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首页> 外文期刊>Journal of Cellular Physiology >Novel approaches for gene-specific interference via manipulating actions of microRNAs: examination on the pacemaker channel genes HCN2 and HCN4.
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Novel approaches for gene-specific interference via manipulating actions of microRNAs: examination on the pacemaker channel genes HCN2 and HCN4.

机译：gene-specific干扰的新方法通过小分子核糖核酸的操纵行为:考试在起搏器频道HCN2基因和HCN4。

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Recent evidence has suggested microRNAs as viable therapeutic targets for a wide range of human disease. However, lack of gene-specificity of microRNA actions may hinder this application. Here we developed two new approaches, the gene-specific microRNA mimic and microRNA-masking antisense approaches, to explore the possibility of using microRNA's principle of actions in a gene-specific manner. We examined the value of these strategies as rational approaches to develop heart rate-reducing agents and "biological pacemakers" by manipulating the expression of the cardiac pacemaker channel genes HCN2 and HCN4. We showed that the gene-specific microRNA mimics, 22-nt RNAs designed to target the 3'untranslated regions (3'UTRs) of HCN2 and HCN4, respectively, were efficient in abrogating expression and function of HCN2 and HCN4. The gene-specific microRNA mimics repressed protein levels, accompanied by depressed f-channel conductance and the associated rhythmic activity, without affecting mRNA levels of HCN2 and HCN4. Meanwhile, we also designed the microRNA-masking antisense based on the miR-1 and miR-133 target sites in the 3'UTRs of HCN2 and HCN4 and found that these antisense oligodeoxynucleotides markedly enhanced HCN2/HCN4 expression and function, as reflected by increased protein levels of HCN2/HCN4 and If conductance, by removing the repression of HCN2/HCN4 expression induced by endogenous miR-1/miR-133. The experimental examination of these techniques and the resultant findings not only indicate feasibility of interfering miRNA action in a gene-specific fashion but also may provide a new research tool for studying function of miRNAs. The new approaches also have the potential of becoming alternative gene therapy strategies.
机译：最近的证据表明小分子核糖核酸是可行的治疗范围广泛的人类的目标疾病。微行动可能会阻碍这个应用程序。这里我们开发了两个新方法,gene-specific microRNA模仿和microRNA-masking反义方法,探索这种可能性使用microRNA的行动原则gene-specific方式。这些策略是理性的方法心脏rate-reducing代理和发展“生物起搏器”通过操作心脏起搏器通道基因的表达HCN2 HCN4。microRNA模仿,22-nt rna为目标而设计的3 'untranslated HCN2 (3 'utrs)和地区在废除HCN4分别是有效的表达和HCN2和HCN4的函数。gene-specific microRNA模仿压抑的蛋白质水平,伴随着沮丧f-channel电导和相关的节律性活动,在不影响HCN2和HCN4的mRNA水平。与此同时,我们还设计了microRNA-masking反义基于miR-1和mir - 133的目标网站的3 'utrs HCN2 HCN4和发现这些反义oligodeoxynucleotides显著增强HCN2 / HCN4表达式和函数,反映在增加蛋白质水平的HCN2 / HCN4如果电导,移除HCN2的镇压/ HCN4的表情引起内源性miR-1 / mir - 133。这些技术和实验考试结果发现不仅显示干扰microrna的行动的可行性gene-specific时尚但也可能提供一个新的研究工具为研究microrna的函数。的新方法也有潜力成为替代基因治疗策略。

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