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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 姜至剛(Chih-Kang Chiang) | |
| dc.contributor.author | Ying-Cheng Lin | en |
| dc.contributor.author | 林穎成 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:28:24Z | - |
| dc.date.available | 2021-08-31 | |
| dc.date.available | 2022-11-24T03:28:24Z | - |
| dc.date.copyright | 2021-08-31 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-20 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81057 | - |
| dc.description.abstract | "慢性腎臟病(chronic kidney disease, CKD)為腎臟受到損傷長達三個月以上無法恢復原有的結構與功能。具有很高的盛行率及死亡率。近年來許多研究指出，腎臟纖維化在CKD進展中扮演重要的角色會加速CKD的惡化並發展成末期腎臟病(End Stage Renal Disease, ESRD)。其中腎小管間質纖維化是最常見的，也是所有腎臟疾病導致CKD的致病機轉。在纖維化的過程中，上皮細胞間質轉換(epithelial-mesenchymal transition, EMT)會參與其中，將近端腎小管上皮細胞轉化成纖維母細胞，造成發炎及細胞外基質(extracellular matrix, ECM )的累積。在調控EMT的方面，乙型轉化生長因子(Transforming growth factor beta, TGF-β)是主要的途徑之一。此外內質網壓力(endoplasmic reticulum stress, ER stress)也會加速纖維化的發展。在實驗室過去的研究中，X-Box Binding Protein 1 (XBP1)的表現量在纖維化的過程中逐漸下降，並與纖維化呈現負相關。藉由蛋白質體學分析，在XBP1缺乏的人類腎臟近端腎小管上皮細胞(human proximal epithelial tubular cell, HK2)中，RNA解旋酶 DEAD-Box Helicase 17 (DDX17)的表現量降低。而DDX17參與在許多RNA的代謝、轉錄、轉譯等，是人體不可或缺的蛋白。先前研究顯示，DDX17會參與在EMT，調控其中的分子機制，但對於其在腎臟纖維化的作用仍需近一步的研究。因此本研究假設在腎臟纖維化過程中，XBP1會影響DDX17在EMT中的作用，並探討DDX17調控EMT在腎臟纖維化進展中扮演的角色。首先，使用PROMO預測XBP1 與DDX17間的調控，XBP1可能會結合在DDX17啟動子。我們發現XBP1s會結合DDX17的啟動子。接著，大量表現或抑制XBP1並不會對 DDX17的表達有太大的影響，因此認為XBP1可能不是主要調控的因子。在動物實驗中，使用單側輸尿管阻塞(unilateral ureteral obstruction, UUO)及單邊腎臟缺血再灌流損傷模式(unilateral ischemia/reperfusion injury, UIRI)來模擬纖維化的產生。發現DDX17的表現量會上升。在體外試驗，使用TGF-β誘導HK2細胞產生EMT中，DDX17的表現量也是上升。在大量表達DDX17後會上調纖連蛋白(Fibronectin)、膠原蛋白I, IV 型(Collagen I, IV)、TGF-β及轉錄因子(Snail Family Transcriptional Repressor 1, Snail)並下調密連蛋白(Claudin 1, CLDN1)。而DDX17的缺乏降低了由TGF-β誘導的纖維化相關基因。在UUO中發現到纖維化的組織DDX17會在核內表達，而使用核質分離與TGF-β處理下，DDX17在核內表現量上升。接著，在調控DDX17上，我們發現在腎纖維化進程中miR-30a-3p會被下調，藉由miRBase 與TargetScan的預測miR-30a-3p可能會結合在DDX17 3’UTR。而在大量表現miR-30a-3p會下調DDX17，相反抑制miR-30a-3p可以上調DDX17。綜合上述結果，本研究發現在纖維化過程中DDX17會受到miR-30a-3p的調控。而DDX17在腎纖維化進展中會大量表現在核內，影響EMT相關基因轉錄、轉譯。在減少DDX17的情況下可以降低EMT基因的表達進而減緩纖維化的產生。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T03:28:24Z (GMT). No. of bitstreams: 1 U0001-1808202117094400.pdf: 5452212 bytes, checksum: baed75483f37b054b7c946a7038b530d (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 口試委員會審定書 I 誌謝 II 中文摘要 IV ABSTRACT VI CONTENTS VIII List of abbreviations XI Part I：Introduction 1 1.1 The kidney and Chronic kidney disease 1 1.2 The Renal fibrosis in CKD 2 1.2.1 Tubulointerstitial fibrosis 3 1.3 Epithelial–mesenchymal transition 6 1.3.1 The EMT in Tubulointerstitial fibrosis 7 1.3.2 The mechanism of TGF-β in EMT 8 1.4 Endoplasmic Reticulum Stress in Tubulointerstitial fibrosis 10 1.5 The epigenetic regulation - MicroRNAs 12 1.5.1 MicroRNAs and kidney diseases 14 1.6 RNA helicases 16 1.6.1 The correlation between RNA helicases and kidney diseases 17 Part II：Aims 19 Part III：Materials and Methods 21 3.1 Animal studies 21 3.2 Unilateral Ureter Obstruction (UUO) Model 21 3.3 Unilateral Renal Ischemia-Reperfusion (UIRI) Model 21 3.4 Kidney histology and immunohistochemistry 22 3.5 Cell culture 23 3.6 In vitro knockdown genes by siRNA strategy 23 3.7 In vitro overexpression genes 24 3.8 Protein extraction and immunoblot analysis 27 3.9 mRNA extraction and real-time quantitative polymerase chain reaction (q-PCR) analysis 29 3.10 miRNA targeting and in vitro miRNA transfections 30 3.11 miRNA extraction and q-PCR analysis 31 3.12 in vitro treatment of TGF-β 32 3.13 in vitro nuclear fractionation 33 3.14 Cell proliferation 33 3.15 Dual Luciferase Reporter Assay 34 3.16 Ingenuity pathway analysis 35 3.17 Statistical analysis 35 Part IV：Results 36 4.1 The regulation of XBP1 on DDX17 in PTCs 36 4.2 DDX17 expression increased gradually in CKD progression with fibrosis formation 38 4.3 Overexpression of DDX17 in the PTCs increased EMT 40 4.4 The knockdown of DDX17 eliminated TGF-β induced EMT and Fibrosis 41 4.5 DDX17 regulated EMT-associated gene at nucleus in the progression of renal fibrosis 42 4.6 DDX17 could be epigenetically regulated by miR-30a-3p in the progression of renal fibrosis 43 Part V：Discussion 46 Part VI：Conclusion 52 Part VII：Future perspectives 53 Part VIII：References 54 Part IX：Figures 72 Figure 1 72 Figure 2 76 Figure 3 78 Figure 4 79 Figure 5 82 Figure 6 87 Figure 7 88 Figure 8 90 Figure 9 93 Figure 10 94 Part X：Supplementary Figures 95 Supplementary figure 1 95 Supplementary figure 2 97 Supplementary figure 3 100 Supplementary figure 4 103 Supplementary figure 5 104 | |
| dc.language.iso | en | |
| dc.subject | 微小RNA | zh_TW |
| dc.subject | 慢性腎臟病 | zh_TW |
| dc.subject | 纖維化 | zh_TW |
| dc.subject | 上皮細胞間質轉化 | zh_TW |
| dc.subject | RNA解旋酶 | zh_TW |
| dc.subject | renal fibrosis | en |
| dc.subject | microRNA | en |
| dc.subject | epithelial-mesenchymal transition | en |
| dc.subject | Chronic kidney disease | en |
| dc.subject | RNA helicase | en |
| dc.title | DDX17調控上皮細胞間質轉化之腎臟纖維化研究 | zh_TW |
| dc.title | The role of DDX17-regulated Epithelial-mesenchymal transition in renal fibrosis | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 劉興華(Hsin-Tsai Liu),洪冠予(Chih-Yang Tseng) | |
| dc.subject.keyword | 慢性腎臟病,纖維化,上皮細胞間質轉化,RNA解旋酶,微小RNA, | zh_TW |
| dc.subject.keyword | Chronic kidney disease,renal fibrosis,epithelial-mesenchymal transition,RNA helicase,microRNA, | en |
| dc.relation.page | 105 | |
| dc.identifier.doi | 10.6342/NTU202102484 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-08-20 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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