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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 湯志永(Chih-Yung Tang) | |
| dc.contributor.author | Yun-Chia Chien | en |
| dc.contributor.author | 簡韻珈 | zh_TW |
| dc.date.accessioned | 2021-06-15T13:49:49Z | - |
| dc.date.available | 2018-02-24 | |
| dc.date.copyright | 2016-02-24 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-10-21 | |
| dc.identifier.citation | Apaja PM, Foo B, Okiyoneda T, Valinsky WC, Barriere H, Atanasiu R, Ficker E, Lukacs GL, Shrier A (2013) Ubiquitination-dependent quality control of hERG K(+) channel with acquired and inherited conformational defect at the plasma membrane. Molecular Biology of the Cell 24:3787-3804.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51788 | - |
| dc.description.abstract | 先天性肌肉強直症(myotonia congenita)是一種遺傳性的骨骼肌病變，是由於第七對染色體上的CLCN1基因發生變異，造成骨骼肌CLC-1氯離子通道之功能改變。本實驗室先前利用野生型(wild-type)CLC-1以及一種與肌肉強直症相關的突變型(A531V)進行研究，發現CLC-1在內質網中會藉由cullin-RING ubiquitin ligase 4 (CRL4)進行蛋白酶體降解，此外也發現了多種分子伴護蛋白(molecular chaperones)對CLC-1蛋白質生合成的影響。本論文的目的為檢測可能參與CLC-1在細胞膜上的調控之分子伴護蛋白及泛素連結酶。
首先，我們利用細胞表面生物素化(surface biotinylation)的方法發現，在與CLC-1共同表現時，分子伴護蛋白FKBP在細胞膜分布的比例會明顯的增加。以相同的方法進行實驗，我們還發現CLC-1也會增加CRL complex在細胞膜分布的比例明顯增加。相反的，我們發現分子伴護蛋白不論是否與CLC-1共同表現時，都不會被細胞生物素化偵測到明顯的訊號。另外，我們也利用次細胞分離法(subcellular fractionation)去探討FKBP在有無CLC-1情況下的次細胞分布狀況，我們發現共同表現CLC-1時，會使FKBP由類似calnexin (內質網標記蛋白)的次細胞分布狀況改變為類似cadherin (膜標記蛋白)之次細胞分布狀況。針對細胞質蛋白質(cytosolic protein)，我們改用差速離心法(differential centrifugation)去觀察CRL complex在有無CLC-1情況下的次細胞分布狀況，我們發現共同表現CLC-1時，會使CRL complex在細胞膜的分布增加，但是Hsp的分布狀況則沒有明顯變化。Brefildin A是一種能夠抑制囊泡由內質網運送至高基氏體的藥物，會干擾諸如CLC-1等膜蛋白被運送到細胞膜上的過程，因此可用以觀察膜蛋白質在細胞膜上的代謝時程(turnover rate)。我們初步的實驗結果顯示，當共同表現FKBP時，似乎會使得細胞膜上的A531V較為穩定。 從以上的研究觀察我們可以推論當細胞大量表現CLC-1時，FKBP及CRL complex在細胞膜分布的機率會明顯增加，這個結果可能暗示著FKBP8及CRL4 complex都可能與位於細胞膜上的CLC-1具有交互作用，並且影響CLC-1在細胞膜上的代謝過程。未來，我們將進一步以brefeldin A確認FKBP、CRL complex及其它分子伴護蛋白是否會影響CLC-1在細胞膜上的代謝時程。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-06-15T13:49:49Z (GMT). No. of bitstreams: 1 ntu-104-R02441019-1.pdf: 1978102 bytes, checksum: 637dfc89a0c2687391ee739ce9dba237 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract iii 目錄 v 圖表目錄 viii 第一章 導論 1 1.1 氯離子通道 (Chloride channels) 1 1.2 CLC-1的結構及生理功能 1 1.3 先天性肌肉強直症 (Myotonia congenita) 2 1.4 Myotonia mutant: A531V 3 1.5 蛋白質平衡 4 1.6 分子伴護蛋白的基本概念 4 1.7 分子伴護蛋白的作用途徑 5 1.8 The Hsp70 system 5 1.9 The Hsp90 system 6 1.10 蛋白質降解系統 8 1.11 蛋白質運送機轉 9 1.12 Peripheral Quality Control 9 1.13 研究目的 10 第二章 材料與方法 11 2.1 DNA construct 11 2.2 Cell culture 11 2.3 DNA Transfection 12 2.4 Immunoblotting 12 2.5 Biotinylation 13 2.6 Subcellular Fractionation 13 2.7 Differential Centrifugation Fractionation 14 2.8 Fluorescence staining 14 2.9 Brefildin A treatment 15 2.10統計分析 16 第三章 結果 17 3.1部分CLC-1的分子伴護蛋白及泛素蛋白酶體會因CLC-1大量表現而出現分布於細胞膜的現象 17 3.2免疫螢光染色觀察CLC-1對FKBP8分布的影響 19 3.3利用次細胞細胞分離方法探討FKBP8及CLC-1在細胞中的分布 19 3.4利用差速離心細胞分離方法探討大量表現CLC-1對CRBN、CUL4A、DDB1及Hsp70在細胞中分布的影響 21 3.5利用BrefeldinA treatment探討FKBP8對CLC-1在細胞膜穩定性的影響 22 第四章 討論 24 4.1 大量表現CLC-1會影響FKBP8與CRL4 complex在細胞內的分布狀況 24 4.2 大量表現CLC-1不會明顯影響其它分子伴護蛋白的分布狀況 26 4.3 FKBP8和CRL4 complex對細胞膜上CLC-1的可能調控角色 28 4.4 待釐清之問題 29 4.5未來實驗方向 30 結論 33 圖表 34 附圖 50 參考資料 52 | |
| dc.language.iso | zh-TW | |
| dc.subject | 品質控管 | zh_TW |
| dc.subject | 分子伴護蛋白 | zh_TW |
| dc.subject | 細胞膜分布 | zh_TW |
| dc.subject | membrane distribution | en |
| dc.subject | peripheral quality control | en |
| dc.subject | CLC-1 | en |
| dc.subject | FKBP8 | en |
| dc.title | 分子伴護蛋白和泛素連接酶與人類第一型氯離子通道蛋白之細胞膜分布 | zh_TW |
| dc.title | Membrane distribution of molecular chaperones and ubiquitin ligases with human CLC-1 channels | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 胡孟君,鄭瓊娟,卓貴美 | |
| dc.subject.keyword | 分子伴護蛋白,細胞膜分布,品質控管, | zh_TW |
| dc.subject.keyword | CLC-1,FKBP8,membrane distribution,peripheral quality control, | en |
| dc.relation.page | 56 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-10-22 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生理學研究所 | zh_TW |
| 顯示於系所單位： | 生理學科所 | |
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