Klotho介导PDLIM2/NF-kB和FGF21/PPARγ通路在氧化应激大鼠认知功能的调控机制

小胶质细胞是大脑内的免疫细胞，其介导的氧化应激和神经炎症是脑血管病和神经退行性疾病发生和发展的关键环节。研究表明，抗衰老蛋白Klotho（KL）通过降低NF-kB活性，抑制神经炎症反应。我们前期研究发现，氧化应激诱导KL、PDLIM2和p-FGFR1的降低，KL活性与NF-kB表达呈负相关；而且肉豆蔻木酚素通过增强KL及PDLIM2蛋白表达，明显改善大鼠认知功能，但上述作用机制尚不清楚。本课题拟通过细胞缺氧模型和氧化应激大鼠模型，从分子、细胞和整体水平，探讨Klotho、酶和受体抑制剂以及肉豆蔻木酚素对PDLIM2、FGF21通路及靶基因的影响，阐明肉豆蔻木酚素通过PDLIM2/NF-kB和FGF21/PPARγ信号通路，改善认知功能的调控机制，为寻找防治脑血管病和神经退行性疾病及新药开发提供有效的理论依据。

Microglia are immune cells in the brain. Microglia-mediated oxidative stress and neuroinflammation are key links in the occurrence and development of cerebrovascular disease and neurodegenerative diseases. Research suggests Klotho (KL), an anti-aging protein, can inhibit neuroinflammation by reducing NF-kB activity. Our previous study found that oxidative stress induced the decrease of KL, PDLIM2 and p-FGFR1, and KL activity was negatively correlated with NF-kB expression. Moreover, macelignan could significantly improve the cognitive function of rats by increasing the expression of KL and PDLIM2 proteins, but the mechanism is unclear. Through the cell hypoxia model and the oxidative stress rat model, this subject explores the effects of Klotho, enzyme and receptor inhibitors, and macelignan are on PDLIM2, FGF21 pathway and target genes from the molecular, cellular and overall levels and macelignan improves the regulatory mechanism of cognitive function through PDLIM2/NF-kB and FGF21/PPARγ signaling pathways, which provide an effective theoretical basis for finding prevention and treatment of cerebrovascular disease and neurodegenerative diseases and new drug development.