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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82304完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許書豪(SHU-HAO HSU) | |
| dc.contributor.author | Peng-Fang Ma | en |
| dc.contributor.author | 馬鵬芳 | zh_TW |
| dc.date.accessioned | 2022-11-25T06:35:22Z | - |
| dc.date.copyright | 2021-11-09 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-09-22 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82304 | - |
| dc.description.abstract | 肥胖誘導的脂肪肝是非酒精性脂肪肝的一種，是由於肝細胞對於脂質代謝異常與脂肪滴堆積的結果。短期的脂肪肝堆積其實是可逆的，只要做好飲食控制與適當運動都可以治癒。然而，當脂肪肝變成慢性且反覆發炎與纖維化，就會導致肝臟受損，過度嚴重時，無法有效治療。 研究顯示在肝臟中miR-192和miR-194高度表現而且和肝的疾病有密切關係。然而，miR-192/194缺失是否導致肝代謝異常仍有待研究，所以本研究的目標是探討miR-192/194的缺失如何影響飲食所導致的脂肪肝。 首先，我們分析餵食正常飼料的miR-192/194缺失組(後稱突變組)，發現與控制組相比，不論在肝臟的型態、血清各項生化指標均相差無幾。接著，我們以高脂飼料餵食六週大(簡稱年輕組)和三個月大(簡稱成年組)的小鼠。每一週測量體重變化，並於第12週犧牲動物，並收取血清做總膽固醇、血糖與三酸甘油脂肪酸的測量、肝組織做蛋白質與RNA表現量測試和H E染色和Trichrome染色。 在餵食12週高脂飼料後，年輕控制組的體重是明顯比年輕突變組高。形態學上的觀察可以發現，不論是年輕組或成年組中，突變組的小鼠肝臟脂肪滴堆積與纖維化比控制組少。血清生化分析結果也可以得知在成年突變組小鼠中，總膽固醇也顯著低於控制組。更進一步分析基因表現量，利用q-PCR與西方墨點法可以得知PPARα、PPARγ、PGC1α和PGC1β在突變組的小鼠中表現量高於控制組。文獻上已知這些基因的上調可以增加肝臟分解脂質與避免形成脂肪堆積。為證實miR-192/194是否直接調控PGC1α，我們利用轉染的方式上調或抑制AML12細胞中的miR-192/194。結果發現PGC1α以及其他PPAR 訊息傳遞的基因均為miR-194所抑制，而非miR-192。 同時，miR-194的過度表現會導致細胞在棕櫚酸的誘導後產生較多的脂肪。最後，我們利用冷光酶報告蛋白確認了miR-194可直接抑制帶有PGC1α 3’-UTR的質體表現。且此抑制的效果在突變miR-194結合位點後消失。綜上，我們確認miR-194可直接調控PGC1α。 總結來說，我們認為miR-192/194的缺失會保護肝臟免於飲食所誘導的脂肪肝，且可能是透過上調PGC1α以及其他PPAR 訊息傳遞來控制。後續會需要再做更多實驗來證實miR-192/194對於非酒精性脂肪肝的潛在治療性。 | zh_TW |
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| dc.description.tableofcontents | "致謝………………………………………………………………………………………i 中文摘要………………………………………………………………………………...ii 英文摘要………………………………………………………………………………..iii 縮寫表……………………………………………………………………………….......v 目錄……………………………………………………………………………………..vi 第一章 緒論…………………………………………………………………………...1 1. 引言…………………………………………………………………………...1 2. 微小核醣核酸在肝臟的功能……………………….......................................1 3. MiR-192/194在肝臟及其他器官中的功能…………………………………2 4. PPAR與肝臟之關係….……………………………………………………...3 5. PPARγ co-activator 1(PGC1) 與肝臟之關係………………………………..3 6. 目前學界對於miR調控PGC1α的研究……………………………………4 7. 研究動機……………………………………………………………………...5 第二章 實驗方法……………………………………………………………………...7 1. 實驗動物均來自本院實驗動物中心………………………………………...7 2. 核醣核酸萃取(RNA)…………………………………………………............7 3. 反轉錄聚合酶連鎖反應(Reverse Transcription-Polymerase Chain Reaction, RT-PCR)…………………………………………….…………………………8 4. 即時定量聚合酶連鎖反應(Real-time Quantitative PCR, RT-qPCR)..............9 5. 西方墨點法(Western blot assay)……………………………………….……..9 6. 組織固定……………………………………………….……………………10 7. 蘇木精-伊紅染色(Hematoxylin and Eosin stain, H E stain)………………11 8. 去氧核醣核酸萃取(DNA)及測定基因型………………………….……….11 9. DNA製備…………..………………………………………………………..13 10. 勝任細胞轉型……………………………………………………………….14 11. 確認勝任細胞轉型成功與否……………………………………………….15 12. 質體純化…………………………………………………………………….16 13. Inverse PCR………………………………………………………………….16 14. 細胞轉染實驗…...…………………………………………………………..18 15. 冷光酵素報導表現測試…………………………………………………….18 16. 組織ORO染色……………………………………………………………...19 17. 脂肪肝形成分數評比……………………………………………………….19 第三章 實驗結果…………………………………………………………..………...20 1. miR-192/194突變小鼠之產生………………………………………………20 2. miR-194-2突變小鼠的形態學上定位………………………………………20 3. miR-192/194的基因缺失後抑制肝臟脂肪堆積……………………………21 4. miR-192/194之缺失降低血液總膽固醇……………………………………22 5. 脂肪代謝與發炎訊息傳遞之相關基因在miR-192/194基因突變的高脂飲食小鼠肝臟表達較高………………………………………………………..22 6. 利用外源基因轉染細胞可發現miR-192/194表達上升與下降…………...22 7. 轉染之後經過棕櫚酸處理的小鼠肝細胞脂肪代謝基因表現量相對於不處理組較高……………………………………………………………………..23 8. 轉染合併棕櫚酸處理的小鼠肝細胞的脂肪合成基因表現量比不處理組別較低…………………………………………………………………………..23 9. 小鼠肝細胞的粒線體氧化壓力代謝反應miR-192/194抑制組表現較高...24 10. MiR-194會直接抑制HEK-293T細胞的PGC1α 3’-UTR表現量……..….24 11. 小鼠肝細胞處理PA後控制組脂肪滴生成比較多……….………………..24 第四章 討論…………………………………………………………………………...25 1. 年輕小鼠與成鼠之間的代謝情況…………………………………………..25 2. MiR-192/194突變小鼠抵抗肝臟脂肪合成的能力...………………………25 3. MiR-194抑制後會促進PGC1α的表現………...…………………………..26 4. MiR-194與代謝基因關係……...…………………………………………...26 5. PA與OA對於細胞毒殺性與脂肪合成的關係……………………………27 6. 動物模型與細胞模型的發炎基因探討……………………………………..27 7. PGC1α會促進粒線體的生化代謝反應…………………………………….28 8. MiR-192/194未來治療策略...………………………………………………29 第五章 結論…………………………………………………………………………...30 第六章 附圖…………………………………………………………………………...31 參考文獻……………………………………………………………………………….61 表1抗體表…………………………………………………………………………….67 表2本篇實驗所使用之引子………………………………………………………….68 附錄一 實驗溶液配製………………………………………………………………...69 1. 反轉錄聚合酶連鎖反應(Reverse Transcription-Polymerase Chain Reaction, RT-PCR)………………………………..…………………………………….69 2. 十二烷基硫酸鈉聚丙烯安凝膠體電泳配置………………………………..69 3. 西方墨點法(Western blot assay)……………………………………………..69 4. 組織固定……………………………………………………………………..70 5. 去氧核醣核酸萃取(DNA)及測定基因型…………………………………...70 6. 細胞培養液…………………………………………………………………..71 7. 棕櫚酸配製…………………………………………………………………..71 8. 細胞螢光染色………………………………………………………………..71 9. 組織脂肪染色………………………………………………………………..71 10. LB agar製備…………………………………………………………………71 11. 冷光酵素報導測試…………………………………………………………..72 12. 葡萄糖溶液配製……………………………………………………………..72" | |
| dc.language.iso | zh-TW | |
| dc.subject | PPAR | zh_TW |
| dc.subject | miR-192/194 | zh_TW |
| dc.subject | 高脂飼料 | zh_TW |
| dc.subject | PGC1 | zh_TW |
| dc.subject | 非酒精性脂肪肝 | zh_TW |
| dc.subject | High-fat diet(HFD) | en |
| dc.subject | miR-192/194 | en |
| dc.subject | Nonalcoholic Fatty Liver Disease(NAFLD) | en |
| dc.subject | PPAR | en |
| dc.subject | PGC1 | en |
| dc.title | MiR-192/194的缺失如何影響飲食誘導的脂肪肝 | zh_TW |
| dc.title | Effect of MiR-192/194 Deficiency on Dietary Induced Fatty Liver | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 許弘明(Hsin-Tsai Liu),蔡欣祐(Chih-Yang Tseng) | |
| dc.subject.keyword | miR-192/194,非酒精性脂肪肝,PPAR,PGC1,高脂飼料, | zh_TW |
| dc.subject.keyword | miR-192/194,Nonalcoholic Fatty Liver Disease(NAFLD),PPAR,PGC1,High-fat diet(HFD), | en |
| dc.relation.page | 72 | |
| dc.identifier.doi | 10.6342/NTU202102860 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2021-09-23 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | zh_TW |
| dc.date.embargo-lift | 2023-09-01 | - |
| 顯示於系所單位： | 解剖學暨細胞生物學科所 | |
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