CypD调控线粒体炫在氟致学习记忆损伤中的作用及机制研究

长期饮用由特殊地质环境等原因引起的高氟水导致的学习记忆损伤已受到广泛关注。线粒体功能紊乱与氟致学习记忆损伤密切相关，近年发现线粒体炫是反映线粒体电化学兴奋性的动态功能事件，然而氟对线粒体炫的影响及其调控机制，目前尚未阐明。本项目组近期分析氟染毒大鼠海马组织线粒体蛋白组测序和SH-SY5Y细胞蛋白表达的结果，发现氟引起对线粒体炫具有重要作用且调控线粒体通透性转换孔（mPTP）的亲环蛋白D（CypD）表达升高。据此推测氟通过调控CypD表达影响mPTP异常开放，引起线粒体炫发生紊乱，进而导致学习记忆损伤。因此本项目拟以“氟暴露—CypD—mPTP—线粒体炫—学习记忆损伤”为主线，建立氟暴露的细胞和动物模型，采用药物、病毒转染、基因编辑等干预方法，阐明CypD通过mPTP开放调控线粒体炫在氟致学习记忆损伤中的作用，进一步揭示氟致学习记忆损伤的分子机制和作用靶点，为其早期预防控制提供新的科学依据。

It has aroused great concern about impairment of learning and memory abilities induced by long-term intake of high-fluoride water, which results from special geological environment and other reasons. Mitochondrial dysfunction is closely related with fluoride-induced learning and memory impairment. Recently, it has been found that mitoflash is a dynamic functional event reflecting electrochemical excitabilities in mitochondria. However, the effects of fluoride on mitoflash and the underlying regulatory mechanisms have not been elucidated. In this project, the new analytic results of hippocampal mitochondrial proteomic sequencing in fluoride-treated rats and protein expression in fluoride-treated SH-SY5Y cells showed that fluoride increased protein expression of cyclophilin D (CypD), which has important influence in mitoflash and can regulate mitochondrial permeability transition pore (mPTP). Accordingly, we speculate that fluoride affects abnormal opening of mPTP through regulating CypD expression, causing mitoflash dysfunction and thus resulting in learning and memory impairment. Therefore, in this project the main line is set as “fluoride—CypD—mPTP—mitoflash—learning and memory impairment”, meanwhile cell and animal models of fluoride exposure are established followed by a series of intervention methods such as drugs, virus transfection, gene editing and so on. We aim to clarify the roles of CypD in fluoride-induced learning and memory impairment through regulating mPTP opening and subsequent mitoflash, which further reveals molecular mechanisms and targets of fluoride-induced learning and memory impairment as well as providing new scientific basis for its early prevention and control.