Neuregulin/MAPKs信号通路对NMDAR抗体介导的血脑屏障及大脑神经元损害的作用

自身免疫性脑炎是由抗神经元细胞表面或突触蛋白的自身抗体引起的脑炎。2007年证实的NMDAR抗体是致病性神经元表面抗体,可引起复发和病死率均较高的抗NMDAR脑炎，然而其中的信号传导机制尚不明确，我们研究提示抗NMDAR脑炎患者预后与异常白蛋白指数和鞘内IgG合成相关，抑制ROCK通路可逆转NMDAR激动剂NMDA诱发的紧密连接蛋白Occludin破坏和血管通透性增加。本项目将通过抑制剂阻断MAPKs信号通路、CRISPR/Cas9基因敲除或激活质粒技术抑制或激活Occludin/Claudin-5或Neuregulin-1以研究脑血管内皮细胞HBEC-5i和NMDAR1/GluN1胞外肽段主动免疫或患者脑脊液提纯抗体被动免疫ApoE−/−小鼠中抗NMDAR抗体是否通过改变血脑屏障功能而损害大脑神经元及Neuregulin/MAPKs信号通路在其中的作用，为抗NMDAR脑炎防治提供新策略。

Autoimmune encephalitis is characterized by autoantibodies to surface epitopes of synaptic and cell surface proteins causing subacute deficits of memory and cognition, often followed by suppressed level of consciousness or coma. Anti-N-Methyl-D-Aspartate receptor (NMDAR) encephalitis with a high recurrence and fatality rate caused by NMDAR antibody identified in 2007. The underlying mechanism associated with signaling pathway of anti-NMDAR encephalitis is unclear. Our previous data indicated that the prognosis of patients with anti-NMDAR encephalitis is associated with abnormal cerebrospinal fluid/serum albumin ratio and 24-hour intrathecal IgG synthesis, and blocking Rho/ROCK signaling pathway by ROCK inhibitor Fasudil attenuated decreasing Occludin mRNA and protein levels and transepithelial electrical resistance induced by NMDAR agonist NMDA in the brain microvessel endothelial cells. This proposal will investigate the role of the disruption of tight junction protein to brain neuron lesions induced by NMDAR antibody as well as the effects of Neuregulin/MAPKs signaling pathway in human brain derived endothelial cells (HBEC-5i) and mice models in vivo immuned by NMDAR1/GluN1 peptides or cerebro-spinal fluid from the patients with anti-NMDAR encephalitis via inhibiting or activating Occludin/Claudin-5 or Neuregulin-1 with CRISPR/Cas9 knockout or activation plasmids and blocking MAPKs signaling pathway with inhibitors. This study will benefit to autoimmune encephalitis patients with new therapy strategy eventually.