Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/23027
標題: 外顯子缺損型犬科乳鐵蛋白基因之選殖與表現及其抗菌與抗癌功能之研究
Cloning and Expression of Exon-Skipped Dog Lactoferrin and Its Functional Study on Antimicrobial and Antitumor Activities
作者: 張藝馨
Chang, Yi-Hsin
關鍵字: lactoferrin
乳鐵蛋白
antibacterial
antitumer
抗菌
抗癌
出版社: 生命科學系所
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摘要: 乳鐵蛋白(lactoferrin)是一種分子量大約78~80 kD,具有與鐵離子螯合能力的蛋白,屬於運鐵家族成員之一,不同物種的乳鐵蛋白基因序列具有高度的相似性,在生物體內,具有多種的生理功能,例如能調節鐵離子的吸附、抗細菌、抗氧化、抗真菌、抗病毒及抗發炎等。在過去的研究中,許多品種的乳鐵蛋白已被證實具有抗菌功效,但有關犬科乳鐵蛋白(dog lactoferrin;dLF)的研究則少之又少。在本實驗中,發現在六隻正處於哺乳期母犬的上皮乳腺細胞中,乳鐵蛋白的基因表現形式具有不同的異構型,有不同表現子剪接(alternative splicing forms)的構型呈現。本實驗使用已構築好之釋泌型酵母菌(Pichia pastoris)真核表現系統中的pGAPZαC-dLF產製exon 9與exon 10刪除之重組犬科乳鐵蛋白。在蛋白3D立體結構預測中發現,片段缺失之犬科乳鐵蛋白的兩端球葉間的距離較完整片段之乳鐵蛋白短,因此本實驗欲探討此種構型之乳鐵蛋白是否還保留其鐵離子螯合能力與抗菌能力。首先使用酵母菌表現系統及發酵槽進行大量產製重組犬科乳鐵蛋白(recombinant dog lactoferrin;rDLF),接著利用快速蛋白液相層析系統進行專ㄧ的純化,再以西方墨點法進行確認,實驗結果顯示重組犬科乳鐵蛋白釋泌到胞外培養基之產製效率為7.26 mg/L,經不同pH的條件測試下,發現在pH=5環境下,具有最佳鐵離子螯合能力。在抗菌實驗中,發現在大腸桿菌(Escherichia coli;CCRC 11509)、金黃色葡萄球菌(Staphylococcus aureus ;CCRC 10781)及白色念珠菌 (Candida albicans ;CCRC 20511)的24小時生長期間,添加重組犬科乳鐵蛋白的粗萃取液能有效抑制其生長,且在10小時後額外添加能繼續抑制其生長。進一步利用掃描式電子顯微鏡(scanning electron microscopy;SEM)觀察經過乳鐵蛋白處理之菌膜外觀,結果顯示重組犬科乳鐵蛋白(500 ug/mL)能對以上三株菌的外觀造成損害,隨著處理時間的拉長,損害越趨嚴重。在本論文中,進一步探討重組犬科乳鐵蛋白的抗癌功效,發現在3.5 mg/mL的劑量處理下,即可有效抑制人類肺癌細胞CL1-0與A549的生長。綜合上述結果,顯示重組犬科乳鐵蛋白在缺乏exon 9/10的連結片段下,會促使兩個球葉緊密相鄰,但仍保有與鐵離子的結合能力,並且具多面相的抗菌能力及抑癌功效,可作為後續開發或寵物保健與醫療用途之非特異性免疫醫藥蛋白。
Lactoferrin (LF) is a 78~80 kD of iron-binding protein that is a namber of transferrin protein family, which has high homology among different species. LF displays multiple physiological functions, including regulation of iron absorption, antibacterial, antioxidant, antifungal, and anti-inflammation. In the past decade, various species of lactoferrin have been extensively investigated in the antimicrobial functions, but not in dog lactoferrin (dLF). In this study, we found that dLF present different variant from the lactating mammary tissues of female dog, and then we constructed a pGAPZαC-dLF yeast expression system which carries an exon-skipped dLF variant with the loss of exon 9 and exon 10. In the 3D structure prediction, this truncated dLF protein has short distance between two lobes compared with the intact LF under X-ray crystallography. It is interesting to know that the exon-skipped dLF will exhibit different antibacterial ability. The recombinant dog lactoferrin (rDLF) was synthesized and purified in yeast Pichia pastoris to produce a great deal of rDLF by yeast fermentation and fast protein liquid chromatography (FPLC). Data showed that output of rDLF was 7.26 mg/L in culture medium and had the best Fe3+ chelating ability in pH=5. In Escherichia coli CCRC 11509, Staphylococcus aureus CCRC 10781 and Candida albicans CCRC 20511 24 hours incubation, we found the supernatant of rDLF can inhibit the bacteria growth. Data showed that in the three kinds of bacteria, rDLF (500 ug/mL) has antimicrobial activity against on their morphological destruction under scanning electron microscopy (SEM) observation. On human lung cancer cell line (CL1-0, A549) and human bronchial epithelial cell line (Beas 2B), the rDLF (3.5 mg/mL) can inhibit cancer cell growth. Results revealed that, the exon 9 and 10 trancated of rDLF exhibited the excellent antimicrobial and antitumer activity and still had Fe3+ chelating ability. The non specificity immunity protein rDLF may development for pet health care and medical use.
URI: http://hdl.handle.net/11455/23027
其他識別: U0005-0702201119062000
文章連結: http://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-0702201119062000
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