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研究生:潘秀玲
研究生(外文):Shiow-Lin Pan
論文名稱:YC-1,TW-01與TW-02對血管平滑肌、內皮細胞生長調控及在敗血症、血管再阻塞和抗癌之藥效評估
論文名稱(外文):Effect of YC-1, TW-01 and TW-02 on Growth Regulation in Vascular Smooth Muscle Cells and Endothelial Cells, and Their Therapeutic Evaluation in Models of Sepsis, Restenosis After Angioplasty and Tumor Growth
指導教授:鄧哲明鄧哲明引用關係
指導教授(外文):Che-Ming Teng
學位類別:博士
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:2002
畢業學年度:90
語文別:中文
論文頁數:153
中文關鍵詞:血管平滑肌細胞內皮細胞敗血症血管再阻塞血管新生YC-1TW-01TW-02
外文關鍵詞:vascular smooth muscle cellsendothelial cellssepsisrestenosisangiogenesisYC-1TW-01TW-02
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血管疾病產生之過程多數是未知的,而一旦疾病產生又是難以處理,其所調控之疾病則包括了動脈粥狀硬化 (atherosclerosis)、鬱血性心臟衰竭 (congestive heart failure)、敗血症 (sepsis) 以及血管新生 (angiogenesis) 產生之相關疾病,例如癌症、風濕性關節炎、乾癬症等。然而構成整個血管之組成主要為內皮細胞和平滑肌細胞。在此論文中主要觀察 (1) YC-1,為 soluble guanylyl cyclase 活化劑,其可經抑制血管平滑細胞凋亡的作用進而治療敗血症,此機轉為一 cyclic GMP-dependent 的作用。由許多文獻得知,lipopolysaccharide (LPS) 會提高血球的浸潤性 (infiltration) 並且造成多重性器官衰竭 (multiple organ failure;MOF),進而造成 septic 死亡。而本研究提出以抑制血管平滑肌細胞凋亡的作用,可以來預防多重性器官衰竭病症的假說。實驗中是以 sodium nitroprusside (SNP,1 mM) 促使血管平滑肌細胞產生凋亡作用,以 YC-1 則可經由 cGMP 相關之的途徑和 phosphatidylinositol 3 kinase (PI3K) 傳遞途徑來阻斷細胞凋亡的訊息,進一步在動物模式中抑制由 LPS 所誘導的 septic 死亡。(2) 化學合成之新藥 TW-01 可藉由抑制 small G protein — Ras 此種早期對細胞增生調節的蛋白質來阻斷血清在血管平滑肌細胞上所誘導的訊息傳遞,包括:p42/p44 MAPK 活性,原致癌基因 (c-myc,c-fos 和 c-jun) mRNA 的表現,轉錄因子 NF-kB 的活化,以及 PI3-kinase 的活化等等進而抑制血管平滑肌細胞的增生 (proliferation),且進一步於氣球損傷手術 (balloon injury) 之動物模式中抑制 neointima 的產生。(3) YC-1 和 TW-02 (化學合成新藥) 可顯著地抑制由 VEGF 與 bFGF 所誘導之血管內皮細胞的增生、移行 (migration) 和分化 (differentiation)。YC-1對於由VEGF和bFGF所引起作用的抑制效果幾乎相同,而相對來說,TW-02對VEGF的抑制作用較bFGF強。延續體外結果接著採用小鼠植入Matrigel的動物模式觀察血管新生的作用。口服投予YC-1 (1-100 mg/kg/day) 可呈現劑量相關性地抑制VEGF和bFGF引起的新生血管作用,然而TW-02 (30-300 mg/kg) 抑制VEGF的作用是呈劑量相依性的作用,對於bFGF則需較高的劑量才能呈現抑制作用。基於實驗的證實,YC-1、TW-01 和 TW-02 未來於血管相關性之疾病的治療上有其應用的價值,值得進一步開發。
縮寫表 1
摘要 4
第一章探討 YC-1 抑制 SNP 在血管平滑肌細胞上所產生之凋亡作用和治療內毒素於小白鼠所誘導之敗血症YC-1 prevents sodium nitroprusside-mediated apoptosis in vascular smooth muscle cells and endotoxin-induced septic death in mice. 7
英文摘要 8
中文摘要 9
緒言 10
材料與方法 12
結果 16
討論 19
結果圖表 23
第二章TW-01 對於在血管平滑肌細胞中 Ras 所調控之細胞增生與大白鼠血管再阻塞之動物模式的作用探討Effect of TW-01 on the regulation of Ras-mediated cell proliferation and angioplasty-induced vascular restenosis in rats. 33
英文摘要 34
中文摘要 36
緒言 38
材料與方法 45
結果 52
討論 59
附圖 64
結果圖表 69
第三章YC-1 和 TW-02 於體內及體外對於 VEGF 和 bFGF 所誘發之血管新生的作用Effect of YC-1 and TW-02 on VEGF- and bFGF-induced angiogenesis in the in vitro and in vivo. 84
英文摘要 85
中文摘要 86
緒言 87
材料與方法 91
結果 (一)Antiangiogenic effect of YC-1 in the in vitro and in vivo angiogenesis models. 95
討論 100
結果 (二)Antiangiogenic effect of TW-02 in the in vitro and in vivo angiogenesis models. 103
討論 106
附圖 108
結果圖表 117
參考文獻 133
著作 148
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