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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 余佳慧 | |
| dc.contributor.author | Hsin-Da Chiu | en |
| dc.contributor.author | 邱新達 | zh_TW |
| dc.date.accessioned | 2021-06-15T02:38:00Z | - |
| dc.date.available | 2013-09-15 | |
| dc.date.copyright | 2009-09-15 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-08-12 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/44055 | - |
| dc.description.abstract | 一氧化氮 (nitric oxide, NO)在腸道生理恆定功能中扮演重要角色，然而過去研究顯示黏膜中過量的一氧化氮可能與腸道發炎和上皮屏障缺損有關。腸道屏障主要由單層上皮細胞構成，並經由緊密連結蛋白 (tight junction, TJ)，例如ZO-1和occludin，和圍連結肌動肌凝蛋白環 (perijunctional actinomyosin ring, PAMR)將細胞緊密相連。緊密連結之破壞與PAMR之收縮會導致上皮通透性上升。腸道上皮細胞與平滑肌細胞相同，可透過兩種磷酸激酶，Rho蛋白激酶 (Rho kinase, ROCK)和肌凝蛋白輕鏈激酶 (myosin light chain kinase, MLCK)將肌凝蛋白輕鏈磷酸化而造成機動肌凝蛋白收縮。磷酸激酶C zeta (PKCzeta)(一種附膜的非典型磷酸激酶C)的活化對緊密連結蛋白的重組扮演重要角色，且被認為與Rho訊息傳遞有關。因此本篇研究的目的即是要確認肌凝蛋白輕鏈的磷酸化和緊密連結蛋白的瓦解是否參與一氧化氮所引起之腸道上皮屏障功能缺損的機制。將人類結腸癌上皮細胞株Caco-2細胞給予0.5到5 mM濃度的一氧化氮供體S-Nitroso-N-acetylpenicillamine (SNAP, a NO donor)刺激24小時後，透過測量跨上皮電阻值 (transepithelial resistance, TER)以及螢光探針dextran-FITC (分子量3000)從頂腔面到底側面的速率當作細胞間通透性的指標。正常控制組的Caco-2上皮細胞在培養14~21天達到過滿狀態，其TER可達250-300 Ω*cm2。給予SNAP刺激則造成TER的下降以及探針通透率的增加，並呈現濃度依賴性。SNAP (1 mM)可以在不引起細胞凋亡的情況下造成TER下降69%並使上皮通透性增加11倍。細胞經預處理pancaspase或caspase-3抑制劑後並不能反轉1 mM SNAP所造成的屏障缺損，證實此現象發生並非因為細胞凋亡之緣故。透過定量西方墨點法的結果可得知SNAP刺激15分鐘後會造成PKCzeta磷酸化程度上升。刺激24小時後會引起緊密連結蛋白occludin的切割、ZO-1表現量的下降以及肌凝蛋白輕鏈磷酸化的增加。利用免疫螢光染色也觀察到SNAP處理的細胞其緊密連結蛋白和細胞骨架之結構不規則化並有細胞圓型化之現象。ROCK抑制劑 (Y-27632, 20 μM)及MLCK抑制劑 (PIK, 125-175 μM)可以降低SNAP所造成肌凝蛋白輕鏈的磷酸化。預處理ROCK抑制劑Y-27632 (20-50 μM)可反轉SNAP所造成的上皮屏障功能缺損，但MLCK抑制劑如PIK (125-175 μM)或ML-7 (20 μM)則未見此效果。此外，將細胞預處理PKCzeta抑制劑PKCzeta pseudosubstrate (20 μM)也可反轉SNAP所造成通透性的增加和緊密連結的破壞，但並無法降低SNAP引起之肌凝輕鏈磷酸化。綜合以上結果，一氧化氮可以活化PKCzeta而促進緊密連結蛋白之瓦解，並經由ROCK造成肌凝蛋白輕鏈之磷酸化，進而導致腸道屏障功能的缺損。 | zh_TW |
| dc.description.abstract | Physiological level of nitric oxide (NO) is crucial for maintaining gastrointestinal homeostasis, yet excessive production of mucosal NO is associated with gut inflammation and barrier defects. Intestinal barrier is composed of a monolayer of enterocytes linked by tight junctional proteins, e.g. ZO-1 and occludin, and perijunctional actinomyosin ring (PAMR). Disruption of TJs or contraction of PAMR leads to the increase of epithelial permeability. The mechanism of actinomyosin contraction was similar between epithelial and smooth muscle cells, which involved the phosphorylation of myosin light chain (MLC) by kinases, e.g. myosin light chain kinase (MLCK) and Rho-associated kinase (ROCK). Activation of PKCzeta (a membrane-associated atypical PKC) played a role in tight junctional remodeling in epithelial cells and was found associated with Rho signaling in smooth muscle cells. The aim was to investigate whether MLC phosphorylation and TJ disruption were involved in NO-induced intestinal epithelial barrier defects. Human colonic carcinoma Caco-2 cells were exposed to 0.5-5 mM S-Nitroso-N-acetylpenicillamine (SNAP, a NO donor) for 24 hr, and the transepithelial resistance (TER) and apical-to-basolateral flux rate of dextran-FITC (MW3000) were used as indicators of paracellular permeability. Post-confluent Caco-2 cells grown on transwells for 14-21 days established TJ and TER of 250-300 Ω*cm2. Exposure to SNAP increased epithelial permeability in a dose-dependent manner. SNAP concentration at 1 mM induced a 69% drop of TER and an 11-fold increase of epithelial permeability that were apoptosis-independent. The loss of epithelial barrier triggered by 1 mM SNAP was not blocked by pretreatment with a pancaspase or caspase-3 inhibitor. Densitometric analysis of western blots showed that 1 mM SNAP caused PKCzeta phosphorylation at 15 min post-challenge, as well as MLC phosphorylation, occludin cleavage and ZO-1 decrease at 24 hr post-challenge. Disorganization of TJs and cytoskeleton was associated with cell rounding in SNAP-exposed cells. Inhibitors to ROCK (Y-27632, 20 μM) and to MLCK (a novel membrane-permeant inhibitor of MLCK (PIK), 125-175 μM) reduced the level of MLC phosphorylation caused by SNAP challenge. Pretreatment with a ROCK inhibitor (Y-27632, 20-50 μM) attenuated SNAP-induced barrier defects whereas MLCK inhibitors, i.e. PIK (125-175 μM) or ML-7 (20 μM) had no effect. Moreover, pretreatment with PKCzeta inhibitory pseudosubstrate (20 μM) blocked SNAP-induced permeability rise and TJ disruption, but did not decrease the MLC phosphorylation. These findings suggest that exposure to NO induced PKCzeta-dependent TJ disruption and ROCK-dependent MLC phosphorylation, resulting in an increase of epithelial permeability. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T02:38:00Z (GMT). No. of bitstreams: 1 ntu-98-R96441003-1.pdf: 2807619 bytes, checksum: bd88c61adaedcf999b32ebb8a61ee3e7 (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | 口試委員會審定書…………………………………………… ………………………… Ⅰ
誌謝………………………………………………………………… …………………… Ⅱ 中文摘要……………………………………………………………………………… … Ⅳ 英文摘要………………………………………………………………………… ……… Ⅵ 中英文縮寫名詞對照表……………………………………………… ………………… Ⅷ 第一章 文獻回顧………………………………………………………………………. 1 1. 腸道屏障功能………………………………………………….…………………1 1.1 緊密連結概述 …………………………………………….…………………1 1.2 圍連結肌動肌凝蛋白環 (perijunctional actinomyosin ring, PAMR)：肌凝蛋白 (myosin)概述 ……………………………………………………………2 1.3 肌凝輕鏈之調控 ……………………………….……………………………3 1.4 肌凝蛋白輕鏈 (MLC)與緊密連結 (tight junctions)之關連 ……….......... ..5 1.5 調控緊密連結之訊息傳遞 …………………….……………………………6 2. 腸道屏障功能喪失………………………………………….……………………8 2.1 細胞凋亡依賴性 (apoptosis-dependent) ……………………………………8 2.2 非細胞凋亡依賴性 (apoptosis-independent) ……………….………………8 3. 一氧化氮與腸道屏障功能之關連性……………………………………………9 3.1 一氧化氮正常生理功能 …………………………………….………………9 3.2 一氧化氮合成機制…………………………………………….……………10 3.3 一氧化氮供體釋出機制……………………………………….……………11 3.4 一氧化氮之訊息傳導路徑…………………………………….……………12 3.5 過量一氧化氮之腸道病理現象……………………………….……………13 3.6 過量一氧化氮與腸道上皮屏障功能之影響………………….……………15 4. 研究目的 ………………………………………………………………………15 第二章 材料與方法 …………………………………………………………………16 1. 細胞培養…………….…………………………………………………………16 2. 一氧化氮供體nitric oxide donor (S-Nitroso-N-acetylpenicillamine (SNAP)) ....……………………………………………………………………..16 3. 抑制劑……………………………………………………………………….…17 3.1 Membrane-permeant inhibitor of MLCK (PIK) ……………………………17 3.2 Y-27632 ………………………………………………………………..……18 3.3 Z-VAD-FMK ……………………………………………………………..…18 3.4 Z-DEVD-FMK………………………………………………………………18 3.5 Gö6983………………………………………………………………………18 3.6 PKCzeta pseudosubstrate, myristoylated……………………………………18 3.7 ML-7 ………………………………………………………………………..18 4. 屏障功能測量………………………………………………………………….19 4.1 跨上皮細胞電阻 (transepithelial resistance, TER) …………………….…19 4.2 探針通透性 (dextran -FITC permeability)………………...………………19 5. TUNEL assay…...………………………………………………………………20 6. NP-40可溶性蛋白質萃取 (extraction of NP-40 soluble proteins) .….…….…21 7. 細胞質與細胞膜蛋白質萃取 (extraction of cytosolic and memebrane-bound fractions) ……..……………………………………………….………..………21 8. 西方墨點法 (western blotting) ……………………………….……….………22 9. 免疫螢光染色 (immunofluorescent staining) ..…………...….………….……25 10. Griess method. ……………………………………….…………… ………...…26 11. 統計分析..………………………………………………….……………. …….27 第三章 結果 ……………………………………………………………………….…28 1. 一氧化氮供體SNAP可穩定釋出一氧化氮……………………………….…28 2. SNAP刺激造成腸道上皮屏障功能缺損現象，並呈現濃度依賴性….….…28 3. SNAP所造成的屏障功能缺損現象可經由細胞凋亡依賴性與非依賴性之途徑..……………………….…………………………………………………..…29 3.1 TUNEL assay結果顯示，1 mM SNAP並不會增加細胞DNA片段化程度. ……………………………………………………………………….......29 3.2 Hoechst staining結果顯示1 mM SNAP並不會引起細胞染色質濃縮…..30 3.3 預先投予Caspase抑制劑並不能減緩1 mM SNAP所造成之屏障功能缺損………………..………………………………………………………….30 4. 一氧化氮引起之Caco-2之肌凝蛋白輕鏈 (MLC)之磷酸化……….……….30 4.1 SNAP造成Caco-2 細胞之MLC磷酸化程度增加……………………….30 4.2 ROCK抑制劑Y-27632可以部分緩和SNAP所造成Caco-2細胞之屏障功能缺損，且呈濃度依賴性……………………………………………......…31 4.3 MLCK抑制劑PIK與ML-7無法預防SNAP所造成Caco-2細胞之屏障功能缺損……………………………………………………………………….31 5. 一氧化氮造成腸道上皮細胞緊密連結蛋白與細胞骨架結構之破壞………32 5.1 以西方墨點法顯示一氧化氮降低ZO-1蛋白表現以及促進occludin切割……………………………………………………………………….……32 5.2 以免疫螢光染色顯示一氧化氮破壞緊密連結蛋白ZO-1與occludin之結構，並使細胞呈現圓形化凸起……………………………………………….…32 5.3 一氧化氮破壞細胞骨架F-actin之結構並造成細胞變形…………………33 6. 一氧化氮造成之屏障功能缺損是經由PKCzeta之訊息傳遞路徑………..…33 6.1 SNAP刺激15分鐘造成PKCzeta磷酸化程度增加…………….……..… 33 6.2 SNAP刺激60分鐘有引起PKCzeta從細胞質轉移至細胞膜上的趨勢…33 6.3 PKC抑制劑 (Gö6983)和PKCzeta抑制劑 (PKCzeta pseudosubstrate)可以防止一氧化氮造成之屏障功能缺損………………..…….……………..…34 6.4 PKCzeta抑制劑PKCzeta psuedosubstrate可以防止一氧化氮造成之緊密連結蛋白破壞………………………………………….…………………..…34 6.5 PKCzeta-PS不能減少SNAP引起之肌凝蛋白輕鏈磷酸化上升……..…35 第四章 討論……………………………………………………………………..……36 第五章 圖表…………………………………………………………….………….…42 第六章 參考文獻…………………………………………………….………….……68 | |
| dc.language.iso | zh-TW | |
| dc.subject | PKCzeta | zh_TW |
| dc.subject | 腸道上皮細胞 | zh_TW |
| dc.subject | 屏障功能 | zh_TW |
| dc.subject | 一氧化氮 | zh_TW |
| dc.subject | 緊密連結 | zh_TW |
| dc.subject | 肌凝蛋白輕鏈 | zh_TW |
| dc.subject | PAMR | zh_TW |
| dc.subject | ROCK | zh_TW |
| dc.subject | MLCK | zh_TW |
| dc.subject | MLCK | en |
| dc.subject | barrier functions | en |
| dc.subject | nitric oxide | en |
| dc.subject | tight junctions | en |
| dc.subject | myosin light chain | en |
| dc.subject | PAMR | en |
| dc.subject | ROCK | en |
| dc.subject | PKCzeta | en |
| dc.subject | ntestinal epithelial cells | en |
| dc.title | 一氧化氮造成腸道上皮屏障功能缺損的分子機制:緊密連結蛋白之瓦解和肌凝蛋白輕鏈之磷酸化所扮演的角色 | zh_TW |
| dc.title | Molecular Mechanisms of Nitric Oxide-Induced Intestinal Epithelial Barrier Defects: Role of Tight Junctional Disruption and Myosin Light Chain Phosphorylation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 張智芬,沈麗娟,李建國 | |
| dc.subject.keyword | 腸道上皮細胞,屏障功能,一氧化氮,緊密連結,肌凝蛋白輕鏈,PAMR,ROCK,MLCK,PKCzeta, | zh_TW |
| dc.subject.keyword | ntestinal epithelial cells,barrier functions,nitric oxide,tight junctions,myosin light chain,PAMR,ROCK,MLCK,PKCzeta, | en |
| dc.relation.page | 85 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2009-08-12 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生理學研究所 | zh_TW |
| 顯示於系所單位： | 生理學科所 | |
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