PI3K/Akt通路对糖尿病雪旺氏细胞SREBP-1表达的影响及机制研究

Reduced lipid content of peripheral nerve leads to abnormal myelin structure and function, which in turn causes decreased nerve conduction velocity in diabetes mellitus. Decreased SREBP-1 expression is an important factor that results in lessened lipid content in Schwann cells and myelin. PI3K/Akt pathway has been confirmed to be the upstream pathway that regulates SREBP-1 expression in various tissues including kidney, muscle and fiber. We speculate that PI3K/Akt pathway may participate in the regulation of SREBP-1 expression in Schwann cells of diabetic peripheral neuropathy. It is revealed in our preliminary experiments that phospho-Akt decreased in both the sciatic nerves of diabetic mice and high glucose-stimulated rat Schwann cells (RSC96) accompanied by reduced SREBP-1. Again, inhibition of Akt phosphorylation lessens SREBP-1 expression in RSC96 cells. However, the exact mechanism is still not known. Therefore, the activities of Akt and its downstream targets, mTOR and GSK-3β, are regulated via phosphorylation status changes that is followed by the detections of SREBP-1 expression and cellular lipid metabolism to illuminate the effect and mechanism of PI3K/Akt pathway on SREBP-1 decrease in Schwann cells of diabetes mellitus.

糖尿病周围神经脂质含量减少是导致髓鞘结构、功能异常，进而造成神经传导速度减慢的原因之一，雪旺氏细胞内固醇调节元件结合蛋白-1（SREBP-1）的表达减少是导致周围神经髓鞘脂质减少的重要原因，PI3K/Akt通路在肾脏、肌肉、纤维等多个组织器官被证实可调控SREBP-1的表达。我们推测PI3K/Akt通路可能也参与了糖尿病雪旺氏细胞SREBP-1减少的调控，在预实验中发现糖尿病小鼠坐骨神经雪旺氏细胞及高糖刺激的大鼠雪旺氏细胞RSC96均出现磷酸化Akt减少和SREBP-1表达下降，抑制Akt磷酸化显著降低了RSC96细胞SREBP-1的表达，然而调控的确切机制还不清楚。故本项目拟针对Akt及其下游靶点mTOR和GSK-3β，通过调控三者磷酸化状态来改变其活性，并检测SREBP-1表达和细胞脂质代谢，阐明PI3K/Akt通路对糖尿病雪旺氏细胞SREBP-1表达减少的影响及机制。

糖尿病周围神经病是糖尿病的最常见并发症，严重影响患者的生活质量，甚至生命。但目前对于糖尿病周围神经病，除了降血糖及营养神经等对症治疗，仍缺少有效的针对性治疗。.PI3K/Akt/mTOR通路是调控细胞增殖、分化及代谢等的重要通路，SREBP-1是细胞内调控脂肪酸代谢的重要转录因子，Bcl-2家族是调控线粒体途径凋亡的主要蛋白，BDNF是中枢神经系统及周围神经系统的重要神经营养因子，本项目采用糖尿病小鼠及体外培养的大鼠雪旺氏细胞，对PI3K/Akt/mTOR通路、脂肪酸合成、细胞凋亡及BDNF表达，进行了深入研究。.研究结果揭示PI3K/Akt及mTOR通路在糖尿病周围神经雪旺氏细胞中被显著抑制，是导致糖尿病周围神经病发生的重要原因，有如下机制：（1）PI3K/Akt及mTOR通路抑制可通过下调SREBP-1表达，影响周围神经的脂肪酸合成及髓鞘结构；（2）PI3K/Akt及mTOR通路抑制可通过影响雪旺氏细胞Bcl2及Bax表达，启动线粒体途径的凋亡；（3）PI3K/Akt及mTOR通路抑制也可通过上调DNMT1，增加BDNF启动子甲基化，抑制其转录。.研究表明PI3K/Akt/mTOR通路抑制是糖尿病周围神经病发生的重要原因，并阐明了致病的相关分子机制，为糖尿病周围神经病的防治调控了干预靶点及理论支持，针对PI3K/Akt/mTOR通路的干预有望延缓和治疗糖尿病周围神经病。