糖尿病性视网膜病变Müller细胞转酮醇酶（TKL）下调的作用及机制

Diabetic retinopathy (DR) that threatens vision, is the leading cause of blindness worldwide. DR is associated with vascular dysfunction and occlusion, retinal edema, hemorrhage, and neovascularization. Müller cell provides nutrients, protect neurons, regulate the homeostasis of potassium, calcium and water balance in the retina, as well as participate in the formation of the blood-retinal barrier, thus play an important role in the pathogenesis of retinal diseases. Increasing evidence suggests that diversion of glycolytic intermediates to the pentose phosphate pathway prevents hyperglycemia-induced microvascular damage. Phosphorylation of this pathway by its key enzyme, transketolase (TKL), is a potential "protective" mechanism in hyperglycemia. Our previous studies reveal that TKL is specifically expressed in retinal Müller cells; the level of TKL protein in the retina of diabetic retinopathy mice is significantly reduced. Based on this, the project will study the key regulatory mechanisms of TKL in diabetic retinopathy. It will verify that the PI3K/Akt/mTOR signaling pathway and candidate microRNAs involved in the regulation of TKL expression under high glucose stress. At the same time, this project will also target on upregulation of TKL in a high glucose environment to correct dysfunction of Müller cells, preventing and slowing the pathogenesis of diabetic retinopathy.

糖尿病视网膜病变(DR)是世界范围内的主要致盲眼病。血管功能障碍和闭塞，视网膜水肿，出血和新生血管生成是DR的主要成因。Müller细胞具有营养、保护神经元，调节视网膜钾、钙离子和水分子的内稳态的功能并参与构成血视网膜屏障。Müller细胞功能失调是许多视网膜疾病的诱因之一。大量证据表明糖酵解中间产物分流到磷酸戊糖途径可以防止高血糖诱导的微血管损伤。此途径通过其关键酶转酮醇酶(TKL)进行磷酸化是高血糖症中潜在的“保护性”机制。我们前期研究表明TKL在视网膜Müller细胞中特异性表达，而糖尿病性视网膜病变小鼠视网膜TKL蛋白水平显著降低。在此基础上，本课题将研究TKL在糖尿病视网膜病变的关键调节机制。验证在高糖应激下，PI3K/Akt/mTOR信号通路以及候选MicroRNA参与TKL的表达调控。同时在体内高糖环境下上调TKL纠正Müller细胞功能失调，预防并减缓糖尿病性视网膜病变。

糖尿病视网膜病变(DR)是世界范围内的主要致盲眼病。血管功能障碍和闭塞，视网膜水肿，出血和新生血管生成是DR的主要成因。Müller细胞具有营养、保护神经元，调节视网膜钾、钙离子和水分子的内稳态的功能并参与构成血视网膜屏障。Müller细胞功能失调是许多视网膜疾病的诱因之一。大量证据表明糖酵解中间产物分流到磷酸戊糖途径可以防止高血糖诱导的微血管损伤。此途径通过其关键酶转酮醇酶(TKL)进行磷酸化是高血糖症中潜在的“保护性”机制。我们的研究表明TKL在人视网膜Müller细胞中特异性表达，而光照小鼠视网膜病变的TKL蛋白水平显著降低。我们的研究表明Müller细胞介导的TKL活性在视网膜应激中起着关键的保护作用。敲低TKL加重 Müller 细胞功能失调及加速光感受器凋亡。在视网膜病变小鼠模型中利用TKL mRNA纠正下调的TKL减缓视糖尿病网膜病变的作用和机制。