SHARPIN介导的NF-κB信号通路的激活在单纯疱疹病毒感染性面瘫中的作用机制

I型单纯疱疹病毒(HSV-I)感染可导致贝尔面瘫，但其致病机制不明。我们前期研究发现，HSV-I感染致贝尔面瘫小鼠的面神经核团中核转录因子κB (NF-κB)被激活，但是目前关于NF-κB信号通路在HSV- I感染性面瘫中的激活机制及其激活后调控靶炎症因子的表达从而参与面神经炎症反应的作用及作用机制尚未见报道。本项目在前期工作的基础上，拟分别通过HSV-I感染致贝尔面瘫的小鼠动物模型及体外原代培养HSV-I感染性面瘫小鼠的脑干面神经核神经元细胞模型，研究NF-κB信号通路的激活导致的多种炎症因子的活性改变与HSV-I感染致贝尔面瘫的关系，并进一步深入探讨SHANK-相关RH结构域反应蛋白（SHARPIN）导致NF-κB必需调节蛋白（NEMO）泛素化后激活NF-κB信号通路的机制, 从而为HSV-I感染导致贝尔面瘫的作用机制研究提供新的理论依据, 进一步为贝尔面瘫的治疗提供新的作用靶点。

It has been documented that infection of Herpes simplex virus type I (HSV-I) contributes to the initiation of Bell's palsy, to date, however, the exact mechanisms responsible for this disorder have not been fully elucidated. Previously, we found that the nuclear factor-κB (NF-κB) was activated in the facial nucleus of brainstem of the paralyzed mice elicited by HSV-I, but the mechanisms about how NF-κB was activated and whether its activation regulates the expressions of certain key target genes in this progress of facial paralysis are still unclear. On the basis of our previous researches, the present project is designed, utilizing HSV-I-induced Bell's palsy of mice and, simultaneously, the primary cultures of facial nucleus cells from brainstem of these infected mice, as the experimental models, to investigate the effects of alteration in activities of several inflammatory factors initiated by the activation of NF-κB pathway, on mouse facial palsy. In particular, this work will focus on exploring the mechanisms underpinning the action of SHANK-associated RH domain-interacting protein (SHARPIN) on linear ubiquitination of the NF-κB essential modulator (NEMO) and, consequently, leading to the activation of NF-κB. Our new research will lends insight into the etiology and mechanisms responsible for the Bell's palsy induced by HSV-I, which may, in turn, offer novel effective therapeutic targets to Bell's palsy.