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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉旻禕 | zh_TW |
| dc.contributor.advisor | Helene Minyi Liu | en |
| dc.contributor.author | 李宇軒 | zh_TW |
| dc.contributor.author | Yu-Hsuan Lee | en |
| dc.date.accessioned | 2021-07-11T15:21:27Z | - |
| dc.date.available | 2024-08-16 | - |
| dc.date.copyright | 2019-03-11 | - |
| dc.date.issued | 2019 | - |
| dc.date.submitted | 2002-01-01 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78816 | - |
| dc.description.abstract | 全基因體分析顯示在哺乳動物中，基因體約有百分之九十八的比例屬於不轉譯成蛋白質的核醣核酸，其中根據鹼基對大小定義:大於兩百個鹼基對的核醣核酸被稱為長鏈非轉譯型編碼核醣核酸。而近年，已有越來越多研究顯示，有一群長鏈非轉譯型編碼核醣核酸會參與調控抗病毒先天性免疫反應，因此我們好奇這群基因調控的詳細分子機制為何，首先直接以Interferon-β刺激肝癌細胞二十四小時後，利用核醣核酸微陣列方法篩選出被誘導的基因群。選取之中一條長鏈非轉譯型編碼核醣核酸，Hepsin Antisense1 (HPN-AS1)做為具研究潛力的候選基因。利用定量即時聚合酶鏈鎖反應再次確認第一型干擾素會誘導HPN-AS1的核醣核酸表現，同時也發現誘導的表現型只有在肝臟細胞株中會被第一型干擾素刺激及仙台病毒感染後觀察到。為了排除是仙台病毒特異性造成的影響，也以轉染質體信號傳導接頭蛋白MAVS,IRF3-5D，去廣泛性活化第一型干擾素路徑，結果顯示誘導的HPN-AS1只表現在肝臟中，再次說明HPN-AS1是一個肝細胞特有的第一型干擾素刺激型基因。接下來從轉錄因子結合位資料庫的預測結果中，偵測到在HPN-AS1序列上游有參與第一型干擾素相關的轉錄因子存在，例如STAT1,NFκB,c-Jun的結合序列，其中特別是在上游1至2 Kb有較多的預測結果，推測這有可能是誘導HPN-AS1表現的原因之一。因此我們將HPN-AS1上游的序列放大、選殖入到帶有螢光基因的質體前，觀察在第一型干擾素路徑活化時，HPN-AS1上游序列是否會受到轉錄因子調控?結果顯示確實在HPN-AS1上游1至2 Kb的序列有較高的螢光表現被誘導，與預測的結果相符合。接下來，為了要找出HPN-AS1調節的機制，我們利用了兩個策略觀察HPN-AS1在抗病毒反應中扮演的角色。從HPN-AS1 knockdown的實驗結果發現，仙台病毒複製的能力較高，並且第一型干擾素的生成顯著較控制組差;另一方面，在HPN-AS1過度表現的研究顯示，誘導表現的第一型干擾素較高，而且在宿主中偵測到病毒核醣核酸顯著較控制組少，顯示HPN-AS1應作為一個第一型干擾素的正向調節者。另外，我們也發現誘導表現的HPN-AS1主要存在於細胞質中。根據以上的實驗結果，本次研究中發現了一個肝細胞特有的第一型干擾素刺激型基因，HPN-AS1在先天性免疫中會正向調節並且參與第一型干擾素的抗病毒反應路徑。 | zh_TW |
| dc.description.abstract | Whole genome analysis has revealed that 98% are non-coding transcripts. Of them, it has been reported that some of the long noncoding RNAs (LncRNAs) could act either as positive or negative regulators in the type I interferon induction and/or response pathway. By an RNA array analysis of LncRNAs induced by IFN-β in hepatocytes, we found that a LncRNA, Hepsin-Antisense 1 (HPN-AS1), was induced. HPN-AS1 transcript is partially overlapped with Hepsin coding sequences. However, the functional role of this LncRNA is unclear. We next tested the expression of HPN-AS1 in several cell lines, and the interferon-inducible expression of HPN-AS1 was only in the hepatocytes. During Sendai virus infection, the expression of HPN-AS1 was as well upregulated only in hepatocytes, indicating that HPN-AS1 is a hepatocyte-specific interferon-stimulated long noncoding RNA. The expression of HPN-AS1 was also induced by overexpression of MAVS or IRF3-5D, suggesting that HPN-AS1 expression is IRF3-dependent. By searching through three different transcription factor binding site databases, we discovered several transcription factors, such as STAT1, NFκB, c-Jun, might prime to the expression of HPN-AS1. We then cloned the upstream sequences of HPN-AS1 into a firefly luciferase-based reporter vector to determine the promoter activity of HPN-AS1, and the results showed that the HPN-AS1 promoter activity was upregulated upon the activation of type I IFN. By pooled knocking-down the expression of HPN-AS1, we found the mRNA expression of IFN-β was lower and Huh7 cells were more permissive to Sendai virus (SeV) infection. In contrast, the induction of type I IFN was higher and SeV viral RNAs were lower in the ectopically expressing-HPN-AS1 HEK293T cells upon virus infection. Furthermore, the results showed that the induction of HPN-AS1 by type I IFN mainly localized in cytoplasm. Taken together, it indicated that a liver-specific IFN-stimulated lncRNA, HPN-AS1 may serve as a cytoplasmic positive feedback regulator of type I IFN. The molecular mechanisms of how HPN-AS1 may contribute to antiviral activities will be discussed. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:21:27Z (GMT). No. of bitstreams: 1 ntu-108-R05442027-1.pdf: 2831964 bytes, checksum: 50f270ed7c9d1cf572f4f7d6f4f64bd6 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 中文摘要………………………………………………………………………………I
Abstract………………………………………………………………………………III Table of Contents……………………………………………………………………...V List of Figures……………………………………………………………….……….IX List of Tables………………………………………………………………………...XII Chapter 1: Introduction………………………………………………………………..1 1.1 Type I IFN Induction and Response Pathway….…………………………….1 1.2 Long Noncoding RNAs………………………………………………………3 1.3 The Regulatory Mechanisms of Long Noncoding RNAs……………………4 1.4 Long Noncoding RNAs Could Regulate Innate Immunity…………………..7 1.5 Specific Aim of This Study………………………………………………....10 Chapter 2: Materials and Methods.......................12 2: Materials and Methods…………………………………………………...12 2.1 Materials…………………………………………………………………….12 2.1.1 Cell Lines…………………………………………………………………12 2.1.2 Competent Cells…………………………………………………………..12 2.1.3 Viruses…………………………………………………………………….12 2.1.4 Plasmids…………………………………………………………………..12 2.1.5 Reagents…………………………………………………....……………..13 2.1.6 Enzymes…………………………………………………………………..15 2.1.7 Antibodies…………………………………………………………………16 2.1.8 Commercial Kits………………………………………………………….16 2.2 Methods……………………………………………………………………..16 2.2.1 Cell Culture……………………………………………………………….16 2.2.2 Construction of Expression Plasmids……………………………………..17 2.2.3 Transfection……………………………………………………………….19 2.2.4 Immunoblotting…………………………………………………………...19 2.2.5 Sendai Virus Cultivation………………………………………………….21 2.2.6 Sendai Virus Infection…………………………………………………….21 2.2.7 IFN-β Treatment…………………………………………………………..22 2.2.8 LncRNA Microarrary……………………………………………………..22 2.2.9 RNA Extraction…………………………………………………………...23 2.2.10 Real-Time PCR……………………………….………………………...24 2.2.11 Luciferase Assay…………………………………………………………23 2.2.12 Cytoplasm Nucleus Extraction…………………………………..………25 Chapter 3: Results……………………………………………………………………27 3.1 A Group of Long Noncoding RNAs Are Upregulated by Interferon-β…….27 3.2 HPN-AS1 Is an Interferon-Stimulated Long Noncoding RNA Hepatocytes.28 3.3 The Promoter Activity of HPN-AS1 Is Induced When Type I IFN Induction pathway Is Triggered……………………………………………………………31 3.4 HPN-AS1 Acts as A Positive Regulator of Type I IFN……………………..32 3.5 The Induction of HPN-AS1 Localizes More in Cytoplasm When type I IFN Response Pathway Is Activated…………………………………………………34 Chapter 4: Discussion………………………………………………………………36 Chapter 5: References………………………………………………………………42 | - |
| dc.language.iso | en | - |
| dc.subject | 長鏈非轉譯型編碼核醣核酸 | zh_TW |
| dc.subject | 第一型干擾素誘發表現反應 | zh_TW |
| dc.subject | 絲氨酸-反譯核醣核酸1 | zh_TW |
| dc.subject | Type I IFN induction pathway | en |
| dc.subject | Hepsin-Antisense1 | en |
| dc.subject | Long noncoding RNA | en |
| dc.title | 長鏈非編碼型核醣核酸Hepsin Antisense-1於第一型干擾素誘發表現路徑之研究 | zh_TW |
| dc.title | The Study of A Long Noncoding RNA Hepsin Antisense-1 in Type I Interferon Induction Pathway | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 107-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 張明富;蘇剛毅 | zh_TW |
| dc.contributor.oralexamcommittee | ;; | en |
| dc.subject.keyword | 長鏈非轉譯型編碼核醣核酸,絲氨酸-反譯核醣核酸1,第一型干擾素誘發表現反應, | zh_TW |
| dc.subject.keyword | Long noncoding RNA,Hepsin-Antisense1,Type I IFN induction pathway, | en |
| dc.relation.page | 75 | - |
| dc.identifier.doi | 10.6342/NTU201900395 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2019-02-13 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | - |
| dc.date.embargo-lift | 2029-02-12 | - |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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