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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 吳信志(Shinn-Chih Wu) | |
| dc.contributor.author | Sheng-Chia Yu | en |
| dc.contributor.author | 余晟嘉 | zh_TW |
| dc.date.accessioned | 2022-11-25T07:59:55Z | - |
| dc.date.copyright | 2022-02-24 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-01-25 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82802 | - |
| dc.description.abstract | 糖尿病為近年來相當常見的慢性代謝性疾病，造成患者眾多不適，並威脅到患者壽命。國際糖尿病聯合會於2021年的報告中，全球有約5.37億糖尿病患者，臺灣則有245萬人患有糖尿病，占總人口約9.7%。第一型糖尿病為慢性自體免疫性疾病，因免疫反應導致患者缺乏β細胞，其對患者之影響不容忽視，而在相關研究中發現Pax4基因的變異與第一型糖尿病的風險有關。而Pax4基因對於胚胎發育中之胰臟β細胞分化作用有重大影響，若失去功能則會造成β細胞缺失，與第一型糖尿病相似。CRISPR-Cas9系統為近年經常被使用的工具，可對目標序列進行辨識並造成雙股斷裂，引發修復機制進而造成缺失突變或修改為特定序列。本試驗欲使用CRISPR-Cas9系統對於小鼠的Pax4基因進行剔除，使其失去功能並影響β細胞分化，藉此模擬第一型糖尿病患者胰島中缺乏β細胞的現象。體外試驗部分，將可表現sgRNA與Cas9的質體轉染至細胞株中，並以流式細胞儀分選成功轉染之細胞，而後檢測不同組別sgRNA的編輯作用效率，結果於體外試驗中挑選出兩組效率較高的sgRNA。體內試驗部分，將兩組sgRNA及Cas9蛋白以顯微注射的方式送入一細胞期的小鼠胚中，並進行胚移置，合計產下155隻小鼠，後續分析結果顯示其中100隻小鼠的基因組出現編輯現象；在DNA序列定序結果中發現部分小鼠出現大片段序列剔除的現象；而在小鼠表現性狀中發現Pax4-/-小鼠出現生長表現異常的現象，並與野生型及Pax+/-小鼠有顯著差異(出生48小時體重，Pax4-/-：1.44±0.24g；Pax4+/-：2.46±0.41g；野生型：2.31±0.31g) (a=0.05) ;同時在血糖數值方面也顯著高於其他兩種基因型小鼠(出生後60小時，Pax4-/-：538.24±65.00 mg/dl；Pax4+/-：103.20±20.61 mg/dl；野生型：96.57±12.12mg/dl) (a=0.01)。為探究造成此差異的原因，進一步執行胰臟組織切片染色及免疫螢光染色，結果發現Pax4-/-小鼠胰島出現型態改變的情形，並且其胰島並無分泌胰島素之現象，由此推論在Pax4基因受到突變後確實影響到β細胞的分化，導致小鼠無法正常分泌胰島素，進而影響生長並處於高血糖的狀態。本試驗藉由CRISPR-Cas9系統成功編輯小鼠之Pax4基因，使其序列產生突變並失去功能，使Pax4-/-小鼠出現體重降低以及高血糖的狀態，並得知原因為與第一型糖尿病相似之胰島中缺乏β細胞的現象。希望以此Pax4基因編輯小鼠模擬第一型糖尿病以作為其模式動物，並可作為未來研究者欲進行相關研究的動物材料，以增進對第一型糖尿病之相關研究。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T07:59:55Z (GMT). No. of bitstreams: 1 U0001-2301202214343200.pdf: 4736908 bytes, checksum: 50be3a123e508e17cb57b5c43ddc3b4b (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | 誌謝 I 中文摘要 II ABSTRACT IV 目錄 VI 圖次 VIII 表次 X 第一章 緒論 1 第二章 文獻探討 2 第一節 基因編輯技術 2 1-1 基因編輯技術演進 2 1-2 ZFN、TALEN 及CRISPR-Cas9 3 1-3 CRISPR-Cas9系統組成以及作用機制 7 第二節 Type 1 diabetes Mellitus 12 2-1-1 Diabetes Mellitus 概況 12 2-1-2 DM類型 12 2-2-1 Type 1 Diabetes Mellitus 13 第三節 Pax4 gene 18 3-1 胰臟構成 18 3-2-1 Pax4 gene 18 3-2-2 Pax4 KO animal model 21 3-2-3 The effect of Pax4 ectopic expression 21 第三章 試驗研究 24 前言 24 第一節 細胞體外試驗 25 1-1 試驗背景 25 1-2 試驗流程 25 1-3 材料方法 26 1-4 試驗結果與討論 35 第二節 以CRISPR-Cas9系統產製基因編輯小鼠 39 2-1 試驗背景 39 2-2 試驗流程 39 2-3 材料方法 40 2-4 試驗結果與討論 52 第四章 綜合討論 62 參考文獻 64 圖次 圖 1.可編輯核酸酶及其辨識目標序列方式。 5 圖 2. CRISPR-Cas系統基因座及系統作用過程。 6 圖 3. Cas9蛋白質結構及其與sgRNA結合後之構型。 9 圖 4. 添加核苷酸將crRNA與tracrRNA結合形成sgRNA。 9 圖 5. NHEJ以及HDR之DNA雙股斷裂修復機制。 11 圖 6. 第一型糖尿病(T1DM)疾病進程。 15 圖 7. 第一型糖尿病慢性自體免疫作用機制。 15 圖 8. Pax家族成員序列依照區塊有無及完整性分組。 20 圖 9. 胰臟內分泌性前驅細胞受到Pax4與Arx調控而走向不同分化細胞群。 20 圖 10. 利用同源重組的方式剔除Pax4基因後，小鼠胰島中的胰島素(b、e)以及升糖素 (c、f) 表現。 22 圖 11於α細胞異位表現Pax4以β-galactosidase追蹤。 23 圖 12. α細胞數量下降誘發epithelial-to-mesenchymal transition (EMT) 示意圖。 23 圖 13. 試驗流程示意圖。 24 圖 14. Modified pU6-(BbsI)_CBh-Cas9-T2A-Cherry質體構築。 31 圖 15. sgRNA目標序列與Pax4基因序列結構對應圖。 35 圖 16. 以CRISPR-Cas9表現質體轉染NIH-3T3細胞圖。 38 圖 17. 細胞試驗之sgRNA編輯效率圖。 38 圖 18. 利用PCR產製sgRNA之DNA序列。 42 圖 19. 同合子基因剔除仔鼠與野生型小鼠的Pax4基因序列對照圖。 55 圖 20. 基因編輯仔小鼠之出生後存活率。 55 圖 21. 基因編輯仔小鼠出生後36小時之外觀。 55 圖 22. 基因編輯仔小鼠出生後體重變化圖。 56 圖 23. 基因編輯仔小鼠血糖變化圖。 56 圖 24. 基因編輯仔小鼠胰臟位置與取下之胰臟圖。 58 圖 25. 基因編輯仔小鼠胰臟切片H E染色圖。 58 圖 26. 基因編輯仔小鼠胰臟切片免疫螢光染色。 59 圖 27. 基因編輯仔小鼠胰臟切片免疫螢光染色。 59 圖 28. 基因編輯小鼠之子代PCR產物膠體電泳圖。 61 圖 29. 親代子代DNA序列比較圖 62 表次 表 1. 挑選出具有潛力的sgRNA序列表 28 表 2. sgRNA辨識序列之單股寡核苷酸序列片段 30 表 3. 細胞試驗中所使用之引子序列表 34 表 4. 細胞轉染效率表 36 表 5. PCR中所使用之引子 42 表 6. 仔鼠基因組檢測與TOPO® Cloning使用之引子序列 47 表 7. 脫靶效應使用之引子 51 表 8. 小鼠顯微注射總表 53 表 9. 脫靶效應效率檢測 60 表 10. 性腺傳承試驗總表 61 | |
| dc.language.iso | zh-TW | |
| dc.title | 利用CRISPR-Cas9系統產製Pax4基因剔除之第一型糖尿病小鼠 | zh_TW |
| dc.title | Generation of Pax4 gene knockout T1DM mouse model by CRISPR-Cas9 system | en |
| dc.date.schoolyear | 110-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳銘正(Wen-Hsin Hsu),陳全木 | |
| dc.subject.keyword | 第一型糖尿病,CRISPR-Cas9系統,Pax4,基因編輯,動物模式, | zh_TW |
| dc.subject.keyword | Type 1 diabetes mellitus (T1DM),CRISPR-Cas9,Pax4,gene editing,animal model, | en |
| dc.relation.page | 77 | |
| dc.identifier.doi | 10.6342/NTU202200159 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2022-01-27 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 動物科學技術學研究所 | zh_TW |
| dc.date.embargo-lift | 2025-01-17 | - |
| 顯示於系所單位： | 動物科學技術學系 | |
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