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研究生:邱俊龍
論文名稱:洛德乳酸桿菌表現分泌載體pESV-nlp1(a-c)之建立
論文名稱(外文):Construction of expression secretion vector pESV-nlp1(a-c) for use in lactobacillus reuteri
指導教授:張登欽張登欽引用關係---
指導教授(外文):Lactobacillus reuteriExpression Secretion Vector
學位類別:碩士
校院名稱:國立中興大學
系所名稱:獸醫學系
學門:獸醫學門
學類:獸醫學類
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
中文關鍵詞:洛德乳酸桿菌表現分泌載體重組質體
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中文摘要
乳酸菌(lactic acid bacteria)長期被利用於食品工業上,其對於人類及動物健康的助益不斷地被發現,目前已被大量利用於表現外來基因,應用於醫療保健或是食品工業。其中洛德乳酸桿菌(Lactobacillus reuteri)代謝甘油後產生的中間產物洛德因(reuterin),具有廣效性的殺菌效果,使洛德乳酸桿菌在腸道中屬於優勢的菌種,故洛德乳酸桿菌廣泛被認定為優良的疫苗載體。本實驗利用洛德乳酸桿菌與大腸桿菌(E. coli)穿梭載體pSTE32(+)為基礎,嵌入一段洛德乳酸桿菌染色體來源的啟動子序列(promoter sequence)R18,並在R18基因下游接上質體pET-28a-c(+)的多重選殖區(multiple cloning site;MCS),完成3個表現分泌載體pLE-R18(a-c)。為測試載體pLE-R18(a-c)的功能,我們將Pasteurella multocida的毒素基因片段(tox2)嵌入pLE-R18c的MCS,成為質體pLER18-Tox2。將質體pLER18-Tox2電孔轉型(electroporation)至L. reuteri DSM 20016後,以豬抗Tox2的抗體作探針進行西方墨點法(Western blot),可以在L. reuteri的菌體內偵測到訊號,證明質體pLER18-Tox2確實能在L. reuteri 中表現tox2基因。為使表現載體具有分泌的功能,依據1998年Poquet等人對Lactococcus lactis訊號序列之研究報告(Poquet et al, 1998),找出在E. coli及L. reuteri中皆具有啟動子(promoter)及訊號序列(signal sequence)功能之Lactococcus lactis來源的基因nlp1序列,取代R18基因,使表現載體具有分泌外源性蛋白之功能。
Abstract
Lactic acid bacteria(LAB) has been applied in food industry for a long time. Their benefits for animals and human health were shown and proven in much of recent research. Among Lactobacillus species, Lactobacillus reuteri was found to be unique in producing an intermediate metabolite during anaerobic fermentation of glycerol, called “ reuterin ”, which was demonstrated as a broad-spectrum antimicrobial substance against protozoa, yeast, gram-positive and gram-negative bacteria. This activity let L. reuteri to be capable of colonizing in gastrointestinal tract quickly. Consequently, L. reuteri was regarded as an attractive candidate for vaccine design. In this work, three L. reuteri expression secretion vectors (ESV), called pLE-R18a-c, were constructed by integrating promoter sequence R18 from L. reuteri chromosome DNA and a multiple cloning site (MCS) from pET-28a-c(+) into the L. reuteri-E. coli shuttle vector-pSTE32(+). Further evaluation of the expression of these ESVs by cloning the Tox2-DNA fragment from Pasteurella multocida toxin gene as a reporter gene into pLE-R18c, generating a recombinant plasmid pLE-R18/Tox2, was able to detect the Tox2 product in cell lysate of L. reuteri DSM 20016 transformed with pLE-R18/Tox2. With an aim of constructing an efficient ESV capable of expression and secretion of foreign gene products, a DNA fragment termed nlp1, 570 bp in length with a standard promoter-signal sequence from Lactococcus lactis subsp. lactis, was found to be functional in both E. coli and L. reuteri and was used to replace the original R18 fragment in pLE-R18a-c. Preliminary analysis of the recombinant plasmid with R18 being replaced by nlp1-DNA fragment was able to detect protein products of the gene, downstreamed of nlp1, to be present in the supernatant as well as lysate of its L. reuteri transforment indicating the success of constructing a L. reuteri ESV
表次……………………………………………………………………………3
圖次……………………………………………………………………………3
中文摘要………………………………………………………………………4
英文摘要………………………………………………………………………5
第一章 前言………………………………………………………………6
第二章 文獻探討…………………………………………………………7
第一節 乳酸菌簡介………………………………………………………7
一、 乳酸菌之種類……………………………………………………7
二、 乳酸菌在動物體內之角色………………………………………8
第二節 洛德乳酸桿菌(Lactobacillus reuteri)之特性……………9
一、 洛得乳酸桿菌之發現……………………………………………9
二、 洛德因的發現與特性……………………………………………9
三、 洛德因的殺菌力…………………………………………………11
四、 洛德乳酸桿菌其他抑菌素的研究………………………………11
第三節 目前乳酸菌表現異源性蛋白之研究近況………………………12
一、 乳酸菌表現系統之優點…………………………………………12
二、 洛德乳酸桿菌表現異源性蛋白之研究…………………………12
三、 其他乳酸菌表現異源性蛋白之研究……………………………13
第四節 Pasterurella multocida toxin(PMT)之研究……………13
一、 巴氏桿菌的特性…………………………………………………14
二、 PMT基因與毒素之特性………………………………………14
三、 PMT之免疫原性………………………………………………15
第三章 材料與方法………………………………………………………17
第一節 菌株培養與質體之操作…………………………………………17
一、 菌株與質體………………………………………………………17
二、 細菌之培養………………………………………………………17
三、 大腸桿菌質體之抽取……………………………………………17
1. 鹼分解法…………………………………………………………17
2. Viogene Mini-MTM Plasmid DNA Extraction System………18
四、 供轉形用E. coli勝任細胞之製備……………………………18
五、 質體轉形至E. coli……………………………………………19
六、 DNA經Agarose gel電泳後之萃取純化………………………19
七、 Topo TA Cloning®………………………………………………20
第二節 表現載體之構築………………………………………………20
一、 L. reuteri-E. coli穿梭載體pSTE32(+)之修改……………20
二、 表現載體之啟動子與多重選殖位區之組合……………………23
三、 L. reuteri表現載體pLE-R18(a-c)之構築……………………26
四、 PMT基因嵌入L. reuteri表現載體pLE-R18(a-c)之策略……27
第三節 表現載體功能之分析……………………………………………29
一、 供電孔轉型勝任細胞之製備……………………………………29
二、 電孔轉型…………………………………………………………29
三、 L. reuteri質體之抽取…………………………………………30
四、 兔子抗澱粉酶血清之製備………………………………………31
五、 免疫計畫…………………………………………………………31
六、 血清抗體力價偵測………………………………………………31
七、 L. reuteri蛋白質產物之收集…………………………………32
八、 蛋白質電泳SDS-PAGE……………………………………………33
九、 西方轉漬法………………………………………………………33
第四節 表現載體之改良…………………………………………………35
一、 細菌染色體核酸之抽取…………………………………………35
二、 訊號序列及啟動子之篩選………………………………………35
三、 α-amylase表現分泌載體之構築………………………………38
四、 Tox2表現分泌載體之構築………………………………………40
五、 表現分泌載體pESV-nlp1(a-c)之構築…………………………41
第四章 結果………………………………………………………………43
第一節 表現分泌載體之構築………………………………………43
一、 L. reuteri-E. coli 穿梭載體pSTE32(+)之修改……………43
二、 穿梭載體之啟動子與多重選殖區之組合………………………43
三、 L. reuteri表現載體pLE-R18(a-c)之構築……………………44
第二節 表現載體pLE-R18(a-c)功能之分析……………………………44
一、 PMT基因嵌入L. reuteri表現載體pLE-R18(a-c) ……………44
二、 pLE-R18/Tox1及pLE-R18/Tox2於L. reuteri表現能力分析……………………………………………………………………………45
第三節 兔子抗澱粉酶血清之製作………………………………………45
一、 瓊膠免疫擴散法試驗…………………………………………45
二、 抗體力價分析…………………………………………………46
第四節 異源性訊號序列及啟動子之篩選……………………………46
一、 α-amylase活性試驗…………………………………………46
二、 N1及nlp1序列之分析…………………………………………47
第五節 表現載體之改良……………………………………………47
一、 α-amylase表現分泌載體pLE-N1/Amy………………………47
二、 Tox2表現分泌載體之構築…………………………………48
第五章 討論..……………………………………………………………72
參考文獻……………………………………………………………76
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