反义lncRNA标志物筛选策略及其在肝脏缺血再灌注损伤中的应用研究

Long non-coding RNAs (lncRNA) have the functions of coding gene expression regulations in a variety of ways, and are also correlated with many diseases development and advances. The features of lncRNA make it possible to become biomarkers of complex diseases. The amount of lncRNA is huge, but only a few of them have been identified with their functions because of their features, like less conservative, high specificity, etc. In our preliminary experiments, there are significant structural characteristics of between antisense lncRNAs and their target genes, yet the functions of antisense lncRNAs are related to the target genes. Bioinformatics techniques were used to Identify the target genes effectively is the first step in characterizing the function of antisense lncRNAs in a genome-wide scale, contributed to predict the functions and realize the genetic regulations of differential expression antisense lncRNAs. Biomarkers of complex diseases will be selected successfully in the end. Based on the fore works, the project plans to further invest the computational bioinformatics strategies of screening antisense lncRNA biomarkers of hepatic ischemia-reperfusion injury (HIRI) and predict the target genes with the significant differences of gene expressions in the mouse model and plasma samples of before and after surgery, construct and analyze the gene co-expression network between differentially expressed antisenses lncRNAs and their targets, select the lncRNA biomarkers in Plasma, then compare and validate. The newfound biomarkers may provide helps for genome-wide understanding of the pathogenesis of HIRI and the identification of intervention targets for drug intervention.

长链非编码RNA（lncRNA）通过多种方式调控编码基因的表达，参与多种疾病的发生发展，具有成为疾病诊断标志物和药物靶点的巨大潜力。lncRNA数量巨大，但因其具有保守性低、特异性高等特点，功能明确的很少。我们的前期研究表明，反义lncRNA与其靶向基因在结构上存在显著关联，功能上密切相关。运用生物信息学方法研发高效的反义lncRNA靶向基因预测策略不仅有助于在全基因组内快速预测反义lncRNA基因靶向基因，也有助于深入分析差异表达反义lncRNA的功能及其调控机制，进而筛选出疾病的反义lncRNA生物标志物。本项目拟以肝脏缺血再灌注损伤（HIRI）为对象，深入研究反义lncRNA靶向基因的预测策略，预测出HIRI小鼠模型和HIRI患者术前、术后血浆标本中显著差异表达反义lncRNA的靶向基因，构建并分析反义lncRNA及其靶向基因的共表达网络，筛选出预防或缓解HIRI的血浆lncRNA分子标志物，并通过实验进行验证，为从全基因组范围内分析HIRI发病机制及其药物干预靶点提供研究基础。

长链非编码RNA（lncRNAs）通过多种方式调控编码基因的表达，参与多种疾病的发生发展，具有成为疾病诊断标志物和药物靶点的巨大潜力。高效的lncRNA靶基因预测策略不仅有助于在全基因组内快速预测lncRNA基因靶向基因，也有助于深入分析差异表达lncRNA的功能及其调控机制，助力筛选出疾病的lncRNA生物标志物。本项目采用生物信息学方法对lncRNA调控疾病功能进行了全面研究，完成了预期的研究目标，取得的成果主要包括：（1）基于整合lncRNA一级序列和二级结构模型lncRNA靶基因预测模型以及基于双重分割策略的筛选核心绑定区域算法；（2）建立基于集合的miRNA的功能富集分析新模型，首次把功能细分为上调和下调两类；（3）基于多属性信息的lncRNA功能富集分析模型以及基于1-N和M-N的lncRNA功能相似性分析算法；（4）基于疾病语义计算的非编码RNA功能相似性预测算法及其工具；（5）预测小鼠肝脏缺血再灌注损伤中的差异表达lncRNA的靶基因，并筛选lncRNA生物标志物；（6）预测人肝脏缺血再灌注损伤血浆样本中的差异表达lncRNA的靶基因，并筛选lncRNA生物标志物；（7）升级人类microRNA疾病数据库并对预测miRNA-疾病关联的软件进行了全面评测。.在本项目的资助下，项目组在国内外重要学术刊物发表学术论文14篇，其中ESI高被引论文1篇，影响因子大于10的学术论文5篇。本项目为包括lncRNA的非编码RNA功能研究提供新方法、新模型、新软件和数据库，为研究非编码基因调控功能提供新选择，并筛选出具有成为肝脏缺血再灌注损伤生物标志物潜力的lncRNA。