一个功能未知lncRNA-uc.40致胚胎心脏发育畸形的机制研究

项目名称： 一个功能未知lncRNA-uc.40致胚胎心脏发育畸形的机制研究

项目编号： No.81470376

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： 余章斌

作者单位： 南京医科大学

项目金额： 73万元

中文摘要： Uc.40是我们采用芯片发现的、不同物种（人、大鼠、小鼠、斑马鱼）间高度保守、高表达于人发育异常胚胎心脏中、功能未知的一条lncRNA。前期发现：过表达uc.40显著抑制P19细胞向心肌细胞分化；过表达uc.40可致斑马鱼出现心脏畸形表型；软件分析与实验提示PBX1可能为uc.40调控靶标；PBX1低表达于人发育异常胚胎心肌组织中，而文献报道敲除PBX1可致小鼠心脏发育畸形，提示uc.40可能通过调节PBX1致胚胎心脏发育异常。研究拟分析uc.40在心脏发育中的时空表达规律；以基因过表达/沉默技术，在P19细胞、斑马鱼中探讨uc.40对心肌细胞功能和心脏发育的影响；以PBX1为线索，分析uc.40与PBX1的相互作用，论证uc.40通过调控PBX1致胚胎心脏发育异常的机制。阐明人uc.40这一未知功能lncRNA在胚胎心脏发育中的作用与机制，可能为先天性心脏病在妊娠期的早期防治提供新靶标。

中文关键词： uc.40；心脏发育畸形；长链非编码RNA；机制

英文摘要： Uc.40 is a novel long noncoding RNA (lncRNA) of unknown function that is conserved in multiple species (e.g.,human,rat,mouse,zebrafish),and is highly expressed in myocardial tissue of fetuses with heart malformation identified by lncRNA microarray. We previously found that overexpression of uc.40 inhibited cardiac differentiation of P19 cells,and overexpression of uc.40 in zebrafish embryos induced cardiac malformation. Furthermore, bioinformatic analyses and experiments suggested that PBX1 was a putative uc.40 target gene. PBX1 gene showed lower levels in myocardial tissue of fetuses with heart malformation, Pbx1 knock-out mice were reported to display cardiac malformations. These results suggest that uc.40 may induce embryonic heart malformations by regulating PBX1 gene. Based on these data,we propose to analyze the temporal and spatial expression pattern of uc.40 during cardiac differentiation and development, and investigate the function of uc.40 using gene overexpression and gene silencing technology in P19 cells and zebrafish. In addition, we take PBX1 as the clue and analyze the interaction between uc.40 and PBX1,which will explore the molecular mechanism of uc.40-induced cardiac malformations in embryos. The effect and mechanism of uc.40 is clarified in embryonic heart development,which will potentially provide a new target for the prevention and treatment of fetal congenital heart disease.

英文关键词： uc.40;cardiac developmental defect;long non-coding RNA;mechanism