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研究生:謝綺文
研究生(外文):ChiWen Hsieh
論文名稱:蛇毒蛋白Echisotin之精製及其對血小板與軟骨細胞活性之探討
論文名稱(外文):Purification of Echisotin, a Snake Venom Peptide from Echis carinatus sochureki, and Its Effects on Pletelet and Chondrocyte.
指導教授:黃德富
指導教授(外文):Huang Tur Fu
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:1999
畢業學年度:87
語文別:中文
論文頁數:90
中文關鍵詞:蛇毒蛋白Echisotin
外文關鍵詞:Snake Venom - Echis carinatus sochureki
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中文摘要
1. Echis carinatus sochureki蛇毒依序利用CM-Sephadex C-50 陽離子交換法、Sephadex G-100膠質過濾法、快速蛋白質液態層析儀 Superdex HR10/30膠質過濾法,最後以高效率液態層析法來進行純化分離,可以得到一種強力具有抑制血小板凝集作用的成份,並將之命名為"echisotin"。
2. echisotin經由SDS-PAGE分析在還原或非還原狀態下,皆可以得到分子量約為5,600 daltons之單鏈 ,繼續由蛋白的烷化及還原反應,再經N端序列分析,可得知它為ㄧ種含有RGD的短鏈disintegrin。
3. 在人類富含血小板血漿,echisotin會抑制collagen (10μg/ml) 及ADP (20 μM) 所引起之血小板凝集作用,且具有劑量相關性的抑制作用,其IC50分別為3.44μg/ml (0.61μM)和1.12μg/ml (0.20μM);而在人類血小板懸浮液製備中,echisotin也會抑制collagen (10 μg/ml) 、thrombin (0.1 U/ml)、 U46619 (1μM) 及ADP (20μM) 所引起之血小板凝集作用,而且隨著濃度的增加而抑制活性增強,其IC50 分別為0.92μg/ml (0.16 μM)、0.74μg/ml (0.13μM)、0.77 μg/ml (0.14μM)和0.53 μg/ml (0.09μM),然而echisotin並不會明顯影響上述致活劑所引起的血小板形態改變。
4. 在人類臍靜脈內皮細胞附著到細胞外基質的實驗中,echisotin可以呈現劑量相關方式地抑制人類臍靜脈內皮細胞附著到fibrinogen (40μg/ml) 和fibronectin (40μg/ml),其IC50 分別為12.92μg/ml (2.31μM) 、11.48 μg/ml (2.05μM);此外,echisotin也可以呈現劑量相關方式地抑制大鼠軟骨細胞附著到fibrinogen 和fibronectin,其IC50 分別為10.23μg/ml (1.83μM) 及10.02μg/ml (1.79μM)。另外,GRGDS也可以劑量相關方式地抑制軟骨細胞及人類臍靜脈內皮細胞附著到fibrinogen、fibronectin,而Integrelin (是ㄧ個專ㄧ性αⅡbβ3 integrin拮抗劑) 在高濃度下(120.2μM)也可抑制人類臍靜脈內皮細胞附著到fibrinogen和fibronectin;但對於軟骨細胞附著到這些細胞外基質的抑制作用較小。
5. 利用雷射流式細胞儀的分析, echisotin會明顯抑制β3的單源抗體結合到軟骨細胞,並呈現劑量相關性的抑制作用;但是對於其他β1及α5 integrin的單源抗體結合於軟骨細胞所呈現的螢光強度,則無拮抗作用;然而在人類臍靜脈內皮細胞及人類血小板, echisotin有劑量相關方式地的抑制7E3結合到細胞的作用。
6. 在大鼠軟骨細胞對於PDGF、TGF-β1刺激之後細胞增生的實驗中,echisotin可以劑量相關方式地抑制軟骨細胞受到PDGF (20 ng/ml)、TGF-β1 (20 ng/ml)刺激24小時之後的細胞增生,其IC50 分別為3.08 mg/ml (0.55mM)和 2.61 mg/ml (0.47 mM)。
7. 綜合以上的結果得知echisotin在軟骨細胞、人類臍靜脈內皮細胞和人類血小板皆可經由β3之結合作用,而影響細胞的功能,包括血小板的凝集之抑制作用。然而對於軟骨細胞、人類臍靜脈內皮細胞的功能探討,除了抑制細胞的附著,同時也抑制軟骨細胞受到生長因子刺激的細胞增生作用,由此推論echisotin是先作用在細胞的β3 integrin,使得訊息無法傳入細胞,而抑制了細胞的附著。在這過程中生長因子之作用與integrin之間的交互作用,以及echisotin如何影響細胞的訊息傳遞,進而調節細胞的功能,則是有待進ㄧ步的研究。

英文摘要
1. By means of column chromatography of CM-Sephadex C-50, gel filtration of Sephadex G-100 and Sephadex HR 10/30, and finally HPLC of a C18 reverse phase column, a new snake venom protein, echisotin, was purified from the venom of Echis carinatas sochureki.
2. Echisotin was homogenous as judged by SDS-PAGE and N-terminal amino acid analysis. The purified protein showed a single-band with an apparent molecular weight of 5,600 daltons under both the reduced and non-reduced conditions. Following S-alkylation and reduction, the N-terminal amino acid sequence of echisotin was identified. Echisotin contained an Arg-Gly-Asp (RGD) sequence at position 24~26 and was highly homologous with those of the recently reported members of disintegrin family.
3. In human platelet-rich plasma, echisotin dose-dependently inhibited the platelet aggregation induced by collagen (10 mg/ml) and ADP (20 mM). The IC50 values were estimated to be 3.44 mg/ml (0.61 mM) and 1.12 mg/ml (0.20 mM), respectively. In human platelet suspension, echisotin also exhibited an inhibitory effect on the aggregation of platelets stimulated by collagen (10 mg/ml), thrombin (0.1 U/ml), U46619 (1 mM) and ADP (20 mM) in the presence of fibrinogen (20 mg/ml) in a concentration-dependent manner, with IC50 values of 0.92 mg/ml (0.16 mM), 0.77 mg/ml (0.14 mM), 0.53 mg/ml (0.09 mM) and 0.35 mg/ml (0.06 mM), respectively. However, echisotin apparently did not affect the shape change caused by these agonists.
4. In the studies of cell adhesion to ECMs, echisotin inhibited on HUVEC adhesion to immobilized fibrinogen (40 mg/ml) and fibronectin (40 mg/ml) in a dose- and RGD-dependent manner. The IC50 values were estimated to be 12.92 mg/ml (2.31 mM) and 11.48 mg/ml (2.05 mM), respectively. In addition, echisotin also concentration-dependently inhibited IRC adhesion to immobilized fibrinogen and fibronectin with IC50 values of 10.23 mg/ml (1.83 mM) and 10.02 mg/ml (1.79 mM), respectively. However, Integrelin (a specific integrin aIIbb3 antagonist) showed an inhibitory effect on HUVEC adhesion to these ECMs at 120.2 mM, but it showed little effect on IRC adhesion.
5. The effects of echisotin on the binding or many anti-integrin monoclonal antibodies (mAbs) were examined by flow cytometry. Echisotin specifically inhibited the binding of anti-b3 integrin mab to IRC in a dose-dependent manner, but not those of other anti-integrin mAbs such as b1 and a5 . However, in human platelet and HUVEC preparations, echisotin concentration-dependently blocked the 7E3 interaction with these cells.
6. The effects of echisotin on growth factors stimulated rat chondrocyte proliferation were evaluated by using MTT assays. Pretreatment of echisotin dose-dependently inhibited the proliferation of IRC by exposure to either PDGF or TGF-b1 (both in 20 ng/ml) for 24-h. The IC50 values were estimated to be 3.08 mg/ml (0.55 mM) and 2.61 mg/ml (0.41 mM), respectively.
7. In conclusion, echisotin, belonging to the membrane of disintegrin family, modulates the functional behaviors of chondrocyte, endothelial cells and platelets by interacting with b3 integrin expressed on these cells. The working mechanisms of the anti-platelet aggregation, anti-adhesive and anti-proliferative activities of echisotin may be closely related to integrin b3 receptor blockade. However, the interactions of signal transduction induced by growth factor and integrin require further investigation. In addition, it remains to be elucidated regarding the regulation of cellular signaling pathway by echisotin in modulating cell functional behaviors.

目 錄
1. 縮寫表 ---------------------------- 1
2. 中文摘要 ------------------------- 3
3. 英文摘要 ------------------------- 6
4. 緒論 ------------------------------- 9
5. 實驗材料 ------------------------- 19
6. 實驗方法 ------------------------- 21
7. 實驗結果 ------------------------- 35
8. 圖表 ------------------------------- 44
9. 討論 ------------------------------- 65
10.參考文獻 -------------------------76

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