载脂蛋白E在视神经脊髓炎发病机制中的作用

Neuromyelitis optica (NMO) is an autoimmune disease that selectively affects the optic nerves and the spinal cord in the central nervous system(CNS).NMO is characterised by frequent relapses,poor outcome,severe disability. Pathologically, not only myelin but also axons and neuron are seriously involved.Many findings support the concept of NMO being an anti-AQP4 antibody predominantly mediated inflammatory disorder.AQP4 is the predominant water channel in the CNS and and highly concentrated in astrocytic membranes，so the antibody from NMO directly induces astrocyte injury.Most of apolipoprotein E(apoE) is synthesized and excreted by astrocytes in the CNS，so the CNS apoE level is decreased in NMO. Generally，apoE is the predominant apolipoprotein in the CNS and is found to play an important role in neuroprotection, neurorepair and immunomodulation.The human apoE have three isoforms whose funtions aren't same in many neural disorders ,apoE4 is one of its isoforms and is closly linked to progression of stroke, vascular dementia, multiple sclerosis, amyotrophic lateral sclerosis.What is the role of apoE and its isforms in NMO?It hasn't been reported in international journals.In this study ,we will establish NMO organ slice models of the changed amount and isoforms of apoE,and detect their protein biomarkers and cell factors with enzyme linked immunosorbent assay,polymerase chain reaction, immunohistochemistry, western blot and other experimental technologies.Moreover，we expand to investigate the mechanism of apoE in the lipid metabolism, immunology, glutamate-mediated toxicity erve injure and repaire of NMO.The result of this study will reveal the role of apoE and its isoforms in pathogenesis of NMO.This research will be helpful to improve the pathogenesis of NMO, and is also deeply significant to treatment and prevention of NMO.

视神经脊髓炎（NMO）是主要损伤视神经和脊髓的自身免疫性疾病，临床上疗效差、发作频繁、致残率高，病理上髓鞘脱失、神经元和轴突损伤严重。该病的特异性抗体损伤的是合成载脂蛋白E（apoE）星形胶质细胞，会导致apoE的含量减少。而研究发现apoE有神经修复、神经保护、调节免疫等作用。此外，人的apoE有三种亚型，其中apoE4与神经元变性、神经免疫相关的疾病关系密切。那么，apoE及其亚型在NMO发病中起何作用？其作用机制是什么？迄今国内外尚无报道。本课题就此展开研究，建立NMO组织片模型，通过干预改变模型的apoE的蛋白量和亚型，用ELISA、PCR、免疫组化、病理染色、蛋白免疫印迹等实验技术，从NMO的免疫学、脂质代谢、谷氨酸毒性、损伤和修复等方面进行研究，观察相关指标的变化，探索apoE在NMO发病机制中的作用。本项目将从新的视觉完善NMO的发病机制，并为NMO的预防和治疗提供新靶点。

视神经脊髓炎（NMO）是主要损伤视神经和脊髓的自身免疫性疾病，临床上疗效差、发作频繁、致残率高，病理上髓鞘脱失、神经元和轴突损伤严重。该病的特异性抗体损伤的是合成载脂蛋白 E（apoE）星形胶质细胞，会导致 apoE 的含量减少。而研究发现 apoE 有神经修复、神经保护、调节免疫等作用。本研究通过建立 NMO 组织片模型，通过干预改变模型的 apoE 的蛋白量和亚型，用 ELISA、PCR、免疫组化、病理染色、蛋白免疫印迹等实验技术，从 NMO 的免疫学、脂质代谢、谷氨酸毒性、损伤和修复等方面进行研究，观察相关指标的变化，探索 apoE 在 NMO 发病机制中的作用。本研究发现;1.我们成功培育出了小鼠离体NMO模型。在后期的实验中我们发现，该造模方法具有NMO主要病理特征，成功率高、稳定性良好，可以精确的控制影响因素，特别适合在诸多NMO的影响因素中研究其各自的独立效应，是NMO基础研究的良好模型。2.NMO-IgG及补体诱导星形胶质细胞损伤及调控AQP4及apoE表达下调的机制之一，可能是通过上调NR表达，从而促进NR介导的兴奋毒性细胞凋亡。因此我们推测NR受体可能参与NMO的致病，这为NMO的病因基础研究开拓出了一个新的方向。3.apoE的缺乏可以促进小胶质细胞的活化、炎症因子的分泌和谷氨酸受体（尤其是NMDAR2b）的上调，但在体外切片模型中，apoE对NMO可能无直接影响作用,但是暂时不能除外是由于损伤积分法自身局限性导致的可能性。