基于sEH/19,20-DHDP/Notch信号通路探讨高糖下利拉鲁肽改善Müller细胞反应性增生的研究

Diabetic retinopathy (DR) has the characteristics of high incidence and blindness rate, which seriously threatens the quality of human life. Previous research have proved expression of glucagon-like peptide-1 (GLP-1) receptor on the surface of retinal ganglion cells, and confirmed that GLP-1 had protective effects on neurodegeneration and vascular lesions in DR. However, the protective mechanism of GLP-1 on Müller cells, which play a key role in nerve injury and vascular, has not been fully elucidated. Recent studies have confirmed that soluble epoxide hydrolase (sEH) ,secreted by Müller cells, is a key enzyme in retinal permeability. Therefore, we hypothesize that GLP-1 can improve the reactive proliferation of Müller cells under high glucose by inhibiting sEH/19, 20-DHDP/Notch signaling pathway. This research will explore the effect of GLP-1 on the proliferation of Müller cells in DR, and establish a comprehensive map of the effect of GLP-1 on the morphological and functional changes of Müller cells under high glucose. On this basis, the relationship between abnormally activated sEH/19,20-DHDP/Notch signaling pathway and Müller cell proliferation was revealed, and the molecular mechanism of GLP-1 inhibiting Müller cell activation based on sEH/19,20-DHDP/Notch signaling pathway was discussed. This study enriches the mechanism of Müller cell reactive proliferation, opens up new ideas for exploring the multiple effect of GLP-1, and provides theoretical basis of new therapeutic targets in DR.

糖尿病视网膜病变（DR）具有高发病率、高致盲率的特点，严重威胁着人类的生存质量。在前期研究中，申请者已证实胰高血糖素样肽-1（GLP-1）对DR中的神经病变及血管病变均有保护作用。但GLP-1对在神经损伤与微循环调节障碍中起关键作用的Müller细胞的保护机制尚未阐明。最新研究证实Müller细胞分泌的可溶性环氧化物水解酶（sEH）是导致DR的关键酶。故我们设想GLP-1可通过抑制sEH/19,20-DHDP/Notch信号通路改善高糖下Müller细胞反应性增生。本项目将探讨GLP-1对DR中Müller细胞反应增生的作用，全面建立GLP-1对高糖下Müller细胞形态和功能变化的影响图谱。在此基础上，揭示异常活化的sEH/19,20-DHDP/Notch信号通路与Müller细胞反应增生的关系。本研究丰富了Müller细胞反应性增生的机制，为GLP-1降糖外的多效性探索开辟新思路。

糖尿病视网膜病变（DR）具有高发病率、高致盲率的特点，严重威胁着人类的生存质量。 在前期研究中，课题组已证实胰高血糖素样肽-1（GLP-1）对DR中的神经病变及血管病变均有保护作用。但GLP-1对在神经损伤与微循环调节障碍中起关键作用的Müller细胞的保护机制尚未阐明。为此本课题组通过单细胞测序、蛋白组学等技术手段在动物及细胞层面中证实Müller细胞在DR发生发展过程中的重要作用及GLP-1 受体激动剂对于 DR 视网膜 Müller细胞局部微环境的影响，发现细胞外基质失调参与DR早期müller细胞反应性胶质增生，证明利拉鲁肽通过GLP-1R/sEH/Notch1/Hes1通路改善DR早期müller细胞反应性胶质增生。全面建立GLP-1对高糖下Müller细胞形态和功能变化的影响图谱。在此基础上，揭示高糖下细胞外基质的变化与Müller细胞反应增生的关系。本研究丰富了Müller细胞反应性增生的机制，为GLP-1降糖外的多效性探索开辟新思路。