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研究生:鄭春梅
研究生(外文):Chung-Mei Chung
論文名稱:降低微囊蛋白-1的表現會抑制內皮細胞進行類血管形成和增加一氧化氮之釋放
論文名稱(外文):Knockdown of caveolin-1 inhibits the tubule-like formation and increases the NO release of MS1 endothelial cells
指導教授:周逸鵬
指導教授(外文):Yat-Pang Chau
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:解剖暨細胞生物學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:56
中文關鍵詞:微囊蛋白-1一氧化氮內皮細胞
外文關鍵詞:caveolin-1NOendothelial cells
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真核細胞中,細胞膜上的蛋白分子的組成、活化狀態與細胞內的訊號傳遞息息相關。在血管內皮細胞膜上含量十分豐富的微囊(caveolae),主要負責內吞作用(endocytosis)及細胞穿越運輸(transcytosis)的功能;微囊蛋白(CAV1)是組成微囊的主要結構蛋白,在微囊內與許多訊號傳遞分子,如一氧化氮合成酶(Nitric Oxide Synthase,NOS),互相結合成異構物。本研究目的觀察在降低微囊蛋白-1表現時,內皮細胞的形態變化和微囊蛋白-1與一氧化氮合成酶兩者間的互動關係。
本研究利用病毒干擾性核糖核酸技術抑制CAV1表現,探討CAV1對老鼠內皮細胞株(MS1)的細胞特性影響。在成功轉染shCAV1後的MS1細胞中CAV1-mRNA表達明顯下降,降低值為對照组的46%;CAV1蛋白質表達降低為對照组的45%。觀察轉染shCAV1後MS1細胞(MS1cav1-)的生長及細胞型態上沒有明顯改變。但在血管新生、細胞附著能力上明顯降低,另外 MS1cav1-細胞釋放一氧化氮含量提高,細胞遷移及傷口癒合能力明顯增加。我們針對血管新生和細胞黏附力表現降低的問題,深入探討MS1cav1-細胞表現血管新生有關因子(VE-cadherin、Tie-2、VCAM-1)的mRNA和蛋白質的情形。發現MS1cav1-細胞表現VE-cadherin (endothelial cell junctional molecules) 及Tie-2 (穩定血管因子)明顯降低。與細胞貼附能力有關的分子JAM-1 (tight junctions) 及Itgb5 (細胞基質附著) 、VCAM-1 (吸附白血球) 也明顯降低。應用西方點墨法也偵測到Tie-2、Itgb5蛋白質表現量下降。此外在eNOS(eNOS與CAV1組合成異構物並共同位於膜上)mRNA及蛋白質的表現上,經PCR及西方墨點法檢測發現MS1cav1-細胞內的eNOS在mRNA或蛋白質的表現量均降低,但以Griess Assay測得MS1cav1-細胞內的一氧化氮表現量卻比具CAV1表現MS1細胞釋放出的含量明顯增加許多。我們認為內皮細胞中CAV1的表現會調控VE-cadherin、Tie-2、JAM-1、Itgb5、VCAM-1等分子的表現,促成血管新生、細胞附著能力程度減低。此外,CAV1調控細胞之eNOS表現情形,MS1cav1-細胞內一氧化氮表現量的增加會促使細胞遷移能力的增加。
The structure and activation of membrane proteins play key regulatory roles in numerous intracellular signal transduction in eukaryotic cells. Caveolae, a 50 nanometer-sized invagination of the plasma membrane, is well-known microstructure for endocytosis and transcytosis in endothelial cells. Caveolin-1 (CAV1) is a major component of caveolae. Strong evidence showed that caveolin-1 acts as a linker for eNOS and plays an important role for NO signaling in endothelial cells.
In this study, we explored the functional roles of CAV1 in endothelial MS1 cells with RNA interference by using VSV-G pseudotyped lentivirus system. By shCAV1-lentiviral infection technique, we downregulated CAV1 expression in endothelial MS1 cells which express high levels of CAV1 mRNA and caveolin-1 protein. The infection of shCAV1 to MS1 cells (MS1cav1- cells) successful reduced the levels of CAV1mRNA and its protein about 46% and 45% compared with mock cells, respectively. Moreover, MS1cav1- cells have no morphological change and alteration of cell growth. However, the knock-down of CAV1 expression resulted in the decrease of angiogenic factors, (VE-cadherin and Tie-2), leading to the failure of tubule-like formation, and the downregulation of cell adhesion molecules (JAM-1、Itgb5、VCAM-1), leading to the decrease of cell adhesion. On the other hand, the knock-down of CAV1 expression in MS1cav1- cells increases the nitric oxide release and promotes the cell migration ability.
目錄 I
中英文名詞縮寫對照表 - 1 -
中文摘要 - 2 -
Abstract - 3 -
一、緒論 - 4 -
1.1微囊 (Caveolae)之簡介 - 4 -
1.2微囊蛋白(Caveolin)是微囊之組成蛋白 - 4 -
1.3微囊蛋白-1( Caveolin-1)基因組及分子結構 - 5 -
1.4微囊蛋白-1 ( Caveolin-1)之功能 - 6 -
1.5微囊蛋白-1(caveolin-1)與血管新生(angiogenesis)之關係 - 6 -
1.6微囊蛋白-1與內皮細胞一氧化氮合成酶 (endothelial nitric oxide synthases) 之關係 - 7 -
1.7微囊蛋白-1與整合素 (integrin) 之關係 - 7 -
1.8微囊蛋白-1在病理上之角色 - 8 -
二、目的 - 10 -
三、材料與方法 - 11 -
3.1材料 - 11 -
3.1.1細胞株 (cell lines) - 11 -
3.1.2 細胞培養材料 - 11 -
3.1.3 試劑(Reagent) - 11 -
3.1.4 TRC lentiviral shRNA system - 11 -
3.1.5 質體抽取製備 - 12 -
3.1.6 細胞活性測試 (MTT assay) - 12 -
3.1.7 RNA表現量分析 - 12 -
3.1.8 PCR (Polymerase chain reaction ) - 12 -
3.1.9 西方點墨法 (Western blotting) - 13 -
3.1.10 類血管生成作用試驗 (Tubule formation assay on Matrigel) - 14 -
3.1.11 免疫螢光染色 (Immunofluorescence staining) - 14 -
3.1.12 細胞遷移分析 (Migration Assay) 之材料 - 14 -
3.1.13 癒傷能力分析 (Wound healing assay) - 14 -
3.1.14 細胞附著能力分析 (Adhesion assay) - 14 -
3.2方法 - 15 -
3.2.1 細胞培養(cell culture) - 15 -
3.2.2菌株的保存與小量質體抽取法 ( plasmid miniprep ) - 15 -
3.2.3 TRC lentiviral shRNA system - 16 -
3.2.4 細胞活性分析 ( MTT assay ) - 18 -
3.2.5 基因RNA表現分析 - 18 -
3.2.6.蛋白質電泳分析 - 20 -
3.2.7 類血管生成作用試驗 (Tubule formation assay on Matrigel) - 22 -
3.2.8 免疫螢光染色 (Imunofluorescence staining) - 22 -
3.2.9 共軛焦顯微鏡(Confocal microscopy) - 22 -
3.2.10 細胞遷移分析 (Migration Assay) - 23 -
3.2.11 癒傷能力分析 (Wound healing assay) - 23 -
3.2.12 細胞附著能力分析 (Adhesion assay) - 23 -
3.2.13 影像定量 - 23 -
3.2.14 生物資訊學 - 23 -
3.2.15 統計分析 - 24 -
四、實驗結果 - 25 -
4.1 Lentiviral shRNA抑制 CAV1的表現 - 25 -
4.2 抑制 CAV1表現對內皮細胞生長及型態之探討 - 25 -
4.3 抑制 CAV1表現缺乏內皮細胞血管新生的能力 - 26 -
4.4 抑制 CAV1表現降低內皮細胞貼附的程度 - 26 -
4.5 抑制 CAV1表現提高內皮細胞遷移能力 - 26 -
4.6 抑制 CAV1表現會提高內皮細胞一氧化氮產生量 - 26 -
4.7 內皮細胞血管新生之相關基因表現 - 27 -
4.8 內皮細胞遷移及貼附之相關基因表現 - 27 -
4.9 內皮細胞中與血管新生與貼附蛋白質之表現 - 27 -
五、討論 - 28 -
六、結論 - 31 -
參考文獻 - 32 -
圖表 - 38 -
附錄 - 51 -
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4. 一氧化氮對骨骼肌胰島素敏感性之調節作用
5. 過量表現內皮細胞一氧化氮合成酶與粒線體超氧離子歧化酶參與大鼠鼻端腹外側核調控心臟血管功能之研究
6. Naphthoquinone類衍生物,Naphthazarin與Methylnaphthazarin調控血管張力與抑制內皮細胞一氧化氮生成機制之探討
7. 第一型小窩蛋白促進第二型環氧酶蛋白降解
8. 即時監測一氧化氮之整合型有機半導體元件
9. 人類多能力的基質細胞調整培養基經由介白質6促進傷口癒合
10. 一氧化氮於長期間歇性低氧引發自發性高血壓大鼠之動脈化學反射與心血管變化所扮演的角色
11. 探討一氧化氮及Gamma-butyrobetaineesters對瓦頓氏凝膠間葉幹細胞骨分化的影響
12. 透過RANKL,多脂糖和雌激素來研究一氧化氮的訊息在破骨細胞中的作用
13. 探討銀杏葉萃取物對於內皮細胞及巨噬細胞之保護效果
14. 糖化蛋白對內皮前驅細胞功能異常之影響及丹參在治療上可能扮演之角色
15. 溶血脂酸在老鼠巨噬細胞中對於脂多醣所誘發第二型環氧化酶及誘發型一氧化氮合成酶表現之抑制作用探討