复杂疾病中ncRNA协同调控的通路高异常区域之间的crosstalk识别与功能研究

Many studies showed that ncRNAs could regulate pathways and expression of key protein encoding genes with them by mainly synergistic effect. Meanwhile, our and other studies indicated that in complex diseases, the abnormal crosstalk between pathways often happens. Therefore, ncRNAs, as important regulators, can obviously regulate information transfer process between pathways. However, which ncRNAs can regulate abnormal crosstalk between key pathways in a specific complex disease is still an important scientific problem in doubt. Therefore, the project will construct new direct graph models based on pathway reconstruction with ncRNAs as key regulatory nodes. Through integrating target sequence information of ncRNAs and protein encoding genes, information of their co-expression and competing endogenous RNAs, and pathway structure information, we will develop new algorithms for effectively identifying crosstalk between high abnormal regions of pathways synergistically regulated by ncRNAs. Finally, through performing cross-validation among data in multiple diseases, ncRNAs and the regions between pathways regulated by them will be systematically analyzed. Then, key functional ncRNAs and regions will be mined. Furthermore, the clinical application value will be evaluated via analyzing relationships between these ncRNAs/regions and environment risk factors, disease diagnosis, prognosis and drug target.

许多研究显示ncRNA主要通过协同合作的方式调控通路及内部的关键蛋白编码基因表达。同时，我们及他人的实验结果表明，复杂疾病中经常发生通路间的异常交互（crosstalk）。那么，ncRNA作为重要的调控子，显然能够调控通路间的信息传递过程。然而，一个重要科学问题，即：哪些ncRNAs调控了特定复杂疾病中关键通路间的crosstalk的异常，尚不清楚。为此，本项目将构建以ncRNA为关键调控节点的疾病特异的有向通路重构图新模型；通过结合ncRNA与蛋白编码基因的序列靶向信息、共表达及竞争性内源关系信息、通路结构信息，开发新算法有效识别ncRNA协同调控的通路高异常区域之间的crosstalk。最后，通过多种复杂疾病数据的交叉验证、系统分析ncRNAs及所调控的通路间区域，挖掘出那些功能关键的ncRNA和区域，进一步评估它们与环境风险因素、疾病诊断、预后和药物靶点的潜在关系和临床应用价值。

许多研究显示ncRNA、mRNA等RNA,借助miRNA调控通路及内部的关键蛋白编码基因表达及通路间的交互。本项目按照研究计划内容，对传统的代谢和信号通路进行有效的重构，整合ncRNA、编码基因和它们在通络内的拓扑结构信息，构建了以ncRNA为关键调控节点的疾病特异的有向通路重构图新模型。我们收集了GEO、TCGA、UCSC和ArrayExpress数据库中各种复杂疾病基因表达谱。通过融合ncRNA与蛋白编码基因的序列靶向信息、基因共表达、竞争性内源关系信息、以及通路拓扑结构信息，开发了新算法有效识别ncRNA调控的高异常通路及通路高异常区域之间的crosstalk。通过多种复杂疾病数据的分析，验证了本项目的方法具有高度的准确性、稳定性、可复现性。进一步系统的分析ceRNA、所调控的通路及它们之间区域的交互属性，发现了复杂疾病共性和特异性的ceRNA关系及通路网络。我们挖掘出功能关键的通路、子通路、ncRNA和crosstalk区域，进一步评估了它们的癌症预后等潜在医学价值。除此之外，我们发现了大量ceRNA相关的癌症lncRNA被增强子和超级增强子操控，暗示了增强子很可能通过调控ncRNA的表达水平，从而借助ceRNA调控通路，扩散它对于癌症等复杂疾病发生和发展的影响。综合以上所述，本项目的执行对阐明复杂疾病发生、发展的生物学通路机制，以及促进生物分子网络在复杂疾病研究中的应用具有重要意义。本项目执行期间，已发表论文6篇,建立了能够支持大量复杂疾病的ncRNA调控的高异常通路区域及交互关系识别的软件分析平台。