SIRT1介导的Resveratrol对糖尿病视网膜病变“代谢记忆”的作用及其机制研究

项目名称： SIRT1介导的Resveratrol对糖尿病视网膜病变“代谢记忆”的作用及其机制研究

项目编号： No.81500734

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 蒋婷婷

作者单位： 复旦大学

项目金额： 18万元

中文摘要： 氧化应激，慢性炎症及细胞凋亡在糖尿病视网膜病变（DR）的发病机制中发挥重要作用，这些改变具有代谢记忆现象。SIRT1调控的组蛋白乙酰化改变可能是糖尿病视网膜损伤代谢记忆产生的潜在机制。Resveratrol是SIRT1的激活剂，可改善糖尿病肾脏病变。但Resveratrol对糖尿病视网膜病变的保护研究较少，特别是其对代谢记忆的影响未清晰阐明。高血糖早期， TXNIP 表达升高，可活化 NF-κ B，激活 NLRP3，调控细胞粘附因子表达，被认为是控制DR发生发展的重要靶点。Nrf2是细胞内调节氧化应激反应的重要转录因子。本实验旨在探讨Resveratrol对糖尿病视网膜病变的作用，重点观察其能否阻止代谢记忆现象，并验证这一作用是否通过 SIRT1 介导的组蛋白乙酰化修饰，调控 TXNIP-NLRP3， NF-κ B 以及 Nrf2 通路，继而调节凋亡蛋白，炎症因子水平及抗氧化酶表达实现。

中文关键词： 糖尿病视网膜病变；去乙酰化酶；代谢记忆；表观遗传

英文摘要： Oxidative stress, chronic inflammation and apoptosis plays an important role in the pathogenesis of diabetic retinopathy (DR). These changes have metabolic memory phenonmenon which means that good glycemic control, if reinstituted after a period of poor control, fails to halt the disease. Epigenetic modifications, especially the post-translational modifications of histone contributes to the metabolic memory. Class III histone deacetylase sirtuin 1 (SIRT1) is a multifunctional protein critically involved in stress responses, cellular metabolism, and aging through deacetylating a variety of substrates, including histones and transcription factors and coregulators, to regulate target gene expression both positively and negatively. SIRT1 may be an underlying mechanism for the metabolic memory of diabetic cells. Oxidative stress, chronic inflammation and apoptosis plays an important role in the pathogenesis of diabetic retinopathy (DR). These changes have metabolic memory phenonmenon which means that good glycemic control, if reinstituted after a period of poor control, fails to halt the disease. Epigenetic modifications, especially the post-translational modifications of histone contributes to the metabolic memory. Class III histone deacetylase sirtuin 1 (SIRT1) is a multifunctional protein critically involved in stress responses, cellular metabolism, and aging through deacetylating a variety of substrates, including histones and transcription factors and coregulators, to regulate target gene expression both positively and negatively. SIRT1 may be an underlying mechanism for the metabolic memory of diabetic cells. Resveratrol is an activator of SIRT1. It can attenuates renal hypertrophy and alleviates cardiac dysfunction in streptozotocin-induced diabetes. But its effect on DR, particularly its impact on the metabolic memory and the underlying molecular mechanisms have not yet been clearly elucidated. TXNIP has a critical role in inflammation and retinal injury in early stages of DR. It can regulate the expressions of NF-κ B, NLRP3 and cell adhesion molecules. It has been considered to be an important target to control the development of DR. Nrf2 is a master regulator of cellular antioxidant response and is a transcriptional factor that controls the expression of phase 2 genes like GCL and HO-1 This study is to investigate the effects and mechanisms of Resveratrol on diabetic retinopathy, focusing on the metabolic memory phenomenon.

英文关键词： diabetic retinopathy ;HDAC ;metabolic memory;epigenetic