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系統識別號 U0026-0408201216162200
論文名稱(中文) 潛在之轉化生長因子β接合蛋白在口腔黏膜上的表現特徵以及功能角色
論文名稱(英文) The expression patterns and functional roles of Latent Transforming Growth Factor-β Binding Proteins(LTBPs)in oral mucosae
校院名稱 成功大學
系所名稱(中) 口腔醫學研究所
系所名稱(英) Institute of Oral Medicine
學年度 100
學期 2
出版年 101
研究生(中文) 江明學
研究生(英文) Ming-Shyue Chiang
電子信箱 s93001037@yahoo.com.tw
學號 t46994066
學位類別 碩士
語文別 中文
論文頁數 96頁
口試委員 指導教授-袁國
口試委員-曾春祺
口試委員-許嘉文
口試委員-劉景勳
中文關鍵字 角化牙齦  非角化牙齦  潛在之轉化生長因子β接合蛋白  轉化生長因子β  角化蛋白 
英文關鍵字 keratinized ginigva  non-keratinized gingiva  LTBPs  TGF-β  keratin 
學科別分類
中文摘要 口腔的上皮組織可以由角化程度分成角化以及非角化上皮。角化上皮表現K1角化蛋白。非角化上皮表現K4角化蛋白。在人類中,大部分的細胞會分泌TGF-β來啟動本身的生物活性。另外,TGF-β不僅僅會抑制表皮生長,也會促進上皮的角質化,表現出角化上皮特性:K1。Latent TGF-β binding proteins(LTBPs)是multidomain proteins。這些protein是用來調節TGF-β之活性。其中LTBP-2以及LTBP-1在上皮角質化的作用目前並不是非常清楚。而我們藉由免疫組織染色法發現在角化口腔上皮組織富含LTBP-2,但在非角化口腔上皮組織裡只有基底層有陽性反應
。另外在角化以及非角化的口腔上皮都富含LTBP-1,但是卻在非角化上皮的基底細胞呈現陰性反應。另外用豬做動物實驗,將豬的去掉上顎角化上皮的結締組織,移植到去掉非角化上皮的傷口。將移植之後長出的上皮來做組織切片以及K1、K4、TGF-β、LTBP-2以及LTBP-1免疫組織染色測試。結果發現和人類正常口腔組織之表現是相同的。

另外我們在正常的培養液以及添加鈣離子的培養液來養人類正常的口腔角質化細胞。接著,利用西方點墨法來偵測正常的口腔角質化細胞裡面K1、K4、LTBP-1、LTBP-2以及involucrin的蛋白質濃度。結果顯示以添加鈣離子的培養液來養人類正常的口腔角質化細胞所偵測到的K1、LTBP-1的濃度較正常培養之角質化細胞為高。

由於在正常口腔角質化細胞裡的LTBP-2以及LTBP-1基因弱化(knowndown)很不容易成功,所以我們另外選用了了OECM-1(口腔癌細胞株)來弱化LTBP-2、LTBP-1,再利用西方點墨法偵測口腔角質化細胞裡面K1、K4的蛋白質濃度。結果發現而西方點墨法結果也顯示出當LTBP-2被弱化,K1或是involucrin的表現會上升,K4的表現會下降。而當LTBP-1的表現被弱化,K1以及involucrin的表現會下降,K4的表現會上升。

最後,利用細胞生長分析來探討弱化OECM-1之LTBP-2,是否有影響到細胞的生長。結果顯示LTBP-2和細胞生長確實有相關性。我們的實驗證明LTBP-1在口腔上皮裡所扮演的角色,調控 TGF-β使上皮走向角化的特徵:K1。而LTBP-2在口腔上皮所扮演的角色,使上皮走向非角化的特徵:K4。此外也和人類正常角質細胞的增生是有關係的。
英文摘要 Epithelium in the oral cavity mainly has two forms: keratinized epithelium and non-keratinized epithelium. Histologically, keratinized epithelium exclusively expresses cytokeratin-1, while non-keratinized epithelium expresses cytokeratin-4. In human, most cells secrete TGF-β to manifest its biological activity; besides, the TGF-β not only inhibit growth of an epithelial cell line, but also influence epithelium biochemical markers of keratinization: K1 expression. Latent TGF-β binding proteins are multidomain proteins. These binding protein moderate TGF-β activity. But the function of LTBP-2 and LTBP-1 for epithelium keratinization were not clear. We used IHC staining found that LTBP-2 were expressed abundantly on oral keratinized epithelium but only on basal layer in nonkeratinized epithelium. LTBP-1 were expressed on keratinized and non-keratinized epithelium but not on basal layer in nonkeratinized epithelium. Furthermore, free grafts of connective tissue from the keratinized gingiva were transplanted into areas of the alveolar mucosa in pig, and these tissue sections were used for IHC staining for the same makers:K1、K4、TGF-β、LTBP-2 and LTBP-1.The results were the same as human.
Besides, we cultivated human normal oral keratinocyte (hNOK) in normal KSFM and KSFM with additive Ca2+. Then, we used Western blot to detect the K1、K4、involucrin、LTBP-1, and LTBP-2 protein level in hNOK. The results show that K1, LTBP-1 protein are at higher levels in hNOK with Ca2+ than in hNOK. Because knocking down gene in hNOK can’t be successful, we knockdown the LTBP-2 and LTBP-1 in OECM-1(SCC cell) to detect the K1, K4 protein levels.
The western blotting results showed that when LTBP-2 was suppressed in OECM-1, the expressions of K1 or involucrin increased, and K4 decreased. However, when LTBP-1 was suppressed in OECM-1, the expression of K1 or involucrin decreased, and K4 increased.

Finally, we used MTT assay to investigate the growth of OECM-1 in which the LTBP-2 was suppressed. The results showed LTBP-2 and cell growth had relevance. Our study demonstrate that the role of LTBP-1 in oral epithelium is to regulate TGF-β, and enable the epithelium to perform the keratinization marker: K1. Moreover, the role of LTBP-2 in oral epithelium is to regulate TGF-β, and enable the epithelium to perform the nonkeratinization marker: K4. Besides, LTBP-2 and cell growth have relevance.
論文目次 目錄
中文摘要..................................................I
Abstract................................................III
誌謝.....................................................VI
目錄....................................................VII
圖目錄....................................................X
英文縮寫檢索表...........................................XI
第一章 緒論...............................................1
1. 口腔黏膜概論.........................................1
1-1 角質化 (keratinization)...........................1
1-2 非角質化 (non-keratinization).....................3
2. 角化蛋白(keratin)概論................................4
3. TGF-β(Transforming growth factors β)概論...........6
4. LTBPs (Latent Transforming Growth Factor-β Binding
Proteins)概論........................................7
5. 研究動機............................................10
第二章 實驗材料與方法....................................12
一、 免疫組織化學染色 (Immunohistochemistry)............12
二、 OECM-1細胞培養 ( Cell culture )...................16
A. 繼代培養 ( Subculture )..........................18
B. 冷凍細胞 ( Freezing cells )......................18
C. 解凍細胞 ( Thawing cells ) ......................19
三、 hNOK細胞培養 ( human normal oral keratinocyte cell culture ) ........................................19
A. 初級培養( primary cluture ) .....................20
B. 繼代培養 ( Subculture )..........................21
C. 冷凍細胞 ( Freezing cells )......................22
D. 解凍細胞 ( Thawing cells ) ......................23
E. 誘導人類正常角質化細胞(hNOK)分化.................23
四、 細胞蛋白質萃取 ( Protein extraction )............24
五、 蛋白質濃度測定 ( Protein assay ) .................25
六、 SDS-PAGE 蛋白質電泳 ( SDS-PAGE protein
Electrophotresis )...............................26
七、西方點墨法 ( Western blotting )....................29
八、慢病毒的製備 ( Lentivirus production ).............31
九、慢病毒的定量 ( Lentivirus titer determination )....35
十、慢病毒的感染 ( Lentivirus infection )..............38
十一、細胞生長分析 ( Cell proliferation assay )........39
十二、動物實驗( Animal model ).........................40
第三章 實驗結果..........................................42
1. 檢測LTBP-2、LTBP-1在人類正常口腔牙周組織樣本之表現.42
2. 檢測LTBP-2在人類其他正常器官組織樣本之表現.........42
3. 利用動物模型來驗證LTBP-2、LTBP-1的表現.............43
4. 西方點墨法鑑定LTBP-2、LTBP-1的表現.................44
第四章 實驗討論..........................................46
1. TGF-β影響角質細胞分化的探討........................48
2. LTBPs會調節TGF-β的訊息傳遞........................50
3. 鈣離子的改變對角質細胞的影響........................51
4. LTBP-2 在牙齦以及口腔黏膜所扮演的角色...............52
4-1.LTBP-2 和老化的關係...............................53
4-2.LTBP-2 和增生的關係...............................54
4-3.LTBP-2 和彈性纖維的關係...........................55
第五章 結論..............................................56
Future work...........................................56
參考文獻.................................................57
附圖.....................................................65
自述.....................................................96
圖表目錄
表一:身體其他器官有LTBP-2表現之組織晶片....................65
表二:不同表型之基因knock out老鼠...........................66
圖一:口腔上皮中的細胞分化...................................67
圖二:口腔上皮中的角化蛋白...................................68
圖三:LTBPs和TGF-β的結構關係...............................69
圖四:人類正常口腔組織之K1、K4、TGF-β、LTBP-1及LTBP-2
免疫組織染色表現.......................................70
圖五:人類正常口腔組織之LTBP-1及LTBP-2免疫組織染色表現.....72
圖六:身體其他器官有LTBP-2表現之組織晶片....................74
圖七:動物實驗蘭嶼豬口腔手術前後之照片.......................84
圖八:蘭嶼豬身上轉植過後所取得之組織的免疫組織染色表現.......85
圖九:利用西方點墨法鑑定NOK養在培養液以及含有鈣離子(o.1mM)
之培養液兩種細胞表現involucrin、K1以及 K4 的情形......87
圖十:利用西方點墨法鑑定NOK養在培養液以及含有鈣離子(o.1mM)
之培養液兩種細胞表現LTBP-1以及LTBP-2的情形...........88
圖十一:利用西方點墨法鑑定OECM-1表現LTBP-1、LTBP-2、
involucrin、K1以及 K4的情形.........................89
圖十二:利用shRNA及慢病毒(Lentivirus)感染的方式來弱化LTBP-1
的表現,再利用西方點墨法鑑定之情形...................90
圖十三:利用shRNA及慢病毒(Lentivirus)感染的方式來弱化LTBP-2
的表現,再利用西方點墨法鑑定之情形...................91
圖十四:弱化LTBP-1後,再利用西方點墨法鑑定K1、K4以及
involucrin 的表現....................................92
圖十五:弱化LTBP-2後,再利用西方點墨法鑑定K1、K4以及
Involucrin 的表現....................................93
圖十六:弱化LTBP-2、LTBP-1的OECM-1生長曲線圖...............94
圖十七:隨著老化,黏附牙齦(attached gingiva)會變寬...........95
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