长链非编码RNA-MALAT1靶向Slit2-Robo4信号调控糖尿病性微血管内屏障损伤的机制研究

项目名称： 长链非编码RNA-MALAT1靶向Slit2-Robo4信号调控糖尿病性微血管内屏障损伤的机制研究

项目编号： No.81470594

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 颜标

作者单位： 南京医科大学

项目金额： 73万元

中文摘要： 微血管病变是糖尿病最常见并发症之一, 是其致死和致残的主要原因之一，主要表现为视网膜、肾脏和神经系统的微血管病变。其中，内屏障的损伤是引发微血管病变的重要病理因素。长链非编码RNA（lncRNAs）是一类重要的基因元件，参与调控众多生理和病理过程。我们前期研究发现，lncRNA-MALAT1主要表达于内皮细胞，在高糖诱发的内皮细胞损伤和视网膜微血管损伤过程发生差异表达。本项目拟采用易于观察的视网膜微血管系统作为研究对象，阐明MALAT1在糖尿病性微血管内屏障损伤过程的调控作用。项目拟建立内皮细胞的高糖损伤模型和糖尿病微血管病变动物模型，分析多个压力和时间点下MALAT1的表达规律；基于MALAT1表达干预，明确MALAT1调控微血管内屏障损伤的作用；基于生物信息学和分子生物学技术，阐明MALAT1调控微血管内屏损伤的分子机制。研究成果有望为防治微血管的功能异常提供新思路。

中文关键词： 长链非编码RNA；微循环；信号通路；微血管内皮细胞；内屏障

英文摘要： Microvascular dysfuntion is one of the most common complications of diabetes mellitus, and one of the leading causes of disability and mortality. Microvascular injury occurs at the small blood vessels all over the body, mainly in the eye, kidney and around nerves. The breakdown of inner barrier is recognized as an important pathologic basis of microvascular dysfunction. lncRNAs have emerged as novel regulatory components of eukaryotic genomes and key players in numerous physiologic and pathological processes. Our previous study has revealed that MALAT1 is mainly expressed in endothelial cells and differentially expressed during hyperglycemia-induced endothelial injury in vivo and in vitro. In this study, we will apply the easily observable vascular system，retinal microvascular, as the model to investigate the role of lncRNAs in microvascular dysfunction. We will detect MALAT1 expression pattern in the retinal endothelial cells or the retina tissue upon high glucose stress at different time points, clarify the role of MALAT1 in retinal endothelial dysfunction through in vitro or in vivo intervention of MALAT1 expression, and reveal the molecular mechanism of MALAT1-mediated endothelial dysfunction. This study will provide novel insights into the prevention and treatment of diabetic-induced microvascular dysfunction.

英文关键词： long noncoding RNA;microcirculation;Signaling pathway;microvascular endothelial cell;inner barrier