Liu Hsueh-Chuan, Peng Yi-Shian, Lee Hoong-Chien
Department of Biomedical Sciences and Engineering, National Central University, Taoyuan City, Taiwan.
Department of Physics, Chung Yuan Christian University, Zhongli District, Taoyuan City, Taiwan.
PeerJ. 2019 Aug 6;7:e7309. doi: 10.7717/peerj.7309. eCollection 2019.
MicroRNA (miRNA) regulates cellular processes by acting on specific target genes, and cellular processes proceed through multiple interactions often organized into pathways among genes and gene products. Hundreds of miRNAs and their target genes have been identified, as are many miRNA-disease associations. These, together with huge amounts of data on gene annotation, biological pathways, and protein-protein interactions are available in public databases. Here, using such data we built a database and web service platform, miRNA disease regulatory network (miRDRN), for users to construct disease and tissue-specific miRNA-protein regulatory networks, with which they may explore disease related molecular and pathway associations, or find new ones, and possibly discover new modes of drug action.
Data on disease-miRNA association, miRNA-target association and validation, gene-tissue association, gene-tumor association, biological pathways, human protein interaction, gene ID, gene ontology, gene annotation, and product were collected from publicly available databases and integrated. A large set of miRNA target-specific regulatory sub-pathways (RSPs) having the form (, , ) was built from the integrated data and stored, where is a miRNA-associated target gene, ( ) is a gene/protein interacting with ( ). Each sequence (, , ) was assigned a -value weighted by the participation of the three genes in molecular interactions and reaction pathways.
A web service platform, miRDRN (http://mirdrn.ncu.edu.tw/mirdrn/), was built. The database part of miRDRN currently stores 6,973,875 -valued RSPs associated with 116 diseases in 78 tissue types built from 207 diseases-associated miRNA regulating 389 genes. miRDRN also provides facilities for the user to construct disease and tissue-specific miRNA regulatory networks from RSPs it stores, and to download and/or visualize parts or all of the product. User may use miRDRN to explore a single disease, or a disease-pair to gain insights on comorbidity. As demonstrations, miRDRN was applied: to explore the single disease colorectal cancer (CRC), in which 26 novel potential CRC target genes were identified; to study the comorbidity of the disease-pair Alzheimer's disease-Type 2 diabetes, in which 18 novel potential comorbid genes were identified; and, to explore possible causes that may shed light on recent failures of late-phase trials of anti-AD, inhibitor drugs, in which genes downstream to whose suppression may affect signal transduction were identified.
微小RNA（miRNA）通过作用于特定靶基因来调节细胞过程，而细胞过程通过多个相互作用进行，这些相互作用通常组织成基因和基因产物之间的途径。已经鉴定出数百种miRNA及其靶基因，以及许多miRNA与疾病的关联。这些数据，连同大量关于基因注释、生物途径和蛋白质-蛋白质相互作用的数据，都可以在公共数据库中获得。在这里，我们利用这些数据构建了一个数据库和网络服务平台，即miRNA疾病调控网络（miRDRN），供用户构建疾病和组织特异性的miRNA-蛋白质调控网络，借此他们可以探索与疾病相关的分子和途径关联，或者发现新的关联，并有可能发现新的药物作用模式。
从公开可用的数据库中收集并整合了疾病-miRNA关联、miRNA-靶标关联及验证、基因-组织关联、基因-肿瘤关联、生物途径、人类蛋白质相互作用、基因ID、基因本体、基因注释和产物的数据。从整合数据中构建了一大组具有（， ， ）形式的miRNA靶标特异性调控子途径（RSPs）并存储起来，其中 是与miRNA相关的靶基因， （ ）是与 相互作用的基因/蛋白质。每个序列（， ， ）都被赋予一个由这三个基因在分子相互作用和反应途径中的参与度加权的 -值。
构建了一个网络服务平台miRDRN（http://mirdrn.ncu.edu.tw/mirdrn/）。miRDRN的数据库部分目前存储了6,973,875个与78种组织类型中的116种疾病相关的 -值RSPs，这些RSPs由207种与疾病相关的miRNA调节389个基因构建而成。miRDRN还为用户提供了从其存储的RSPs构建疾病和组织特异性miRNA调控网络的工具，以及下载和/或可视化部分或全部产物的功能。用户可以使用miRDRN探索单一疾病，或一对疾病以深入了解共病情况。作为示例，miRDRN被应用于：探索单一疾病结直肠癌（CRC），其中鉴定出26个新的潜在CRC靶基因；研究阿尔茨海默病-2型糖尿病这对疾病的共病情况，其中鉴定出18个新的潜在共病基因；以及探索可能揭示近期抗AD 抑制剂药物晚期试验失败原因的潜在因素，其中鉴定出 下游其抑制可能影响信号转导的基因。
