDL-IC, may prolonger the chronic pain in the time course. This is the core assumption of this study. According to the previous results, we will prove that the AGE-LDL-IC in serum of type 1 diabetic rats was involved in develop of chronic pain. In this part of study, we will use behavioral tests, electrophysiological experiments in vivo recording, calcium imaging techniques and molecular signaling pathway analysis. By means of molecular biology, we will expose that the changes in neurons, glial cells and microRNA associated with autoimmunity are matched the behavioral tests of prolonged and consistent chronic. Finally, we will focus on miR155 as a target for treatment intervention. Because the expression of miR-155 may only go with the autoimmunity related to IgG type. When chronic pain is expected to shorten, thus may verify miR-155 treatment for diabetic chronic pain as a new target.

糖尿病人易发生慢性疼痛时程延长，严重损害患者围手术期和日常生活质量，延缓康复，消耗医疗资源。晚期糖化终末产物是糖尿病非酶糖基化反应产生的不可逆产物，其与体内低密度脂蛋白及IgG 抗体形成的自身免疫复合物（AGE-LDL-IC），是神经损伤等病变的主要原因；增加AGE-LDL-IC 浓度可能延长慢性疼痛时程，是本研究核心假设。结合前期成果，从行为学--在体电生理实验记录--原代DRG 细胞钙成像分析--分子生物学信号通路四个方面，从细胞到系统，证明I 型糖尿病血清AGE—LDL—IC，参与并延长慢性疼痛时程。通过分子生物学手段，从神经元细胞-胶质细胞-自身免疫微小RNA，三个途径验证慢性疼痛时程延长分子生物学与行为学改变相符；最后以自身免疫相关miR-155（只与IgG 类型自身免疫相关，而不影响IgM 类型急性免疫）为干预目标，预期慢性疼痛时程缩短，为治疗糖尿病慢性疼痛提供新靶点。

糖尿病患者易发生慢性疼痛时程延长，严重损害患者围术期及日常生活质量、延缓患者康复、消耗医疗资源。晚期糖化终末产物是糖尿病非酶糖基化反应产生的不可逆产物，其与体内低密度脂蛋白（AGE-LDL）结合后可造成神经损伤，降低AGE-LDL浓度可能缩短慢性疼痛时程，其机制可能与钙调蛋白-HMGB1-PKC调控有关。我们研究结果发现，辛伐他汀、吡哆胺通过降低AGE-LDL/RAGE对下游NF-κB和MAPKs的活化，可以减轻糖尿病神经病理性疼痛。同时，我们还在多种其他疼痛模型研究中发现：中枢和外周神经组织中HMGB1-TLR4-MyD88-NF-κB参与调控子宫内膜异位症疼痛形成；开胸术后慢性疼痛的脊髓和DRG组织中钙调蛋白和TLR4被活化；同时，参与糖尿病病神经病理性疼痛的CXCL12/CXCR4轴同样在免疫介导的过敏性接触性皮炎相关的疼痛和瘙痒中发挥重要作用。疼痛尤其是糖尿病神经病理性疼痛的形成机制是复杂的，我们通过聚焦研究AGE-LDL-钙调蛋白-TLR4相关调控机制，并结合多种其他疼痛模型，充分阐述了该机制在神经病理性疼痛中的可能作用，有望为日后疼痛治疗提供强有力的理论依据。