miRDRN-疾病相關微 RNA 之調控網路:應用於探索 疾病與組織特異性微 RNA 調控網路的工具

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劉學銓(Hsueh-Chuan Liu) 查詢紙本館藏

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系統生物與生物資訊研究所

論文名稱

miRDRN-疾病相關微 RNA 之調控網路:應用於探索疾病與組織特異性微 RNA 調控網路的工具
(miRDRN－miRNA Disease Regulatory Network: A tool for exploring disease and tissue-specific microRNA regulatory networks)

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摘要(中)

微 RNA 透過調控特定的靶基因來達到調節細胞過程。當前已有許多已知數百種微 RNA 和其調控的靶基因，以及許多跟疾病相關的微 RNA 資訊。跟疾病相關的生成，在細胞過程中，通常是經過基因之間的相互作用與基因作用的產物，進而組織並共同參與同一功能反應路徑上，包括一連串複雜的交互作用。大型的蛋白質交互作用資料庫是一個非有有用的資源。在這個研究中，透過彙整上述的相關資訊，我們建構了一個網路服務平台，我們稱為 miRDRN (miRNA Disease Regulatory Network)。它可提供使用者進行建構疾病特異性相關微 RNA 調控網路。該平台公開網址為 http://mirdrn.ncu.edu.tw/mirdrn/，此平台具備兩個特色: (1) 擁有 6,973,875 筆 P 值子路徑資料庫，子路徑是由微 RNA 調控的靶基因-基因 1-基因 2 所構成的鏈，由 78 種組織類型中的 116 種疾病相關 207 種微 RNA，所調控的 389 個靶基因所建構的子路徑清單。(2) 應用於建構疾病和組織特異性相關微 RNA-蛋白質調控網路的可視化工具，可應用於單一疾病或兩種不同疾病的共病研究。依據使用者在搜尋介面上的輸入條件，以及具備互動式的可視化圖形工具，呈現微 RNA-蛋白質調控網路結果。 miRDRN 應用示範，示範一:在大腸癌(colorectal cancer; CRC)單一疾病的研究，識別出 34 個目前未列為 CRC 靶基因的新基因，其中有 26 個基因具有與 CRC 相關的文獻支持。示範二:在阿茲海默症(Alzheimer′s disease; AD)與二型糖尿病(Type 2 diabetes; T2D)的共病研究中，其中 20 個基因是已知的 AD 靶基因或 T2D 的靶基因，並非同時共存在兩個疾病之間。而在我們的研究結果中，其中有 18 個基因是被文獻支持，視為共病的相關基因。在另一個議題上，關於阿茲海默症的抑制劑藥物 BACE1 在晚期的試驗中，最近公告為失敗。為了探究其原因，我們建構以 BACE1 為中心的腦組織特異性微 RNA-蛋白質調控子網路，結果顯示，BACE1 的下游基因，對其抑制可能影響腦神經傳遞的受損。

摘要(英)

miRNA regulate cellular processes through acting on specific target genes. Hundreds of miRNA genes and their target genes are known, as are many miRNA-disease associations. Cellular processes, including those related to disease, proceed through multiple interactions, often organized into pathways among genes and gene products. Large databases on proteinprotein interactions are available. Here, through integration of the information mentioned above, we have constructed a web service platform, miRNA Disease Regulatory Network (miRDRN) that constructs disease specific miRNA-protein regulatory networks. The platform, publicly accessible at http://mirdrn.ncu.edu.tw/mirdrn/, contains two parts: (a) a database that contains 6,973,875 p-valued sub-pathways, in the form of miRNA-target genegene-gene, associated with 116 diseases in 78 tissue types built from 207 diseases-associated miRNAs regulating 389 genes, and (b) a tool that facilitates the construction and visualization of disease and tissue specific miRNA-protein regulatory networks, for single diseases, or disease pairs for the case of comorbidity studies. Results are presented in the form of userinput enabled tables and interactive visualization of the entire constructed miRNA-protein regulatory networks, or parts thereof, such as a sub-regulatory network connected to a specific gene. As demonstrations, miRDRN was applied: to study the single disease colorectal cancer (CRC), in which 34 novel genes not currently listed as CRC target genes were identified, 26 of which have literature support as being CRC related; to study the comorbidity of the disease pair Alzheimer′s disease-Type 2 diabetes (AD-T2D), in which 20 genes that are known as either AD or T2D target genes but not both were identified, 18 of which have literature support to be comorbid; and, for exploring possible causes that may shed light on recent failures of late-phase trials of anti-AD, BACE1 inhibitor drugs, to construct an AD, brain tissue-specific miRNA-protein regulatory sub-network centered on BACE1, in which genes downstream to BACE1 whose suppression may affect signal transduction were identified.

關鍵字(中)

★ 共病基因
★ 大腸癌
★ 阿茲海默症
★ 二型糖尿病
★ 疾病與組織特異性微 RNA 調控網路
★ 資料庫與網路服務工具

關鍵字(英)

★ comorbidity gene
★ colorectal cancer
★ Alzheimer′s disease
★ Type 2 diabetes
★ anti-AD BACE1 inhibitor drug
★ disease and tissue-specific miRNA-protein regulatory network
★ disease-miRNA association
★ target-specific regulatory pathway
★ miRNA-target association
★ database and web service tool

論文目次

Table of Contents
摘要 ............................................................................................ i
Abstract ........................................................................................ ii
Table of Contents ............................................................................... iv
List of Figures ................................................................................. vi
List of Tables .................................................................................. vii
List of Abbreviations ........................................................................... viii
Chapter 1. Introduction ......................................................................... 1
1.1 Interactome resources: Protein-Protein interaction databases ................................ 1
1.2 MicroRNA regulatory network ................................................................. 2
1.3 Molecular and physiopathological mechanisms of diseases ..................................... 3
1.4 A web-accessible interface .................................................................. 4
1.5 Significance and Project Aims ............................................................... 4
Chapter 2. Materials and methods ................................................................ 6
2.1 Data integration ............................................................................ 6
2.2 Construction of miRNA-associated target-specific regulatory sub-pathways .................... 6
2.3 Jaccard score of a regulatory sub-pathway ................................................... 7
2.4 P-value of a regulatory sub-pathway ......................................................... 8
2.5 Assembly and storage of target-specific regulatory sub-pathways ............................. 8
2.6 Construction of disease-specific miRNA regulatory network.................................... 9
2.7 Environment of the service platform ......................................................... 9
2.7.1 Operating system. ......................................................................... 9
2.7.2 Development script ........................................................................ 9
2.7.3 Network visualization ..................................................................... 10
Chapter 3. Results .............................................................................. 11
3.1 miRNA Disease Regulatory Network (miRDRN) – A database and web service platform ............ 11
3.2 Comparison of miRDRN with other miRNA related databases ..................................... 11
3.3 Brief description of usage of miRDRN ........................................................ 11
Chapter 4. Three applications of miRDRN and Discussion........................................... 14
4.1 Case 1: A single disease study of colorectal neoplasm ....................................... 14
4.2 Case 2: A Comorbidity study of the disease-pair Alzheimer′s disease-Type 2 diabetes (AD-T2D) ................................................................................................. 15
4.3 Case 3: A sub-RRN centered on the AD-associated gene BACE1 .................................. 16
Chapter 5. Conclusion ........................................................................... 18
References ...................................................................................... 19

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指導教授

李弘謙(Hoong-Chien Lee)

審核日期

2019-6-21

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