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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 葉秀慧(Shiou-Hwei Yeh) | |
dc.contributor.author | Chia-Yu Fan | en |
dc.contributor.author | 范家瑀 | zh_TW |
dc.date.accessioned | 2021-06-16T05:16:59Z | - |
dc.date.available | 2019-10-09 | |
dc.date.copyright | 2014-10-09 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-08-17 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/56149 | - |
dc.description.abstract | Mallory-Denk body (MDB) 為肝臟病理變化中出現的一種細胞內涵體(Inclusion body),其主要成分為肝細胞中異常堆疊的細胞中間絲─角蛋白8 (Keratin 8, K8) 與角蛋白18 (Keratin 18, K18)。目前已在許多基因轉殖與基因剔除動物之研究中,證實K8蛋白質表現量多於K18之現象是MDB形成之關鍵,然而,在肝細胞中何以造成K8與K18蛋白質表現量之失衡仍未釐清。本實驗室先前之研究,在細胞實驗中,利用RNA干擾技術將FAP-1基因knockdown,發現當FAP-1表現量下降後,K8 Ser73之磷酸化上升,且K8之蛋白質表現量也同時上升,因此,我們提出在MDB之形成過程中,FAP-1可能藉由影響其形成關鍵中K8多於K18之現象,進而扮演一負向調控之角色。
在本研究中,我們希望藉由FAP-1去磷酸酶缺失小鼠 (FAP-1-/-) 探討FAP-1是否參與MDB形成過程之調控及其可能的分子機轉。首先,我們進行肝臟組織之蛋白質分析,與野生型小鼠相比,發現FAP-1去磷酸酶缺失小鼠之K8 Ser73磷酸化程度顯著增加,此與細胞實驗所得之結果一致。先前研究指出3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) 在給予野生型小鼠約3個月後,能在小鼠之肝細胞中觀察到MDB之形成,因此,我們希望利用DDC藥物建立MDB形成之動物模式,並進一步利用FAP-1去磷酸酶缺失小鼠分析其對MDB之形成過程可能造成的影響。實驗結果發現在DDC藥物誘發之下,野生型小鼠之肝臟中FAP-1蛋白質與mRNA表現量皆顯著上升,而與野生型小鼠相比,FAP-1去磷酸酶缺失小鼠在給予DDC藥物後,K8 Ser73之磷酸化有上升之現象,此外,其TG2之表現量明顯增加,已知TG2為參與MDB形成之重要關鍵,且其cross-linking受K8 Ser73位點之磷酸化調控。而在免疫螢光染色之分析中,相較於野生型小鼠,FAP-1去磷酸酶缺失小鼠之p62較早形成聚合物,此結果支持FAP-1可能在MDB之形成過程中扮演一負向調控角色。更進一步地,我們發現在FAP-1去磷酸酶缺失小鼠之MDB形成過程中,JNK之磷酸化明顯增加,此結果顯示JNK可能參與FAP-1影響K8 Ser73位點磷酸化之調控。總結上述之結果,本研究在動物模式中證實了FAP-1為一新穎之MDB調控因子,且其可藉由影響K8 Ser73之磷酸化進而參與肝細胞中MDB的形成,然而,詳細的分子機轉仍待進一步之探究。 | zh_TW |
dc.description.abstract | Mallory-Denk body (MDB), as a hepatic cytoplasmic inclusion body identified in several human liver diseases, is composed primarily of the intermediate filament component keratin 8 (K8) and keratin 18 (K18). The clues from mouse genetic studies have suggested the increased ratio of K8 over K18 is important for MDB formation, however the underlying mechanism for causing this imbalance is largely remained unclear. Using cell culture based assay, our previous studies have revealed that knocking down of fas associated phosphatase-1 (FAP-1) could cause an upregulation of the phosphorylation of K8 at Ser73 and also the accumulation of K8 protein. It thus raised a possibility that FAP-1 could be a regulator for the event of K8>K18 in hepatocytes, as a potential negative regulator in MDB formation. In the current study, we have tried to further confirm this hypothesis in the FAP-1 enzyme domain deficient mice (FAP-1-/-). We first validated the increase of K8 phosphorylation at Ser73 in the liver tissues of FAP-1-/- mice, in comparison with that in the wild type mice. Next, we have examined the effect of depleting FAP-1 for the formation of MDB in FAP-1-/- mice by treating them with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which can induce MDB in the liver of wild type mice after ~3 months of treatment. We found that FAP-1 was upregulated in the wild type mouse liver after DDC treatment. Depletion of FAP-1 not only led the increased phosphorylation of K8 at Ser73 but also increased the expression of transglutaminase (TG2) in the liver tissues, a key regulator for MDB by cross-linking the phosphorylated K8 at Ser73. As revealed by the immunofluorescence staining, the signal of p62 is detected in FAP-1-/- mice earlier than the control wild type mice, which is thus in vivo supporting FAP-1 as a negative regulator for MDB. The activation of JNK in FAP-1-/- mice further pointed out its possible role in mediating the function of FAP-1 for the phosphorylated K8 at Ser73. In conclusion, the current study has in vivo verified FAP-1 as a novel regulator in regulating MDB formation, through its influence on the phosphorylation of K8 at Ser73, although the detail mechanism is still needed further investigation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T05:16:59Z (GMT). No. of bitstreams: 1 ntu-103-R01445106-1.pdf: 4216437 bytes, checksum: ef2aae9089f1dd28025b629a13ba76b7 (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 中文摘要 ......................................................................................................................... I
英文摘要 ...................................................................................................................... III 序論 ................................................................................................................................ 1 Fas-associated phosphatase-1 之蛋白質結構與特性 ............................................... 1 角蛋白 (Keratin) 之蛋白質結構及其生理特性 ..................................................... 2 角蛋白 8/18 (Keratin 8/18) 在肝臟中之重要性及其磷酸化修飾 ......................... 3 Mallory-Denk body (MDB) 之組成與其形成機制 ................................................. 4 MDB之動物模式顯示肝細胞中K8蛋白質表現量多於K18的現象為MDB形成早期之關鍵因素 ........................................................................................................ 5 細胞自噬 (Autophagy) 與其參與MDB形成之重要性 ........................................ 7 p62之蛋白質結構與其對蛋白質降解之重要性 ..................................................... 8 Transglutaminase 2 (TG2) 之蛋白質結構與其重要性 ............................................ 9 Mitogen-activated protein kinase (MAPK) 之訊息傳遞路徑與其參與K8磷酸化之調控角色 .................................................................................................................. 10 研究目的 ...................................................................................................................... 12 材料與方法 .................................................................................................................. 14 研究結果 ...................................................................................................................... 19 1. 利用FAP-1去磷酸酶缺失小鼠探討FAP-1對K8 Ser73磷酸化之調控 1-1. FAP-1去磷酸酶缺失小鼠之建立與基因分型之確認 ............................ 19 1-2. FAP-1之酵素功能影響K8 Ser73之磷酸化 ........................................... 19 2. 建立DDC藥物誘發MDB之動物模式,並利用FAP-1去磷酸酶缺失小鼠探討FAP-1是否參與MDB形成之調控 2-1. DDC藥物誘發MDB動物模式之建立 ................................................... 20 2-2. 分析在DDC藥物誘發MDB之形成過程中,FAP-1與其他相關參與因子之變化 .................................................................................................... 21 2-3. 肝臟切片染色之初步結果顯示FAP-1去磷酸酶缺失小鼠之MDB較早形成 ................................................................................................................ 22 2-4. 利用Western blot比較FAP-1去磷酸酶缺失與野生型小鼠在DDC藥物誘發MDB形成過程之差異 ..................................................................... 23 2-5. 探討FAP-1去磷酸酶缺失是否造成MDB之自發形成 ......................... 25 3. 進一步探討FAP-1在MDB形成過程中可能的調控機制 3-1. FAP-1對K8 Ser73磷酸化的影響藉由調控MAPK路徑之可能性 ...... 25 3-2. 在DDC藥物誘發MDB之形成過程中JNK可能參與FAP-1之調 ..... 26 結果討論 ...................................................................................................................... 27 1. FAP-1參與K8 Ser73磷酸化之調控與其對細胞中間絲結構之影響 .............. 27 2. FAP-1參與MDB形成初期之調控 .................................................................... 27 3. FAP-1參與MDB形成過程之可能性與其可能機制........................................ 28 4. FAP-1參與TG2之調控而影響MDB形成之可能性 ...................................... 29 5. FAP-1參與細胞自噬路徑之調控而影響MDB形成之可能性 ........................ 30 6. FAP-1參與p62 Ser403磷酸化的調控而影響MDB形成之可能性 ............... 31 7. FAP-1藉由MAPK的調控進而參與MDB形成之可能性 .............................. 32 參考文獻 ...................................................................................................................... 34 圖附錄 .......................................................................................................................... 43 | |
dc.language.iso | zh-TW | |
dc.title | 利用FAP-1去磷酸酶缺失小鼠探討FAP-1為Mallory-Denk body形成過程之一新穎調控因子 | zh_TW |
dc.title | FAP-1, a novel regulator for Mallory-Denk body formation in the FAP-1 phosphatase-deficient mice | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳培哲(Pei-Jer Chen),鄧述諄(Shu-Chun Teng),鄭永銘(Yung-Ming Cheng) | |
dc.subject.keyword | FAP-1,MDB,角蛋白8/18,TG2,p62, | zh_TW |
dc.subject.keyword | FAP-1,MDB,K8/K18,TG2,p62, | en |
dc.relation.page | 60 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-08-18 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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