ApoB及补体蛋白C1q在静脉高压性脊髓损伤中的作用及机制研究

静脉高压性脊髓损伤（VHM）是脊髓血管畸形最重要的致病机制。虽然病变大多可通过手术获得解剖治愈，但术后仍有高达80%患者的脊髓功能得不到完全恢复，长期随访发现约50%患者的脊髓功能经过短暂恢复后再次加重，缺乏有效的治疗手段。前期VHM动物模型研究发现损伤的关键在炎性反应。去除病因后，炎性反应还在继续。介导这一过程的分子机制尚不清楚。申请人前期完成了VHM患者脑脊液蛋白组学分析发现：ApoB和补体蛋白C1q的上调最为明显。我们推测VHM导致血脑屏障（BBB）破坏后，ApoB透过BBB激活了免疫细胞诱导炎性反应，免疫细胞高表达C1q激活补体途径加重炎性反应和诱导髓鞘清除。基于此，本研究（1）通过对VHM患者脑脊液行细胞学分析和动物模型体内研究探明ApoB和C1q介导炎性反应的分子机制以及两者之间的关系；（2）探明抗C1q是否能够缓解炎性反应和髓鞘损伤，为VHM诊疗及脊髓损伤修复提供新的思路。

Venous hypertensive myelopathy (VHM) is the most important pathogenic mechanism of spinal vascular malformations. Although most of the lesions can be anatomically cured by operations, 80% of patients still cannot get fully recovery after the operation, and long-term follow-up showed that about 50% of patients experienced aggravation after a short period of recovery, the effective interventions remain insufficient. Previous studies of VHM animal models indicated that the main pathology is inflammatory response. After removing the lesions, the inflammatory reaction continued. The molecular mechanism that mediates this process is unclear. The applicant completed the proteomic analysis of the cerebrospinal fluid of VHM patients and found that the up-regulation of ApoB and complement protein C1q was the most obvious. We speculate that after the destruction of the blood-brain barrier caused by VHM, the release of ApoB activates immune cells to induce inflammatory response, and the high expression of C1q on immune cells activates the complement pathway to aggravate the inflammatory response and induce myelin clearance. Based on this, this study is designed to further explore: (1) the molecular mechanism of ApoB and C1q-mediated inflammatory response through cytological analysis of the cerebrospinal fluid of patients with VHM and in vivo studies in animal models; (2) the anti-C1q whether can alleviate inflammatory response and myelin damage or not, providing new ideas for therapy of patients with VHM.