請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/53910完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 郭彥彬 | |
| dc.contributor.author | Wan-Hsien Yang | en |
| dc.contributor.author | 楊椀纖 | zh_TW |
| dc.date.accessioned | 2021-06-16T02:33:10Z | - |
| dc.date.available | 2020-09-24 | |
| dc.date.copyright | 2015-09-24 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-07-29 | |
| dc.identifier.citation | References
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/53910 | - |
| dc.description.abstract | 轉化生長因子-β1 (Transforming growth factor-β1，TGF-β1) 在牙齦過度增生 (Gingival overgrowth，GO) 的疾病發展進程中扮演重要角色。GO 的高復發率可能和凝血連鎖反應有關。結締組織生長因子 (Connective tissue growth factor，CTGF/ CCN2) 表現被報告和 GO 的疾病嚴重程度呈正相關。過去研究發現 TGF-β1 可經 Smad3 和 JNK 誘導人類牙齦纖維母細胞(Human gingival fibroblast，HGF) 中 CCN2 的表現，但是詳細機制並不清楚。我們首先以 Src 抑制劑前處理 HGF 發現可以有效抑制 TGF-β1 誘導的 JNK 和 Smad3 的磷酸化以及 CCN2 的蛋白質表現，顯示 Src 位於 JNK 和 Smad3 的上游。以 TGF-β1 刺激 HGF 後，NOX4 蛋白表現量以及細胞中 ROS 產量明顯增加，而前處理 NOX4 抑制劑或 NOX4 si-RNA 可以抑制 TGF-β1 誘導的ROS 量、Src、JNK 和 Smad3 的磷酸化以及 CCN2 和 Type I collagen 的蛋白質表現，因此 TGF-β1 是透過 NOX4/ ROS/ Src 活化 JNK 及 Smad3，而導致HGF 中 CCN2 的表現量增加。
我們同時發現凝血酶 (Thrombin) 和 PAR1 促效劑 SFLLRN 皆可誘導HGF 中 CCN2 的表現。前處理抗氧化劑 NAC、ASK1 抑制劑 Thioredoxin、JNK抑制劑 SP600125 能顯著降低 Thrombin 誘導的 CCN2 表現。顯示它是透過 PAR1/ ROS/ ASK1/ JNK/ AP-1路徑來誘導 CCN2 的表現。NOX 抑制劑亦能顯著降低 Thrombin 誘導的 CCN2 表現。因此我們進一步探討 Thrombin 和TGF-β1 路徑的關係。發現 Thrombin 和 PAR1 促效劑 SFLLRN 皆能誘導 HGF 的 Smad3 磷酸化表現。使用 TGF-β1 中和抗體、ALK5 抑制劑、Smad3 抑制劑可以有效降低 Thrombin 誘導的 CCN2、Type I collogen 以及 α-SMA 表現。顯示 Thrombin 的前纖維化特性可能經由 TGF-β1 訊息路徑調控。進一步發現 Thrombin 可使細胞培養液中活化態的 TGF-β1 表現量增加。由於 Integrin 和蛋白酶可使前 TGF-β1 轉化釋出活化態的 TGF-β1，因此我們以可與 Integrin 結合的 GRGDSP 胜肽 (Peptide) 及泛細胞基質金屬蛋白酶抑制劑 GM6001 前處理 HGF，發現 GRGDSP 胜肽能夠抑制 Thrombin 誘導的活化態TGF-β1 表現。接著以 Integrin αvβ3, αvβ5, αv與β1中和抗體與 HGF 作用，結果僅有 Integrin αv與 β1 中和抗體能降低 Thrombin 誘導的活化態 TGF-β1、Smad3 磷酸化以及 CCN2 表現；使用 Src 抑制劑、ROCK 抑制劑、Actin/ myosin 抑制劑 Blebbistatin 前處理 HGF 亦有相同效果；GM6001 則沒有影響。過去研究發現，牙齦上皮細胞受到 TGF-β1 刺激會產生上皮-間質細胞轉化 (Epithelium- mesenchymal transition，EMT)，在GO的進程中扮演重要角色。Thrombin 則未見報告。我們以 Thrombin 處理兩株牙齦表皮細胞 Ca9-22 和 OECM1，發現它們可使 Ca9-22 和 OECM1 細胞 EMT 相關蛋白 Vimentin、Snail、Slug的表現量明顯增加，亦可使培養液中活化態的 TGF-β1 量增加。進一步以抑制劑研究發現 Thrombin 可透過 PAR1/ Src/ ROCK/ Integrin αvβ6 促使活化態的 TGF-β1量增加，而誘導 EMT 的產生。因此 Thrombin 在牙齦表皮細胞及 HGF 都是透過 PAR1/ Src/ ROCK 影響細胞骨架聚合，牽動細胞膜上的 Integrin (αvβ6或αvβ1)，使得前 TGF-β1 構型改變而轉成活化態的 TGF-β1。 此外，前處理 20 μM 的薑黃素 (Curcumin) 幾乎可以完全阻斷 NOX4、p-Src、p-JNK、p-Smad3 和 CCN2 的表現，並且對於 TGF-β1 促進的細胞移動以及纖維母細胞活化成為肌纖維母細胞 (Myofibroblast) 有顯著抑制效果；Curcumin 也能夠有效抑制 HGF、Ca9-22 以及 OECM1 中由 Thrombin 誘導的活化態 TGF-β1 表現量。Curcumin 對於預防或治療 GO 以及 GO 的復發具有極大的潛力。 | zh_TW |
| dc.description.abstract | Transforming growth factor-β (TGF-β) plays a central role in the pathogenesis of gingival overgrowth (GO). Connective tissue growth factor (CTGF/CCN2) is induced by TGF-β1 and sustain the pro-fibrotic response in GO. CCN2 expression is positively related to the degree of fibrosis in GO. Previous studies have shown that JNK and Smad3 activation is required for TGF-β1-induced CCN2 expressions in human gingival fibroblasts (HGFs). In this study, we found pretreatment with two Src kinase inhibitors (PP2, Src inhibitor-1) significantly reduced TGF-β1-induced CCN2 synthesis and JNK and Smad3 activation in HGFs. Src is an upstream signaling transducer of JNK and Smad3 with respect to TGF-β1-stimulated CCN2 expression in HGFs. We also found TGF-β1 upregulated NOX4 protein expression and increased reactive oxygen species (ROS) production in HGFs. Genetic or pharmacologic targeting of NOX4 abrogated TGF-β1-induced ROS production; Src, JNK, and Smad3 activation; CCN2, and type I collagen protein expression in HGFs. NOX4-derived ROS play pivotal roles in activating Src kinase activity leading to the activation of both canonical (Smad3) and noncanonical (JNK) cascades that cooperate to attain maximum CCN2 expression.
Even under meticulous periodontal maintenance, the recurrence rate after surgical excision in 18 mounths was still up to 34%. The potential mechanism for rapid recurrence is the early recruitment of platelets and coagulation factors to the surgical wound. We found thrombin induced CCN2 expression in HGFs through the activation of PAR1. Pretreatment with antioxidant N-acetyl-L-cysteine (NAC), and c-Jun NH2-terminal kinase (JNK) inhibitor SP600125 significantly reduced thrombin-induced CCN2 expression in HGFs. Thrombin induced CCN2 via PAR1/ ROS/ JNK in HGFs. Furthermore, we found thrombin induced Smad3 phosphorylation and increased activated TGF-β1 levels in HGFs. Pretreatment with Src inhibitor PP2, ROCK inhibitor Y27632, actin/myosin destablizer blebbistain, integrin αv and β1 blocking antibody significantly reduced thrombin-induced activated TGF-β1 levels in HGFs. Thrombin induced CCN2 via PAR1/ Src/ ROCK/ integrin αvβ1/ TGF-β1 in HGFs. Epithelium-mesenchymal transition (EMT) is involved in the pathogenesis of GO. We found thrombin significantly increased vimentin、snail and slug expression in two human gingival epithelial cell lines OECM-1 and Ca9-22. Furthermore, we found thrombin induced Smad3 phosphorylation and increased activated TGF-β1 levels in OECM-1 and Ca9-22 cells. Pretreatment with Src inhibitor PP2, ROCK inhibitor Y27632, actin/myosin destablizer blebbistain, Integrin αvβ6 blocking antibody significantly reduced thrombin-induced activated TGF-β1 levels in OECM-1 and Ca9-22 cells. These results suggested that thrombin induced EMT via PAR1/ Src/ ROCK/ integrin αvβ6/ TGF-β1 in OECM-1 and Ca9-22 cells. We further found curcumin significantly abrogated the TGFβ1-induced CCN2 cell migration and myofibroblast transdifferentiation in HGFs through inhibiting NOX4 protein expression. Furthermore, curcumin inhibited thrombin-induced the activated TGFβ1 level in HGF, OECM-1 and Ca9-22. Curcumin potentially qualifies as a useful agent for the control of GO. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T02:33:10Z (GMT). No. of bitstreams: 1 ntu-104-D00422001-1.pdf: 11817540 bytes, checksum: d8bf78e4345802be3e3ae0e61730ceec (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 致謝 Ⅰ
中文摘要 Ⅱ Abstract Ⅳ 導論 1 第一節 牙齦過度增生 ( Gingival overgrowth，GO ) 1 1-1 GO 簡介 1 1-2 GO 的流行病學 1 1-3 GO 的致病機制 3 1-4 GO 的治療 4 第二節 轉化生長因子 ( Transforming growth factor，TGF-β1 ) 6 2-1 TGF-β1的簡介 6 2-2 TGF-β1與 Integrin 7 2-3 TGF-β1的訊息傳遞路徑 9 2-4 TGF-β1與纖維化 11 第三節 凝血酶 ( Thrombin ) 13 2-1 Thrombin的簡介 13 2-3 Thrombin 的訊息傳遞路徑 13 2-4 Thrombin與纖維化 15 第四節 結締組織生長因子(Connective tissue growth factor，CTGF/CCN2 ) 16 4-1 CCN2的簡介 16 4-2 CCN2與纖維化 17 第五節 Src 與纖維化 20 第六節 過氧化物 ( Redox oxygen species ) 21 6-1 ROS 簡介 21 6-2 ROS 與纖維化 22 6-3 NADPH oxidase 4 與纖維化 23 第七節 薑黃素 ( Curcumin ) 24 實驗目的 26 材料與方法 28 第一節 細胞株與細胞培養 28 第二節 藥物處理 29 第三節 西方墨點法 32 第四節 即時定量聚合酶連鎖反應 (Quantitative Real-Time Polymerase Chain-Reaction (Q-RT-PCR)) 35 第五節 細胞遷移分析-傷口癒合檢測 37 第六節 流式細胞儀檢測過氧化物含量 37 第七節 si-RNA 轉染 (Transfection) 38 第八節 SBE-luciferase Reporter Assay (TGF-β/ SMAD signaling pathway) 38 第九節 Enzymed linked Immunosorbent Assay (Elisa assay) 39 第十節 統計分析 40 結果 41 第一節 Curcumin抑制HGF內TGF-β1誘導 CCN2、α-SMA蛋白表現及細胞移動能力 41 第二節 TGF-β1於HGF中透過NOX4/ ROS/ Src/ JNK及Smad3誘導 CCN2 表現 44 第三節 Thrombin誘導HGF內CCN2表現 47 第四節 Thrombin經TGF-β1訊息傳遞路徑誘導HGF中前纖維基因的表現 50 第五節 Thrombin經TGF-β1訊息傳遞路徑誘導牙齦表皮細胞中EMT相關蛋白質的表現 53 討論 56 結論-圖與表 62 References 94 就學期間發表之論文目錄 111 附錄1 112 附錄2 118 附錄3 125 | |
| dc.language.iso | zh-TW | |
| dc.subject | 結締組織生長因子 | zh_TW |
| dc.subject | 轉化生長因子-β1 | zh_TW |
| dc.subject | 凝血? | zh_TW |
| dc.subject | 薑黃素 | zh_TW |
| dc.subject | Connective tissue growth factor (CTGF/ CCN2) | en |
| dc.subject | Transforming growth factor (TGF-β1) | en |
| dc.subject | Curcumin | en |
| dc.subject | Thrombin | en |
| dc.title | 轉化生長因子及凝血酶誘導人類牙齦纖維母細胞結締組織生長因子表現機轉之研究 | zh_TW |
| dc.title | TGF-β1- and thrombin-stimulated CCN2 production in human gingval fibroblast: Inhibition by curcumin | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 張瑞青,張正琪,張育超,傅鍔 | |
| dc.subject.keyword | 轉化生長因子-β1,凝血?,結締組織生長因子,薑黃素, | zh_TW |
| dc.subject.keyword | Transforming growth factor (TGF-β1),Thrombin,Connective tissue growth factor (CTGF/ CCN2),Curcumin, | en |
| dc.relation.page | 132 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-07-29 | |
| dc.contributor.author-college | 牙醫專業學院 | zh_TW |
| dc.contributor.author-dept | 臨床牙醫學研究所 | zh_TW |
| 顯示於系所單位： | 臨床牙醫學研究所 | |
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