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研究生:李嘉祥
研究生(外文):Chia-Hsiang Lee
論文名稱:BACE1螢光共振能量轉移探針報導細胞株之建構
論文名稱(外文):Establishment of BACE1 FRET Reporter Cell Line
指導教授:陳賽君陳賽君引用關係
指導教授(外文):Sai-Koong Tan
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術暨檢驗學系暨研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:81
中文關鍵詞:阿滋海默症
外文關鍵詞:BACE1FRET
相關次數:
  • 被引用被引用:0
  • 點閱點閱:135
  • 評分評分:
  • 下載下載:10
  • 收藏至我的研究室書目清單書目收藏:0
Beta-secretase (BACE1)是阿滋海默症致病因子beta-amyloid 產生過程中第一關鍵酵素,因此是研發治療阿滋海默症藥物之重要標靶。目前市面廠商提供篩檢抗BACE1 藥物的方法,主要是利用fluoerescenc resonance energe transfer (FRET)原理於試管內測定BACE1 酵素活性,不旦昂貴、且無法觀察藥物對細胞內BACE1 基因或訊息傳遞路徑之影響。本論文計劃開發出能即時偵測BACE1 活性
的細胞系統,即建構螢光能量共振轉移(FRET)探針,送入能表現amyloid precursorprotein(APP)和BACE1 基因的細胞內即時偵測BACE1 的活性。我首先設計相同限制酶切位之primer,利用PCR 原理將pGFP2-MCS-DsRed2 載體上的兩種突變螢光蛋白(GFP2 和DsRed2)序列夾出來,送入pDisplay 載體,此載體具有murine Igκ-chain leader sequence 和platelet-derived growth factor receptor transmembrane domain (PDGFR-TM),可將目標基因所表現出來的蛋白表現在細胞膜上。成功建構出含有GFP2和DsRed2的pDisplay 載體之後,再設計BACE1 substrate site (BSS)
序列,插入此pDisplay 載體,建構成BACE1 FRET 探針。再將FRET 探針轉染到能表現APP 和BACE1 基因的腦下垂體似濾泡星狀細胞株(TtT/GF)或HeLa 細胞內,共軛聚焦影像結果顯示此載體於此二種細胞內成功出表現出GFP2 和DsRed2 二螢光蛋白於細胞膜和細胞質上,在prebleach 及postbleach 分析下,由FRET efficiency 計算出此載體表現出蛋白質具有螢光共振轉移的現象產生,螢光受質蛋白能被BACE1 所作用,希望將來可提供活體BACE1 抑制藥物之篩選平
台。
Alzheimer’s disease (AD) is the most common cause of dementia, affecting up to 15 million individuals worldwide. Beta-secretase (BACE1) that cleaves amyloid precursor protein (APP) to produce the amyloid 42 peptide fragment, ultimately resulting in the formation of amyloid plaques, plays a key role in the pathogenesis of AD. Thus, BACE1 is an attractive target for the development of inhibitor drugs to treat AD. Nowadays numerous in vitro BACE1 activity assay are commercially available. Our current efforts focused on the establishment of a FRET-based screening
cell line for the identification and assay of BACE1 inhibitor. To assay for BACE1 activity, we first designed a FRET reporter probe that contained a BACE1 substrate
site (BSS) flanked by GFP2 and DsRed2 two fluorophores. The FRET reporter probe was then constructed into an expression plasmid pDisplay containing κ-chain leader sequence and platelet-derived growth factor receptor transmembrane domain
(PDGFR-TM). After transient transfection of the FRET reporter expression plasmids into HeLa and TtT/GF cell lines, our result indicated successful FRET protein were
expressed in cytoplasma and anchored on cell surface. Endogenous BACE1 activity could be obtained by calculation of the FRET efficiency. After the BACE1 stable line
is fully established, we will use it to potentially identify specific chemical compounds that inhibit BACE1 activity. This BACE1 FRET reporter cell line could lead to the discovery of a drug for the treatment of AD.
目錄
中文摘要……………………………………………………….3
英文摘要……………………………………………………….4
緒論…………………………………………………………….5
研究目的……………………………………………………...16
材料與方法…………………………………………………...17
實驗結果………………………………………………...……37
討論…………………………………………………………...43
參考文獻……………………………………………………...47
實驗結果圖表………………………………………………...56
附錄…………………………………………………………...67
附圖……………………………………………………...……77
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