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研究生:游佳融
研究生(外文):Chia-Jung Yu
論文名稱:第一部份:以蛋白質體學法鑑定分析草蝦過敏原,並探討其免疫特性第二部份:點青黴菌與黃麴黴菌主要過敏原絲胺酸蛋白質水解酶的鑑定,選殖與免疫特性分析
論文名稱(外文):Identification, cloning and characterization of major allergen from Penicillium notatum and Aspergillus flavus as serine protease.
指導教授:周綠蘋周綠蘋引用關係
指導教授(外文):Lu-Ping Chow
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生物化學暨分子生物學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:96
中文關鍵詞:蛋白質體學過敏原質譜分析
外文關鍵詞:proteomicallergenmass spectrometry
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主題一:
異位性疾病諸如過敏性鼻炎、皮膚炎與氣喘的盛行率在已開發國家中具有顯著增加的趨勢。然而長久以來,許多人類的過敏性疾病已經被證實和吸入徽菌的孢子有關。據統計,大約有20 % 到30 %的異位性病人會對黴菌產生過敏症狀;而6 %的一般個體也會對黴菌過敏。
已知點青黴菌 (Penicillium notatum) 是一種常見的室內性黴菌,同時也是導致呼吸性過敏的最主要來源之一。依據免疫轉漬與蛋白質N 端定序的研究分析,得知青黴菌 (Penicillium) 與麴黴菌 (Aspergillus) 這兩屬黴菌的主要過敏原蛋白質是鹼性絲胺酸蛋白質水解酶 (alkaline serine proteases ) 或是液泡內絲胺酸蛋白質水解酶 (vacuolar serine proteases)。本實驗係利用會辨識橘青黴菌鹼性絲胺酸水解酶的單株抗體 ”G11A10” 進行免疫二次元電泳後,將標的蛋白質以in-gel digestion技術切割成小的 peptide片段,接著進行MALDI-TOF質譜分析,得知其peptide map而鑑定到一個點青黴菌的主要過敏原,命名為Pen n 18。進一步地,藉由分子生物得技術完成Pen n 18基因選殖的工作,並依照cDNA序列推演其相對應的蛋白質序列。由於依據cDNA所推演出來的Pen n 18共有494個胺基酸,這與實際上所見的成熟蛋白質分子量( 37 kDa) 並不一致,故推測這之間的差異是由位在蛋白質N 端與C 端的前序列 (prosequences) 所造成。經由蛋白質的序列比對分析,發現Pen n 18與來自其它種類黴菌的液泡內絲胺酸蛋白質水解酶之間具有相當高的序列相似度。利用大腸桿菌M15 pQE30表現系統大量製造出帶有His標籤的重組蛋白質,再以親和力管柱純化重組蛋白質。該純化後的重組蛋白質不但具有辨識病人IgE的能力,同時以抑制試驗得知Pen n 18與來自橘青黴菌的主要過敏原 ”Pen c 18”之間有高度交叉反應,暗示這兩個分子具有相同的IgE結合決定點。未來,該重組過敏原或許可應用於診斷和免疫療法上。
主題二:
過敏性疾病在全世界到處可見,然而在最近的這二十年間,其盛行率是日漸增加。依據世界各個地理區域的相關報導,均指出因接觸到暴露在空氣中的黴菌過敏原而罹患呼吸性過敏疾病是經常可見的。同時青黴菌 (Penicillium) 與麴黴菌 (Aspergillus) 黴菌已被鑑定為會引發外生性支氣管性氣喘疾病的室內型常見之黴菌菌屬。
黃麴黴菌 (Aspergillus flavus) 與黑色麴黴菌 (Aspergillus niger) 是大台北地區患有異位性疾病的兒童,最主要接觸到的室內型黴菌菌種,其出現頻率大於 50 %。利用會對黴菌過敏的病人混和血清進行二次元免疫電泳分析而鑑定到一個重要的黃麴黴菌過敏原” Asp fl 1”。 藉由分子選殖技術將該過敏原的cDNA選殖出並完成其序列分析。全長的cDNA是一段載有403個胺基酸,分子量為 42 kDa 的原生蛋白質 (precusor) 序列。經由切割掉由21個胺基酸所組成的putative signal peptide和100個胺基酸構成的propeptide後,形成一個分子量為 33 kDa,等電點為 6.3,共包含282個胺基酸的成熟蛋白質。分析比對該 Asp fl 1蛋白質序列後發現其與來自細菌的過敏原: subtilisin、橘青黴菌 (Penicillium citrium) 過敏原:Pen c13以及煙色麴黴菌 (Aspergillus fumigatus) 的毒性因子存在有 27 % 至84 % 的序列相同度。利用載體PQE-30於大腸桿菌M15菌株表現系統,大量製造出重組蛋白質 (rAsp fl 1),經由親和力管柱純化的重組Asp fl 1具有辨識對麴黴菌過敏的病人血清IgE之能力。此外由抑制試驗得知該重組蛋白質 (rAsp fl 1) 與天然型的Asp fl 1 ( nAsp fl 1) 或是Pen c1之間具有很強的交叉反應,推測黃麴黴菌與橘青黴菌這兩種黴菌應該是擁有共同的IgE決定點的。

Topic I:
Atopic disorders, such as allergic rhinitis, dermatitis and asthma, are increasingly prevalent in the developed countries. It has long been recognized that inhalation of fungal spores are associated with a number of allergic diseases in human. The prevalence of respiratory allergy to fungi is estimated at 20 to 30 % among atopic individuals and up to 6 % in the general population.
Penicillium notatum is a well-known indoor airborne mold and a major source of fungal inhalant allergens. According to the immunoblotting and N-terminal amino acid sequence analysis, it has been reported that the alkaline and/or vacuolar serine proteases are the major allergens in Penicillium and Aspergillus species. In this study, a major allergen from P. notatum, Pen n 18, was identified by two-dimensional immunoblotting using monoclonal antibody G11A10, raised against the vacuolar serine protease of P. citrinum, followed by MALDI-TOF MS analysis of the peptide digest. Pen n 18 was then cloned and the amino acid sequence deduced from the cDNA sequence. The cDNA coded for a 494 amino acid protein, considerably larger than mature Pen n 18, the differences being due to the N-and C-terminal prosequences. The deduced amino acid sequence showed extensive similarity with those of vacuolar serine proteases from various fungi. The Pen n 18 coding sequence was expressed in E. coli as a His-tag fusion protein and purified by Ni2+-chelate affinity chromatography. On immunoblots, the purified recombinant protein specifically bound IgE from mold allergic patients, and cross-inhibition assays demonstrated the presence of common IgE-binding epitopes on Pen n 18 and a major allergen of P. citrinum, Pen c 18. In the future, this recombinant allergen may be used in clinical diagnosis and immunotherapy.
Topic II:
Allergic diseases occur worldwide and their prevalence appears to have been on the increase in the last 2 decades. Reports from different geographical areas have shown that sensitization to moulds through exposure to airborne fungal allergens are common among patients to respiratory allergic diseases. In addition, Penicillium and Aspergillus species have been identified as prevalent indoor airborne fungi that are associated with extrinsic bronchial asthma.
Aspergillus flavus and Aspergillus niger are predominant (> 50 % occurrence frequency) airborne fungi in the residences of atopic children in the Taipei area. One important A. flavus allergen (Asp fl 1) was identified by means of immunoblotting with serum pool of allergic patients on two-dimensional electrophoretic gel. The cDNA coding for Asp fl 1 was cloned and sequenced. The clone encodes a full length protein of 403 amino acid precursor of 42 kDa. After cleavage of a putative signal peptide of 21 amino acids and a prepeptide of 100 amino acids, a mature protein of 282 amino acids was obtained with a molecular mass of 33 kDa and a pI of 6.3. The degree of identity were found in a range of 27 % to 84 % among related allergens derived from bacteria allergen subtilisin, mold allergen Pen c 1 and virulence factor of A. fumigatus. Recombinant Asp fl 1 (rAsp fl 1) was cloned into vector pQE-30 and expressed in E. coli M15 as a histidine-tag fusion protein and purified to homogeneity. The IgE binding capacity of rAsp fl 1 was tested by immunoblotting using serum pool of Aspergillus-allergic patients. Recombinant allergen cross-reacted strongly with IgE specific for natural Asp fl 1 and Pen c 1, indicating that common IgE epitopes may exist between allergens of A. flavus and P. citrinum.

點青黴菌與黃麴黴菌主要過敏原絲胺酸蛋白水解酶的鑑定,選殖與免疫特性分析------------------------------------------------------------------------------------------------------------1
緒論--------------------------------------------------------------------------2
第一節 前言-------------------------------------------------------------------2
第二節 過敏機制---------------------------------------------------------------2
第三節 過敏的因素-------------------------------------------------------------3
第四節 過敏原的種類-----------------------------------------------------------4
第五節 黴菌過敏原-------------------------------------------------------------4
第六節 過敏疾病的治療策略-----------------------------------------------------5
主題一:點青黴菌主要過敏原絲胺酸蛋白質水解酶 Pen n 18的選殖與免疫特性分析----------9
中文摘要---------------------------------------------------------------------10
英文摘要---------------------------------------------------------------------11
第一章 動機與目的------------------------------------------------------------12
實驗方法---------------------------------------------------------------------13
第一節 黴菌過敏原之鑑定------------------------------------------------------13
第二節 點青黴菌過敏原之選殖--------------------------------------------------15
第三節 點青黴菌過敏原之表現--------------------------------------------------19
第四節 點青黴菌過敏原之免疫特性分析------------------------------------------20
第三章實驗結果---------------------------------------------------------------21
第一節 點青黴菌過敏原之鑑定--------------------------------------------------21
第二節 點青黴菌過敏原之選殖與序列比對----------------------------------------22
第三節 點青黴菌過敏原之表現--------------------------------------------------23
第四節 點青黴菌過敏原之免疫特性分析------------------------------------------24
第四章 討論------------------------------------------------------------------25
第一節 點青黴菌的重要性------------------------------------------------------25
第二節 點青黴菌過敏原的鑑定--------------------------------------------------25
第三節 Pen n 18 序列的分析---------------------------------------------------26
第四節 重組過敏原-rPen n 18與其免疫交叉反應----------------------------------26
第五節 Pen n 18 的B 細胞抗原決定點-------------------------------------------26
第六節 未來展望--------------------------------------------------------------27
第五章 參考文獻--------------------------------------------------------------29
第六章 圖 表-----------------------------------------------------------------35
主題二:黃麴黴菌新的重要過敏原絲胺酸蛋白質水解酵素Asp fl 1之鑑定與特性分析--------50
中文摘要---------------------------------------------------------------------51
英文摘要---------------------------------------------------------------------52
第一章 動機與目的------------------------------------------------------------53
第二章 實驗方法--------------------------------------------------------------54
第一節 黃麴黴菌過敏原之鑑定--------------------------------------------------54
第二節 黃麴黴菌過敏原之選殖--------------------------------------------------55
第三節 黃麴黴菌過敏原之表現--------------------------------------------------57
第四節 黃麴黴菌過敏原之免疫特性分析------------------------------------------58
第三章 實驗結果--------------------------------------------------------------60
第一節 黃麴黴菌過敏原之鑑定--------------------------------------------------60
第二節 黃麴黴菌過敏原之選殖與序列比對----------------------------------------60
第三節 黃麴黴菌過敏原之表現--------------------------------------------------62
第四節 黃麴黴菌過敏原之免疫特性分析------------------------------------------62
第四章 討論------------------------------------------------------------------63
第一節 黃麴黴菌的重要性------------------------------------------------------63
第二節 黃麴黴菌過敏原的鑑定--------------------------------------------------63
第三節 Asp fl 13序列的分析---------------------------------------------------64
第四節 重組過敏原- rAsp fl 其免疫交叉反應-------------------------------------64
第五節 黃麴黴菌鹼性絲胺酸水解酶的分類與演化----------------------------------65
第六節 過敏原生物活性與致敏性------------------------------------------------65
第七節 未來展望--------------------------------------------------------------66
第五章 參考文獻--------------------------------------------------------------67
第六章 圖 表-----------------------------------------------------------------71
發表著作 -------------------------------------------------------------------------------------------------------79

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