长链非编码RNA异常表达对早产儿视网膜病变的影响机制研究

Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides.LncRNAs are evolutionally conserved in the brain and eye and important in regulating neural and retinal development. Recent studies suggest that the abnormal expression of some lncRNAs may be associated with diabetic retinopathy; However, the relation between lncRNA and retinopathy of prematurity (ROP) remains unknown. We previously found that dysregulation of CCN1/VEGF and PEDF expression is critical for retinal neovascularization (RNV) in a mouse model of oxygen-induced retinopathy. We recently found that lncRNAs were abnormally expressed in ROP mouse, suggesting the potential roles of lncRNAs in ROP.Our study explore abnormal expression law of lncRNA in ROP,analyze the mechanism of lncRNA on ROP specific related protein expression, and hypothesize that lncRNA promote ROP/RNV.To test our hypotheses, we will use lncRNA expression microarray to identify the expression profile of lncRNA related to ROP, the critical lncRNA(s) to regulate CCN1/VEGF and PEDF to promote ROP/RNV and the molecular mechanism, and the therapeutic effects of targeting lncRNA for inhibition of ROP/RNV in vivo. We believe that our study will not only elucidate the novel functions of lncRNA in ROP/RNV but also provide new strategy for ROP therapy.

长链非编码RNA（lncRNAs）是具有调控功能长度大于200个碱基的非编码RNA，在脑眼组织中高度保守，对神经系统及视网膜发育至关重要。近期有研究发现lncRNAs表达异常与糖尿病视网膜病变相关，但有关早产儿视网膜病变（ROP）与lncRNA的关系尚未见报道。我们前期研究发现CCN1/VEGF及PEDF表达失调是ROP的视网膜新生血管（RNV）形成的关键因素，近期研究提示ROP小鼠存在lncRNAs表达的异常。本研究探索ROP中lncRNA的异常表达规律，解析其对ROP特定相关蛋白表达的影响机制，建立其促进ROP/RNV形成的工作假说。我们拟用lncRNA表达芯片从基因组水平探讨lncRNA的表达与ROP的关系，建立ROP相关的lncRNA差异表达谱，鉴定影响ROP/RNV形成的关键lncRNA及阐明其调控机制，并检测靶向lncRNA对体内抑制RNV形成的作用，为ROP的治疗提供新途径。

早产儿视网膜病变（ROP）为严重的致盲眼病，视网膜新生血管 (RNV) 形成在该病发病机理中起主导作用，因此有必要从基因组和分子水平深入寻找RNV的关键性靶点。长链非编码RNA（lncRNAs）是具有调控功能长度大于200个碱基的非编码RNA，在脑眼组织中高度保守，对神经系统及视网膜发育至关重要。近期有研究发现lncRNAs表达异常与糖尿病视网膜病变相关，但有关ROP与lncRNA的关系尚未见报道。本项目采用了高通量lncRNA表达芯片分析，比较ROP组与对照组小鼠视网膜中lncRNA表达的差异性，通过芯片数据库分析及生物信息分析，确定了与ROP/RNV相关的lncRNA表达谱，并选取其中差异表达最大者深入研究其在ROP/RNV形成过程中的生物作用及可能分子机制。结果显示与对照组小鼠比较，ROP组有43个lncRNA和24mRNA表达上调，14个lncRNA和18mRNA表达下调。异常表达的lncRNA参与了视网膜发育相关通路，在视网膜RNV形成中发挥了重要作用。选取差异表达最大者TUG1、MALAT1，发现其上调VEGF从促进RNV形成，再者，通过siRNA敲低TUG1、MALAT1，可抑制视网膜RNV的形成。综上所述，本项目的研究结果为ROP防治提供了新的思路和途径，从而为广大ROP患儿及其家庭带来了福音。