CircHIPK3介导的miR-124/JAK/STAT3信号通路轴在Behcet病发生中的作用及机制研究

Behcet's disease(BD) is a subtype of uveitis with high morbidity and the high rate of blindness in China, its pathogenesis is not clear. Our previous studies showed that JAK/STAT3 signaling pathway play a significant role in the pathogenesis of BD. Bioinformatics prediction and previous literature both suggest that miR-124 is involved in the regulation of JAK/STAT3 signaling pathway，and circHIPK3 acted as a miR-124 sponge to regulate its expression and involved in the occurrence of disease. Notably, our pilot study found that circHIPK3 expression increased and miR-124 expression decreased significantly in both peripheral blood and iris tissues among BD patients, which means they two could be in the mechanism of BD occurrence. This project proposed to enroll BD patients and normal controls and clarify the role of circHIPK3 and miR-124 in different disease courses and clinical manifestations. Besides, we will investigate the effects of circHIPK3 on miR-124/JAK/STAT3 signaling axis by circHIPK3 function deficiency and acquisition on both cell and EAU mouse model. Finally, we will explore the regulation function of circHIPK3 by its differential miR-124 signaling pathway.This study aims to clarify the mechanism and function of circHIPK3 and miR-124/JAK/STAT3 in the process of BD, thus providing a new strategy for the prevention and treatment of this disease.

Behcet病（BD）是我国最常见致盲性葡萄膜炎之一，发病机制不明。我们前期发现JAK/STAT通路在其中发挥关键作用；生物信息学预测及既往文献均提示此通路可被miR-124调控。有意思的是，研究发现circHIPK3通过对miR-124的“吸附”作用调节后者表达，参加疾病的发生。我们通过芯片谱筛选发现BD患者外周血和虹膜组织circHIPK3表达升高，miR-124降低，提示两者均可能参与该病的发生。本项目拟以BD患者为研究对象，通过对BD和正常人大样本的表达研究阐明circHIPK3和miR-124在疾病不同病程和临床表现中的作用；通过细胞和动物模型中的circHIPK3功能缺失/获得实验探讨其对miR-124/JAK/STAT3信号轴的影响；从miR-124差异性表达探讨circHIPK3通过其介导信号的调控作用。通过上述研究阐明它们在BD发生中的作用及机制，为该病防治提供新的策略。

糖尿病角膜病变(DK)是重要的糖尿病并发眼病。糖尿病的高血糖状态引起细胞糖代谢失衡，进而改变蛋白质翻译后修饰。通过蛋白质组学测序，我们发现与糖基化修饰相关的AGE-RAGE信号轴在模型组中激活，AGEs累积可导致氧化应激损伤，炎症因子表达增加，而既往研究提示小分子药物α-硫辛酸(ALA)可以抑制AGEs。据此我们提出科学假设：ALA可以减少糖尿病导致的AGEs累积，进而减轻角膜内皮氧化应激损伤和炎症反应，减缓DK的进展。本项目构建了人角膜内皮细胞(HCECs)高糖损伤模型，利用ALA减少AGEs的累积。探讨AGEs与细胞增殖能力、氧化应激、凋亡、炎症因子表达等方面的相关性，并探索其作用机制。研究结果显示，ALA处理可减少细胞内AGEs累积，进而改善高糖处理的HCECs增殖能力，减少ROS产生和细胞凋亡，同时，AGEs减少可抑制TLR4/NLRP3信号通路，减轻HCECs的炎症因子表达。我们还进一步探明AGEs在糖尿病视网膜病变中具有相似作用。本研究为ALA应用于DK患者提供了理论基础，并提示AGEs可能是以糖尿病角膜病变为代表的糖尿病并发症的潜在治疗靶点。