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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳佩燁(Rita Pei-Yeh Chen) | |
| dc.contributor.author | Yun-Ting Yu | en |
| dc.contributor.author | 尤韻婷 | zh_TW |
| dc.date.accessioned | 2021-06-17T03:10:11Z | - |
| dc.date.available | 2023-07-26 | |
| dc.date.copyright | 2018-07-26 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-07-19 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69180 | - |
| dc.description.abstract | 目前已知導致阿茲海默症的其中一個因素是類澱粉前驅蛋白，此蛋白跨膜區域會被 γ-分泌酶切割而形成不同比例的 Aβ42 及 Aβ40，但目前 γ-分泌酶決定切位的機制仍未被充分了解。而在類澱粉前驅蛋白的跨膜區序列中，含有四個容易破壞二級結構的甘胺酸，其中兩個相鄰的甘胺酸會形成 GG-kink，並根據 Nadezhdin 與 Barrett 等人研究發現，不同的脂質組成對於 GG-kink 彎曲的角度有明顯的變化，故我們認為此段跨膜區域結構具有彈性並且能隨著外在環境變化而影響蛋白構型。在另一方面，有研究進一步指出膽固醇含量與病患腦中的類澱粉蛋白堆積程度呈現正相關，因此我們推測膽固醇可能是決定 γ-分泌酶切位的重要關鍵之一。
在本研究我們合成類澱粉前驅蛋白跨膜區序列 (28-53)，而為了提高溶解度以及方便純化，我們額外延長序列 (22-55) 並在 N 端加上 KKWK，另外再挑選位於跨膜區的位點 (G29、V40、I47、V50)，將其突變成半胱胺酸以利於自旋標記物之標定，最後將標定之胜肽與 DOPC 混和形成脂質體，以定向圓二色光譜儀、多片層 X 光繞射技術、以及電子自旋共振進行量測，觀察在有無膽固醇狀態之下，類澱粉前驅蛋白跨膜區在膜中的結構和方向性所產生的變化。從實驗結果中我們發現以多片層 X 光繞射技術量測的膜厚度資訊，確實在膽固醇存在時明顯增加，而使用定向圓二色光譜儀偵測胜肽在膜中的方向性，則可得到胜肽垂直插入於膜中的比例相對降低，以此結果表示膽固醇可能會改變胜肽在膜中的位置狀態。再透過電子自旋共振測量胜肽跨膜區 C 端上兩個位點 (V40–I47) 的自旋交互作用影響，由距離模擬結果可觀察到膽固醇對於此區段的影響並不大，其距離數值在有無膽固醇存在時皆為相似，並且明顯超過典型 α-螺旋之長度。根據這些資訊我們以結構模擬圖形推測，在胜肽跨膜區 C 端的 3 至 5 個胺基酸在 DOPC 脂質體中可能會被拉長成 310-螺旋結構，而膽固醇的影響位置或許是位在胜肽的 N 端區域，因此導致其 GG-kink 形成不同角度之彎折，或者是胜肽於膜內的整體位置產生改變，因而影響 γ-分泌酶的決定切位。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-06-17T03:10:11Z (GMT). No. of bitstreams: 1 ntu-107-R05b46008-1.pdf: 13959990 bytes, checksum: 2233eb5fa922965767a29d58b3ecedfe (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract iii 縮寫表 Abbreviations v 第一章 緒論 1 1.1 阿茲海默症 (Alzheimer's Disease, AD) 1 1.1.1 疾病研究史 1 1.1.2 致病成因 2 1.1.3 疾病種類 4 1.3 形成與清除 Aβ 過程 8 1.4 類澱粉纖維蛋白生成機制 (Fibrillization) 10 1.5 γ-分泌酶 12 1.5.1 γ-分泌酶的組成 12 1.5.2 影響 γ-分泌酶切點位置的因素 13 1.6 脂質成分對於阿茲海默症之關聯性 15 1.7 實驗研究目的與實驗設計 17 第二章 材料與方法 26 2.1 材料 26 2.1.1 化學藥品 26 2.1.2 脂質試劑 28 2.1.3 透析膜與過濾管柱 29 2.1.4 脂質體製備材料 29 2.1.5 儀器 30 2.2 方法 32 2.2.1 KKWK-Aβ(22-55) 胜肽合成 32 2.2.1.1 溶劑配製 32 2.2.1.2 合成儀程序設定 32 2.2.1.3 清洗樹脂及切除反應 (Cleavage reaction) 33 2.2.2 KKWK-Aβ(22-55) 胜肽純化及鑑定 34 2.2.2.1 分子篩層析 (Size exclusion chromatography) 34 2.2.2.2 以透析膜及濃縮離心管方式過濾小分子 34 2.2.2.3 鑑定純化後的胜肽 34 2.2.3 胜肽進行定位自旋標記法及純化與鑑定 35 2.2.3.1 定位自旋標記法 35 2.2.3.2 以 ACN 為溶劑使用逆向-高效液相層析儀進行純化 35 2.2.3.3 以 TFE 為溶劑使用逆向-高效液相層析儀進行純化 35 2.2.3.4 使用 PD-10 及濃縮過濾離心管進行過濾 36 2.2.4 脂質薄膜及脂質體製備 36 2.2.4.1 脂質薄膜製作 36 2.2.4.2 脂質體形成 37 2.2.5 以動態光散射測量脂質體粒徑大小 37 2.2.6 以 (定向) 圓二色光譜儀量測胜肽之二級結構以及其方向性 37 2.2.7 利用多片層 X 光繞射測量膜厚度 38 2.2.8 用電子自旋共振量測胜肽上的自旋標記物 38 第三章 結果 39 3.1 KKWK-Aβ(22-55) 胜肽樣品製備 39 3.1.1 KKWK-Aβ(22-55) 胜肽合成及質譜鑑定分析 39 3.1.2 KKWK-Aβ(22-55) 胜肽由分子篩層析管柱純化及質譜鑑定分析 41 3.1.3 KKWK-Aβ(22-55) 胜肽經由透析膜及濃縮離心管純化並以質譜鑑定分析 44 3.2 胜肽進行定位自旋標記法及純化與質譜鑑定 45 3.2.1 使用 C18 管柱純化與質譜鑑定經定位自旋標記法之胜肽 45 3.2.2 以 PD-10 管柱及濃縮離心管過濾與質譜鑑定經定位自旋標記法之胜肽 48 3.3 透過圓二色光譜儀觀察不同類型之脂質對胜肽二級結構的影響 52 3.4 使用動態光散射量測脂質體大小與樣品均質度 56 3.5 以定向圓二色光譜儀探討膜組成變化對於胜肽在膜中位置之影響 59 3.6 以多片層 X 光繞射量測脂質膜厚度 60 3.7 用電子自旋共振量測在脂質體中胜肽的自旋標記物之距離 61 3.8 以結構模擬軟體進行 APP 跨膜區結構之預測 72 第四章 討論 74 第五章 未來展望 79 參考文獻 80 附錄 90 | |
| dc.language.iso | zh-TW | |
| dc.subject | 膽固醇 | zh_TW |
| dc.subject | 阿茲海默症 | zh_TW |
| dc.subject | GG-kink | zh_TW |
| dc.subject | γ-分泌? | zh_TW |
| dc.subject | 類澱粉前驅蛋白跨膜區 | zh_TW |
| dc.subject | APP transmembrane region | en |
| dc.subject | γ-secretase | en |
| dc.subject | cholesterol | en |
| dc.subject | GG-kink | en |
| dc.title | 研究脂質成分對類澱粉前驅蛋白跨膜區結構的影響 | zh_TW |
| dc.title | Studying the Effect of Lipid Composition on the Membrane Spanning Region of Amyloid Precursor Protein | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 廖永豐(Yung-Feng Liao),江昀緯(Yun-Wei Chiang),李明道(Ming-Tao Lee) | |
| dc.subject.keyword | 阿茲海默症,類澱粉前驅蛋白跨膜區,γ-分泌?,GG-kink,膽固醇, | zh_TW |
| dc.subject.keyword | APP transmembrane region,γ-secretase,GG-kink,cholesterol, | en |
| dc.relation.page | 90 | |
| dc.identifier.doi | 10.6342/NTU201801681 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-07-19 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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