糖尿病患者对局麻药(LA)神经毒性更敏感，本团队发现该临床现象与活性氧(ROS)产生过多有关。转录因子KLF9可促进过氧化物酶体增殖物激活受体γ(PPARγ)转录，后者减少ROS而保护高糖环境中的(HG)神经细胞。预实验发现：暴露于布比卡因(Bup)后，HG神经细胞的组蛋白去乙酰化增加，KLF9的保护作用转为损伤，伴PPARγ表达下降，ROS产生增多，损伤加剧。组蛋白去乙酰化酶(HDAC)的拮抗剂可逆转KLF9的损伤作用。因此提出假设：暴露于Bup后，HG神经细胞KLF9与HDAC紧密结合，组蛋白去乙酰化增加，KLF9从促进PPARγ转录转为抑制，增加ROS产生，损伤加剧；若阻断KLF9与HDAC结合，则从表观遗传学层面增强其保护作用。本研究拟采用质粒转染，基因编辑等手段，诱导人多能干细胞(iPSC)获得的的神经细胞及特异性转基因动物为研究对象，予以证实。有利于防治LA加重糖尿病神经损伤。

Patients with diabetic are more sensitive to local anesthetic(LA) neurotoxicity. Our team found that the reason for neurons in hyperglycemia more susceptible to LA is excess production of reactive oxygen species (ROS) . Previous studies have shown that PPARγ as a target of transcription factor KLF9 can regulate intracellular ROS levels and protect cells. Preliminary data showed Preliminary data from our team showed bupivacaine reverse the effect of KLF9 in neurons cultured in HG, from protect to damage effect with histone deacetylation, lower PPARγ expression and ROS overproduction. Inhibitor of Histone deacetylases(HDAC) could stop inhibition effect of KLF9 on PPARγ to improve, reduce ROS, protect cells. We speculate that under exposure to bupivacaine more KLF9 binding to HDAC which result to epigenetically inhibition of KLF9 transcription effect, result in lower PPARγ expression, ROS burst, and neuronal damage. If we could inhibitor the binding between KLF9 and HDAC, KLF9 would only show protective effect. In this study plasmid transfection, gene editing and other molecular biology techniques will be used, and Induced pluripotent stem cells(ipsc)-induced human neural cells and specific transgenic animals will be recruited as the research objects. The aim of the study is to investigate the mechanism underlying the patients with DM is more sensitive to neurological toxicity of LA and to provide a potential target for treatment of the nerve damage caused by bupivacaine.