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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林俊宏 | |
dc.contributor.author | Shang-Chuen Wu | en |
dc.contributor.author | 吳尚錞 | zh_TW |
dc.date.accessioned | 2021-06-08T02:38:48Z | - |
dc.date.copyright | 2018-07-19 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-07-12 | |
dc.identifier.citation | 1. Everhart, J. E. (2000) Recent developments in the epidemiology of Helicobacter pylori. Gastroenterol Clin North Am 29, 559-578
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20015 | - |
dc.description.abstract | 在全世界的人口中約有一半的人遭受幽門螺旋桿菌感染,大多數的感染者並沒有明顯的症狀,即使產生症狀,會有不同程度的病徵,例如胃炎、胃潰瘍和胃癌。這可能是因為細菌和胃表皮細胞本身的變異性;但也有可能是因細菌和宿主細胞不同的交互作用。根據先前文獻指出,受幽門螺旋桿菌感染時,胃部表皮細胞會分泌第三型半乳糖凝集素 ( galectin-3) 到胃表皮黏膜層,當 galectin-3結合到細菌上之脂多醣 ( Lipopolysaccharides, LPS) 時,會使細菌產生聚集和具有殺菌效果。然而幽門螺旋桿菌 LPS 所含外端的 O-antigen結構上,已知會有不同程度的岩藻醣化修飾 (fucosylation),本論文目的在探討 LPS上岩藻醣化的程度是否會影響到 galectin-3 的結合力和功能,進一步瞭解 galectin-3抑制細菌生長的詳細機制。首先合成數個具有岩藻醣修飾之路易士抗原分子 (LeY-LeX、LeX-LeX 和 α 1,2-fucosyl type 2-tetraose), 測試它們與 galectin-3的結合能力,這些分子和細菌 LPS 上 O-antigen 結構相似。研究結果顯示出路易士抗原分子具有岩藻醣修飾,會明顯降低 galectin-3的結合力。另外,過去的文獻指出細菌感染時,宿主胃部表皮細胞會釋放出第二型岩藻醣水解酶 (FUCA2),本研究使用LC-MS/MS質譜分析,發現該酵素會對具有岩藻醣修飾的寡糖產生水解作用,而且該酵素對於不同鍵結岩藻醣的專一性依序為 α 1-2 > α 1-3> α 1-4;醣體上若具有多重 α 1-3 鍵結,會偏好非還原末端的 α 1-3 鍵結。相對地,只存在溶酶體的人類第一型岩藻醣水解酶 (FUCA1),卻只能移除 α 1-2 鍵結之岩藻醣;因此 FUCA2能將 LPS 上大部分岩藻醣去除,暴露出醣體骨幹結構 poly- or oligo-LacNAc,使得水解產物與 galectin-3的結合力相較於未修飾的 LPS 提升了十倍,而殺菌效果增加一倍;這個結果說明了在 FUCA2和Galectin-3的協同作用下能增強殺菌效果。 | zh_TW |
dc.description.abstract | Helicobacter pylori has persistently colonized over 50% of the global human population. Although most of infected remain asymptomatic, minor percentage of people develop gastritis, gastric ulcers, and gastric carcinomas. The reason is due to the highly stringent host immunity against pathogens and existence of dynamic host-pathogen interplay. More recent studies have shown that galectin-3 is up-regulated and secreted out by the gastric epithelial cells into the surface mucus layer as a response to H. pylori infection. This lectin can directly bind to the lipopolysaccharides (LPS), leading to bacterial aggregation and subsequent bactericidal effects. However, fucose decorated O-antigen of H. pylori LPS is not a preferred epitope for galectin-3 binding. Thus, it is of significant scientific interest to decipher how fucosylated LPS influences binding affinity of galectin-3 and its effect on galectin-3 mediated bactericidal effects.
In order to evaluate the interaction between galectin-3 and H. pylori LPS, we synthesized various fucosylated Lewis antigens (including LeY-LeX, LeX-LeX and α 1,2-fucosyl type 2-tetraose) which are similar to O-antigen, representing the differential levels of fucosylation. The results clearly demonstrated the modulatory role of fucose, as fucose residues reduced the binding affinity of galectin-3. Our lab previously reported that human FUCA2 is secreted upon H. pylori infection. Interestingly, our current data shows that FUCA2 could remove fucose on LPS with the order of cleavage preference as α 1-2 > α 1-3> α 1-4. Since H. pylori LPS has many α 1-3 fucose residues, the preference of cleavage is from non-reducing end of O-antigen. On the other hand, FUCA1, a human lysosomal fucosidase could only remove α 1-2 linkage. Hence, the FUCA2 treatment was able to remove fucose residues on its LPS to expose the poly- or oligo-LacNAc structure that consistently, appeared to be a favored epitope for galectin-3 binding (10-fold higher binding ability, compared with the untreated LPS). Consequently, the galectin-3-mediated bactericidal effect is increased in FUCA2-treated H. pylori. Taken together, these results clearly depict that galectin-3 and human FUCA2 act synergistically to enhance bactericidal effects. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:38:48Z (GMT). No. of bitstreams: 1 ntu-107-D00b46009-1.pdf: 28684706 bytes, checksum: e1169ca2f42c08b1d78c7ed602dd909f (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | Chapter 1 緒論 ....................................................................................................... 15
1.1 幽門螺旋桿菌和脂多醣結構概述 ............................................................... 15 1.2 半乳糖凝集素之功能概述 .......................................................................... 20 1.3 岩藻醣水解酶 (a-L-Fucosidase) 及其生物功能概述 ................................ 23 1.3.1 第一型人類岩藻醣水解酶 (a-L-Fucosidase 1, FUCA1) ...................... 24 1.3.2 第二型人類岩藻醣水解酶 (a-L-Fucosidase 2, FUCA2) ...................... 25 1.4 研究動機和目的 ......................................................................................... 27 Chapter 2 結果 ....................................................................................................... 29 2.1 探討半乳糖凝集素和幽門螺旋桿菌之結合力分析..................................... 29 2.1.1 人類半乳糖凝集素對於不同第二型路易士抗原分子之配體選擇性 .... 29 2.1.2 幽門螺旋桿菌 LPS 經過 FUCA2 處理後,能大幅提升和 Galectins-3 之結合能力 ..................................................................................................... 30 2.1.3 當幽門螺旋桿菌感染後,能偵測到細胞分泌之 FUCA2 活性增加和 Galectin-3 蛋白質表現量上升 ......................................................................... 31 2.2 人類第二型岩藻醣水解酶之生化分析 ....................................................... 32 2.2.1 利用大腸桿菌系統建構人類第二型岩藻醣水解酶之表現及純化 ....... 32 2.2.2 利用畢赤酵母 (P. pastoris) 表現人類第二型岩藻醣水解酶................ 34 2.2.3 利用 Expi 293 系統表現人類第二型岩藻醣水解酶 ............................ 34 2.2.4 醣基化現象能夠增加重組人類第二型岩藻醣水解酶之活性和穩定性 36 2.2.5 利用 Expi 293 系統表現人類第一型岩藻醣水解酶和鑑定 ................. 39 2.3 使用人類岩藻醣水解酶處理前後之幽門螺旋桿菌表面醣的變化.............. 40 2.3.1 FUCA2 能修飾幽門螺旋桿菌上之岩藻醣結構,因此降低 Lewis X 和 Lewis Y 含量 .................................................................................................. 40 2.3.2 FUCA2 能修飾幽門螺旋桿菌上之岩藻醣結構,因此降低整株細菌和 純化之 LPS 上的 LewisX 含量...................................................................41 2.4 人類岩藻醣水解酶之酵素專一性分析......................................................... 42 2.4.1 檢測人類岩藻醣水解酶之受質專一性 ................................................ 42 2.4.2 以標準品為受質利用 Thin layer chromatography 來進行分析............ 43 2.4.3 利用市售路易士抗原分子搭配 UPLC-MS 進行 FUCA1 和 FUCA2 之 酵素專一性分析。 .......................................................................................... 44 2.4.4 FUCA2 能移除 LeY – LeX 上之 a 1-2 和 a 1-3 鍵結岩藻醣,然而 FUCA1 只能移除 a 1-2 鍵結岩藻醣 .............................................................. 45 2.4.5 FUCA2 首先移除 LeY – LeX 上之 a 1-2 鍵結岩藻醣,然後水解 LeX – LeX 上非還原端之 a 1-3 鍵結岩藻醣,最後水解 LN – LeX 上之 a 1-3 鍵 結岩藻醣 ......................................................................................................... 46 2.5 半乳糖凝集素-3 和第二型人類岩藻醣水解酶酵素的協同作用 ................. 48 2.5.1 幽門螺旋桿菌表面岩藻醣化的程度為影響存活率之關鍵因素 ........... 48 2.5.2 Galectin-3 和 FUCA2 會使細菌產生聚集和增加膜上之通透性藉此達成 殺菌效果 ......................................................................................................... 49 2.5.3 Galectin-3 和 FUCA2 會使細菌產生破損藉此達成殺菌效果.............. 51 2.6 SP-D 和第二型人類岩藻醣水解酶酵素的協同作用 ..................................... 51 2.7 FUCA2 能增強宿主細胞的免疫反應...............................................52 Chapter 3 討論 ....................................................................................................... 53 Chapter 4 結論 ....................................................................................................... 59 Chapter 5 實驗材料與方法..................................................................................... 62 5.1 人類岩藻醣水解酶的表現與純化................................................................62 5.1.1 轉殖作用 (Transformation)....................................................................62 5.1.2 質體的大量製備 .................................................................................... 62 5.1.3 人類第二型岩藻醣水解酶 (MBP_FUCA2) 之大量表現 ...................... 63 5.1.4 人類第二型岩藻醣水解酶 (MBP_FUCA2) 之純化..............................63 5.1.5 人類第一型岩藻醣水解酶 (FUCA1) 重組蛋白之表現與純化 ............. 64 5.1.6 哺乳類細胞表現之人類第二型岩藻醣水解酶 (FUCA2).......................65 5.1.7 人類半乳糖凝集素 1、3 和 8 在 E. coli 之大量表現和純化............... 65 5.2 岩藻醣水解酶重組蛋白之特性分析.............................................................66 5.2.1 西方墨點法 (Westernblotting)...............................................................66 5.2.2 銀染色法 (Silver stain) .......................................................................... 66 5.2.3 岩藻醣水解酶重組蛋白之活性測定......................................................67 5.2.4 岩藻醣水解酶之酵素動力分析..............................................................67 5.2.5 利用 PNGase F 切除 N-linked glycans .................................................. 68 5.2.6 利用質譜分析醣基化位置 ..................................................................... 68 5.3 幽門螺旋桿菌和細胞株培養方法 ................................................................. 69 5.4 萃取 H. pylori LPS ....................................................................................... 70 5.5 使用生物膜干涉技術 (Bio-Layer Interferometry, BLI) 測量 Galectin 和 LPS 之結合能力 ......................................................................................................... 70 5.6 凝集素微陣列分析.......................................................................................71 5.7 UPLC MS 分析標準品和酵素產物定量 ....................................................... 71 5.8 細菌存活實驗 (Bacterialsurvivalassay).......................................................72 5.9 偵測在濃縮共同培養液內之 Fucosidase 酵素活性和 Galectin-3含量.......73 5.10 Fluorescence Polarization (FP) 偵測以 LacNAc 為主要結構的多醣和人類 Galectin-1, -3 and -8 之結合能力 ......................................................................... 74 5.11 凝集素墨點法分析 (Lectin blotting) ........................................................... 75 5.12 利用質譜儀分析醣類樣本的前處理 (Permethylation)................................75 5.13 利用共軛焦顯微鏡 (Confocal microscopy)觀察細菌聚集和膜通透性現象 76 5.14 利用穿透式電子顯微鏡 (Transmission Electron Microscopy) 觀察細菌膜的結構改變......................................................................................................................... 76 5.15 哺乳類細胞表現之人類 Surfactant protein D (SP-D)...................................... 77 5.16 利用 Dynamic Light Scattering (DLS) 來測量 H. pylori LPS 的顆粒大小 . 78 5.17 利用差異性掃描螢光法 (Differential scanning fluorimetry, DSF) 來篩選適 合保存 FUCA2 的條件.............................................................................................79 5.18 利 用 Human cytokine quantikine ELISA assay (R&D Systems) 來 定 量 Dendritic cell 釋放出來的 Cytokine.......................................................79 參考文獻....................................................................................................................... 139 圖次 圖 1:幽門螺旋桿菌感染之疾病進展...................................................................80 圖 2:幽門螺旋桿菌上之路易士抗原結構...........................................................81 圖 3:幽門螺旋桿菌 26695 上之脂多糖結構.......................................................82 圖 4:幽門螺旋桿菌在不同的 pH 值會有不同的 O-antigen 結構....................83 圖 5: DC-SIGN 受體選擇性和辨認之病原體。 ..............................................84 圖 6:幽門螺旋桿菌和 DC-SIGN 結合能力分析。 ...........................................84 圖 7:幽門螺旋桿菌利用具有岩藻醣修飾之配體來和 DC-SIGN 結合,進而促 進下游抗發炎基因和細胞激素釋放。.................................................................. 85 圖 8:利用 siRNA 抑制巨噬細胞上的 Mincle 表現量時,會增加前發炎性細胞激 素(Pro-inflammatory cytokine)釋放和降低抗發炎性激素(Anti-inflammatory cytokine)的產生。 ..................................................................................................86 圖 9:幽門螺旋桿菌 J178 和 J178V 上之結構差異.........................................87 圖 10:加拿大臨床病人幽門螺旋桿菌檢體之路易士抗原表現量。.................88 圖 11:Galectin-3 能降低細菌的存活率。...........................................................89 圖 12:Glycan microarray 測量 Galectin-3 和不同醣分子之結合能力。.........90 圖 13:Surface Plasmon Resonance (SPR)測量 Galectin-3 和不同醣分子之 Kd。91 圖 14:半乳糖凝集素家族.....................................................................................91 圖 15:Galectin-3 辨認細菌表面之 LPS 醣鏈。圖中利用淡藍色標示之醣鏈為 Galectin- 3 結合位置。...........................................................................................92 圖 16:白色念珠菌 (Candida albicans) 表面之 b-1,2-linked mannans。 ........93 圖 17:大腸桿菌上之 Blood group B antigen。..................................................94 圖 18:半乳糖凝集素對於細菌之影響。.............................................................95 圖 19:幽門螺旋桿菌貼附能力比較。.................................................................96 圖 20:利用哺乳類細胞表現之 FUCA2。..........................................................97 圖 21:利用動態光散射 (Dynamic light scattering) 測量 LPS 顆粒大小。 .100 圖 22:幽門螺旋桿菌 LPS 經過 FUCA2 處理後,大幅提升和 Galectins-3 結合 能力。.................................................................................................................... 101 圖 23:當幽門螺旋桿菌感染後,能偵測到細胞分泌之 FUCA2 活性增加和 Galectin-3 蛋白質表現量上升。..........................................................................102 圖 24:利用 Coomassie blue 偵測 MBP_FUCA2 的表現情況。....................104 圖 25:使用 Size-exclusion chromatography column Superdex-200 來偵測並進一 步純化 MBP_FUCA2。 ......................................................................................105 圖 26:使用 TEV 蛋白酶處理後的二次純化。 ..............................................106 圖 27:使用 Expi 293 表現之 FUCA2。 ...........................................................107 圖 28:重組人類第二型岩藻醣水解酶之純化鑑定。......................................108 圖 29:醣基化現象能增加重組人類第二型岩藻醣水解酶之活性和穩定性。110 圖 30:分析重組人類第二型岩藻醣水解酶之醣基化位置。 .......................... 111 圖31:使用 Expi293表現之 FUCA1。..........................................................112 圖 32:重組人類第一型岩藻醣水解酶之純化鑑定。 ...................................... 113 圖 33:重組人類第一型岩藻醣水解酶之特性分析。 ...................................... 114 圖 34:FUCA2 修飾幽門螺旋桿菌上岩藻醣結構,降低 Lewis X 和 Lewis Y 含 量。........................................................................................................................ 115 圖 35:FUCA2 能修飾幽門螺旋桿菌上之岩藻醣結構,因此降低整株細菌和純化之 LPS 上的 Lewis X 含量。.......................................................................116 圖 36:標準品為受質利用 Thin layer chromatography 進行酵素專一性分析。117 圖37:使用 UPLC-MS 搭配標準品來進行定量分析。.................................119 圖 38:利用市售路易士抗原分子搭配 UPLC-MS 進行 FUCA1 和 FUCA2 之 酵素專一性分析。................................................................................................ 120 圖39: FUCA2能移除 LeY –LeX 上之 a1-2和 a1-3鍵結岩藻醣,然而 FUCA1 只能移除 a 1-2 鍵結岩藻醣。..............................................................121 圖 40:FUCA2 首先移除 LeY – LeX 上之 a 1-2 鍵結岩藻醣,然後水解 LeX – LeX 上非還原端之 a 1-3 鍵結岩藻醣,最後水解 LN – LeX 上之 a 1-3 鍵結岩 藻醣。.................................................................................................................... 123 圖 41:幽門螺旋桿菌表面岩藻醣化的程度為影響存活率之關鍵因素。.......126 圖 42:Galectin-3 和 FUCA2 使細菌聚集和增加膜通透性達成殺菌效果。..128 圖 43:Galectin-3 和 FUCA2 會使細菌產生破損藉此達成殺菌效果。.........131 圖 44:Galectin-3 和 FUCA2 會使細菌產生聚集和轉型為球形體 .............133 圖 45:FUCA2 能增強 SP-D 的抑菌效果。 ....................................................135 圖 46: FUCA2 能增強宿主細胞的免疫反應。....................................137 表次 表 1:利用 Fluorescence Polarization (FP) 來偵測以 LacNAc 為主要結構的多醣 和人類 Galectins-1, -3 and -8 之結合能力..................................................................98 表 2:利用差異性掃描螢光法 (Differential scanning fluorimetry, DSF) 進行條件篩 選,以增加蛋白質穩定度 (Thermal stability)。.......................................................109 | |
dc.language.iso | zh-TW | |
dc.title | 第二型人類岩藻醣水解酶和半乳糖凝集素-3針對
幽門螺旋桿菌之協同殺菌作用 | zh_TW |
dc.title | Synergistic Action of Human α-L-fucosidase 2 and Galectin-3 in the Bactericidal Effect Against Helicobacter pylori | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 邱繼輝,安形高志,賈景山,高茂傑 | |
dc.subject.keyword | 幽門螺旋桿菌,半乳糖凝集素,人類岩藻醣水解?,殺菌效應,凝集素-碳水化合物相互作用, | zh_TW |
dc.subject.keyword | Helicobacter pylori,Galectin,Fucosidase,Bactericidal effect,Lectin-carbohydrate interaction, | en |
dc.relation.page | 193 | |
dc.identifier.doi | 10.6342/NTU201801465 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2018-07-12 | |
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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