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研究生:吳振誠
研究生(外文):Jhen-cheng Wu
論文名稱:登革病毒套膜蛋白domain III對造成凝血缺陷及血管病變所扮演的角色
論文名稱(外文):Role of dengue viral envelope protein domain III in dengue induced coagulopathy and vasculopathy
指導教授:張新侯
指導教授(外文):Hsin-hou Chang
學位類別:碩士
校院名稱:慈濟大學
系所名稱:分子生物及細胞生物研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:57
中文關鍵詞:登革套膜蛋白血小板低下內皮細胞肝素血管內皮細胞生長因子
外文關鍵詞:dengueenvelope proteinthrombocytopeniaendothelial cellheparinVEGF
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登革病毒是屬於黃熱病毒科的成員,在全球各地皆引起了很嚴重健康危害的問題。感染登革病毒可導致各種程度不一的症狀,其中比較嚴重的症狀為登革出血熱及登革熱休克症候群,患者往往伴隨有嚴重血小板低下,任何的出血性徵候及增加血管通透性的證據;不過時至今日,對於由登革熱轉變為登革出血熱及登革熱休克症候群的病理機制卻還不甚了解。在我們的實驗中,我們發現經純化的重組登革套膜蛋白domain III可直接結合上血小板,進一步以流式細胞儀分析發現血小板上P-selectin表現有上升趨勢,證實了可誘導血小板的活化。同時小鼠以靜脈注射重組登革套膜蛋白domain III可引起小鼠血小板低下及白血球低下的情況,與早期感染登革病患所觀察到的臨床現象相似。同時,藉由aPPT 實驗我們亦發現登革套膜蛋白domain III具有中和掉抗凝血劑heparin的能力,其功用與臨床上使用的heparin解毒劑-protamin具有類似的效果。此外,經由體外及體內試驗我們也證實了登革套膜蛋白domain III具有抑制血管新生的能力。所有實驗證據皆顯示出登革套膜蛋白domain III在登革引起的凝血缺陷及血管病變當中可能扮演重要的角色。
Dengue virus , a member of the flavivirus family , causes an emerging global health threat. Infection of dengue virus can result a range of clinical symptoms, the more severe forms are DHF/DSS, which are characterized by thrombocytopenia, hemorrhagic manifestations and evidence of increased vascular permeability;however, the mechanisms of DHF or DSS development are not completely understood. In this study, we found that purified recombinant soluble dengue envelope protein domain III (rsEIII) bound to human platelet directly, and sequently induced platelet activation as measured by P-selectin expression on flow cytometry. Treatment of rsEIII can induce thrombocytopenia and leukopenia in B6 mice, wich were similar to clinical sign observed at early stage of dengue virus infection patients. Data from activated partial thrombin time ( aPPT ) assay showed that rsEIII could also neutralize heparin function and prolong plasma clotting time similar to the usage of protamine, a heparin antidote for clinical use. At the same time, we also found rsEIII has antiangiogenic effect as observed it’s can inhibit endothelial survival and impaired VEGF165 mediate endothelial cell proliferation in vitro and chorioallantoic membrane assay in vivo. These data suggest that dengue EIII protein region might be an important role in dengue-induced coagulopathy and vasculopathy.
目錄

摘要 2
誌謝 3
緒論 6
登革病毒感染之分子機制 8
登革病毒感染 8
登革套膜蛋白於病毒感染中所扮演的角色 9
研究目的 10
材料與方法 11
A. 實驗動物 11
B. 細胞株 11
C. 細胞繼代、保存與解凍 12
D. 病毒株 12
E. 重組蛋白 12
F. 重組蛋白的純化 13
G. 實驗小鼠免疫注射 14
H. 兔子抗體製備 14
I. 抗體效價測定 14
J. 人類血小板製備 15
K. Protein Biotinylation 16
L. 重組蛋白內毒素測定(Endotoxin test) 16
M. rsEIII與人類血小板結合測試 17
N. 血小板活化測試 17
O. 不同GAGs對rsEIII與血小板之阻斷效果測試 17
P. in vivo 測試rsEIII 對小鼠血液中血小板及白血球之影響 18
Q. in vivo 測試不同GAGs、Aspirin或anti-EIII antibody對rsEIII所引起血小板低下之保護效果。 18
R. rsEIII與heparin中和性試驗(aPPT test) 18
S. 小鼠血清aPPT time test 19
T. 內皮細胞存活實驗 19
U. rsEIII 對不同生長因子所刺激之細胞增生影響 19
V. 雞尿囊膜試驗(chick chorioallantoic membrane assay) 20
實驗結果 21
1. 登革病毒對小鼠體內血球變化及抗凝血蛋白之影響 21
2. rsEIII 可直接結合至人類血小板並刺激血小板的活化 21
3. 分析rsEIII 對小鼠體內血小板及白血球數目的變化 22
4. 分析不同glycosaminoglycans (GAGs) 對rsEIII結合至人類血小板的效果 22
5. rsEIII 對血清凝集時間及heparin中和影響 23
6. rsEIII對小鼠血清凝集時間之影響 24
7. rsEIII對內皮細胞及VEGF165促進內皮細胞生長具有抑制作用 24
8. rsEIII對雞胚胎絨毛尿囊膜血管新生的影響 25
討論 26
參考文獻 30
實驗圖表 38
附錄 50
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