MFHAS1-praja2-PKA通路在脓毒症相关脑病海马长时程增强作用中的机制研究

脓毒症相关脑病（SAE）是脓毒症常见并发症并影响预后。SAE认知功能障碍与海马长时程增强（LTP）密切相关，E3泛素连接酶praja2能调控蛋白激酶A（PKA）活性，进而影响海马LTP和认知功能，然而praja2-PKA在SAE中的作用机制尚未阐明。本项目前期研究发现脓毒症患者血浆中恶性纤维性组织细胞瘤扩增序列1（MFHAS1）浓度升高，MFHAS1被praja2泛素化后促进炎性反应。本项目预实验表明MFHAS1能抑制PKA活性；脑室内注射MFHAS1 siRNA改善SAE大鼠认知功能，降低海马IL-1β表达，缓解树突棘密度降低。因此，我们提出假设：MFHAS1-praja2-PKA通路能调控海马LTP和突触功能，进而影响SAE的认知功能。为验证假设，本项目将从基础和临床多维度，利用神经元高尔基染色法和大鼠脑室内注射等手段，研究MFHAS1在SAE中的作用机制，为SAE诊治提供潜在新靶点。

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis and affects prognosis. The cognitive impairment of SAE is closely related to long-term potentiation (LTP) in the hippocampus. E3 ubiquitin ligase praja2 can regulate the activity of protein kinase A (PKA), thereby affecting the LTP and cognitive function in the hippocampus. However, the mechanism of praja2-PKA in SAE has not been clarified. Our previous research findings showed that the concentration of MFHAS1 in plasma of septic patients increased, and MFHAS1 was ubiquitinated by praja2 to promote inflammatory response. Preliminary experiments showed that MFHAS1 could inhibit the activity of PKA, and intraventricular injection of MFHAS1 siRNA could improve the cognitive function of SAE rats, reduce the expression of IL-1β in hippocampus and alleviate the decrease of dendritic spine density. Therefore, we hypothesize that the MFHAS1-praja2-PKA pathway can regulate LTP and synaptic function in hippocampus, and then affect the cognitive function of SAE. To verify the hypothesis, this project will study the mechanism of MFHAS1 in SAE from the basic and clinical dimensions by means of neuron Golgi staining and intraventricular injection in rats, so as to provide a potential new target for SAE diagnosis and treatment.