磷脂酸磷酸酶Lipin1通过调控突触线粒体动力学影响糖尿病脑病发生的机制研究

糖尿病脑病是糖尿病常见的中枢神经系统并发症，临床缺乏有效的防治手段。近年发现，突触线粒体损伤是糖尿病脑病的重要病理变化，但机制不清。申请人前期研究表明，糖尿病脑病大鼠海马区神经突触可塑性失调，高通量测序显示miR-203a表达显著增加。进一步研究发现，糖尿病脑病大鼠海马区突触线粒体动力学稳态失衡，并伴随miR-203a靶向调控蛋白Lipin1的表达降低；而过表达海马区Lipin1则显著改善线粒体动力学紊乱和突触可塑性失调，并改善大鼠的认知功能障碍。由此我们推测，Lipin1可能通过调控线粒体动力学稳态，影响突触可塑性调节，继而参与糖尿病脑病的发生。因此本项目拟研究：1）Lipin1通过调控线粒体动力学稳态影响突触可塑性的分子机制；2）miR-203a/Lipin1通路在认知功能障碍及糖尿病脑病发生中的作用。从而阐明突触线粒体动力学稳态介导糖尿病脑病发生的机理，为临床治疗提供新的药物靶点。

Diabetic encephalopathy is a common central nervous system (CNS) complication in diabetes mellitus. Currently, no effective therapy exists to prevent or cure these CNS deficiencies. Recent studies have highlighted synaptic mitochondrial damages as an important pathological change in diabetic encephalopathy, but the precise mechanism remains unclear. Applicant’s preliminary data found hippocampal synaptic plasticity depression in our diabetic encephalopathy rat model with increased miR203a expression in high-throughput sequencing. Later study demonstrated imbalanced hippocampal mitochondrial dynamics in our diabetic encephalopathy rat model with decreased Lipin1 level, which is miR-203a targeted regulatory protein; restored Lipin1 expression in diabetic encephalopathy rat hippocampi could significantly ameliorate mitochondrial dynamics imbalance, synaptic plasticity depression and also rescue cognition in diabetic encephalopathy rat model. Thus, we speculate that Lipin1 could affect the regulation of synaptic plasticity through adjusting mitochondrial dynamic homeostasis and then play a role in the onset of diabetic encephalopathy. Therefore, this project intends to study: 1) the molecular mechanism of how Lipin1 affects synaptic plasticity through regulating mitochondrial dynamics homeostasis; 2) the role of miR-203a/Lipin1 pathway in cognitive impairment and diabetic encephalopathy pathogenesis. Thereby we could expound the mechanism of how synaptic mitochondrial dynamics mediated diabetic encephalopathy pathogenesis and provide new therapeutic target.