MicroRNA网络生物学：协同得分定量评估人体MicroRNA协同相互作用

It has been proven that there are more than 2000 miRNAs being expressed in human genome. Although studies have confirmed that single miRNA play physiological and pathological role via regulating the expression of multiple mRNA genes, the inherent functional interactions between different miRNAs is still unclear. Revealling of the nature and scale of human miRNA-miRNA interactions and especially discovery of potential miRNA combinations with synergisitic theray effect has implications for better apllications of such endogenous substances for the prevention and treatment of major diseases. Innovative establishment of a quantitative assessment parameter synergy score prompted us find and evaluate the significant synergistic effect of miR-1 and miR-21 on anti-mycardial-apoptosis. This result strongly suggests that this miRNA combination can be applied for the treatment of myocardial ischemia and the related human diseases. Based on the fact that a large number of miRNAs are implicated in celluar apoptosis and cellular apoptosis plays vital roles in the development of many major disease pathology, this study will further experimentally evaluate the quantitative assesement performance of synergy score in potent miRNA synergy using the median effect drug synergy theory from the cellular apoptosis perspective, reveal the general law of synergistic miRNA interactions by applying network biology methods, and discover and experimentally comfirm other significant synergistic miRNA combinations expect the above pair of miR-1 and miR-21 in cellular apoptosis.The research results are expected to provide theoretical guidance for the miRNA combination therapy for major human diseases.

现已探明人体中表达超过2000 种miRNA。虽然研究证实单一miRNA可调控多个基因表达而发挥生理病理作用，但对于miRNA之间是否存在内在功能联系还不清楚。揭示人体miRNA相互作用的本质和规模，尤其是发现具有协同治疗效果的miRNA组合，可更好地将此类内源性物质用于重大疾病的预防和治疗。通过创建协同得分这一定量评价参数，我们在前期研究中发现和证实miR-1和miR-21存在显著抗心肌凋亡协同作用，强烈提示此组合可用于心肌缺血相关疾病的治疗。基于以下事实即存在大量miRNA参与细胞凋亡以及细胞凋亡在许多重大疾病病理发展中发挥关键作用，本研究将依据药物协同中效理论，从细胞凋亡角度出发，对协同得分的定量评价性能进行进一步地生物学实验确证，网络生物学揭示miRNA发生协同作用的一般规律，以及发现和证实其它存在显著细胞凋亡协同作用的miRNA组合。研究结果有望为miRNA联合治疗提供理论指导。

microRNAs （miRNAs）在人体疾病过程中起着重要作用。深入揭示miRNAs的作用规律，尤其是当多miRNAs共同参与时，对我们更好地了解和认识这类遗传物质具有意义。本次研究从系统角度入手，运用网络生物学及其他技术和研究方法，在miRNA协同作用可能性、miRNA参与人体复杂疾病的内在关系、如何利用miRNA表达改变进行疾病预防和预后、以及如何理解miRNA在病理发展过程中的中间介质作用等方面展开研究。研究结果表明，协同等分可以有效用于识别协同作用的miRNA组合以及可能参与某一人体复杂疾病的miRNAs。尽管单一miRNA可以作为疾病生物标记物，但多个异常表达miRNAs通过人工神经网络级联模型构成疾病标记物更加稳定。miRNA时序图谱反映出疾病病理发展过程的特点。改变某一基因表达，可导致细胞内miRNA表达谱改变，但这一改变与该基因表达改变导致的表型改变相一致，提示miRNA作为生物信号的中间传递载体。该项研究将加深目前对miRNA作用规律的认识，对将来有效利用该遗传物质用于人体疾病的预防和治疗提供理论指导。