外源性尿酸调控SP1-Annexin a1在大鼠肝性脑病中的保护作用及机制研究

肝性脑病（HE）急性发作后，患者认知障碍可能不会完全逆转，预后较差。研究HE病理过程和治疗方式具有重要社会意义。最近有研究发现，HE与星形胶质细胞衰老有关。尿酸具有神经保护作用，但是否与减缓星形胶质细胞衰老有关，少见报道。预实验发现，大鼠HE模型中，海马SP1、膜联蛋白A1（AnxA1）、以及衰老标记物p21表达增加，应用外源性尿酸后，海马SP1表达下降，而p21以及AnxA1与GFAP存在共定位；生物学软件分析发现SP1可能调控AnxA1。故推测SP1- AnxA1参与HE星形胶质细胞衰老过程。因此本项目拟使用AnxA1基因敲除大鼠，在细胞水平以及在体水平，使用染色质免疫共沉淀，荧光素酶活性实验，海马微注射等方法，探讨外源性尿酸是否通过SP1- AnxA1，抑制星形胶质细胞衰老，在HE中发挥神经保护作用。以期为HE临床治疗提供新思路和研发相关药物提供理论依据。

It has been found that the patient’s congnitive impairment could not be completely reversed after an acute episode of hepatic encephalopaphy (HE) and HE predicted a poor prognosis. Therefore, to study the pathological process and therapy method of HE is with social significance. It was found recently that astrocyte senescence is involved in HE. It is not known that whether the neuroprotective effect of uric acid (UA) is relative to alleviate astrocyte senescence. The resulsts of pilot study showed that HE induced the expression of SP1, Annexin a1(AnxA1) and p21 in hippocampus; AnxA1 and p21 were co-localized with GFAP. We also found that exogenous UA decreased the expression of SP1. Using biological software, it was supposed that SP1 may regulate the expression of AnxA1. Therefore, it was hypothesized that UA regulate SP1-Anxa1 which was involved in astrocyte senescence in the rat HE model. In this project, the inhibitor of SP1, the adenovirus of overexpressioned SP1, AnxA1 knockout rats will be used to study the effect of exogenous uric acid on astrocyte senescence in rat HE model, and to study whether SP1-Anxa1 is involved in the protective effect of UA. The project is designed to provide new ideas for the treatment of HE and proofs for the development of related drugs.