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系統識別號 U0026-0812200911332176
論文名稱(中文) 登革病毒感染內皮細胞對人類凝血酶調節素的影響
論文名稱(英文) Dengue virus infection of endothelial cell alters the expression of thrombomodulin
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 93
學期 2
出版年 94
研究生(中文) 林慧敏
研究生(英文) Hui-Min Lin
電子信箱 t3692107@ccmail.ncku.edu.tw
學號 t3692107
學位類別 碩士
語文別 中文
論文頁數 80頁
口試委員 口試委員-劉校生
口試委員-曾大千
指導教授-葉才明
口試委員-林尊湄
中文關鍵字 登革病毒  內皮細胞  人類凝血酶調節素 
英文關鍵字 endothelial cell  Dengue virus  thrombomodulin 
學科別分類
中文摘要   血管內皮細胞表面富含人類凝血酶調節素(Thrombomodulin , TM),其主要功能是作為凝血酶(thrombin) 活化protein C 的輔助因子,具有抗血液凝固的特性。近來有證據顯示凝血酶調節素及protein C的活化除了具有調控凝血的功能,在發炎、纖溶路徑甚至在細胞的增殖都扮演著重要的角色。登革病毒感染可能造成兩種病症:輕微的登革熱(dengue fever, DF)及致命的登革出血熱/休克症狀(dengue hemorrhagic fever/ dengue shock syndrome, DHF/DSS)。對引起DHF/DSS的機制,目前尚不清楚。在本論文中我們發現在登革病毒感染病人的血清中可以觀察到TM上升及protein C/S下降,。因此我們進一步以人類內皮細胞及肝細胞作為標的,探討感染登革病毒對其表面纖溶分子的影響。利用逆轉錄多聚酶鏈反應法偵測到內皮細胞受登革病毒感染後TM mRNA表現量增加,並利用免疫螢光染色、西方墨點法、流式細胞儀等技術測得其感染後不論在細胞總TM抗原量亦或細胞表面TM的表現皆有上升的情形。但是進一步使用TM啟動子分析,卻發現登革病毒感染後其表現量並無明顯差異。然而加入RNA 合成抑制劑actinomycin D後,登革病毒感染會使內皮細胞TM RNA穩定度增加。另一方面,以登革病毒感染內皮細胞和肝細胞皆可使PS mRNA及蛋白質表現增加,但登革病毒感染引起之PS表現是屬於轉錄依賴性的層次。由以上結果我們認為,登革病毒感染是以不同的機制讓TM和PS上升,使得內皮細胞傾向抗凝血的方向。

英文摘要   Thrombomodulin (TM), a cell surface-expressed glycoprotein, predominantly synthesized by vascular endothelial cells, is a critical cofactor for thrombin-mediated activation of protein C (PC). Activated protein C, in turn, is best known for its natural anticoagulant properties. However, recent evidence has revealed that TM and APC have activities that impact not only on coagulation but also on inflammation, fibrinolysis, and cell proliferation. Dengue virus (DV) infections cause mild dengue fever or severe life-threatening dengue hemorrhagic fever/dengue shock syndrome. The mechanism to cause hemorrhage in DV infections remain poorly understood. In this study, we demonstrated that the serum levels of soluble TM were increased while protein C and protein S (PS) were decreased in DHF/DSS at compared to those in DF patients or normal controls. Therefore, the effects of DV infection on the expression of these molecules were studies in human endothelial and hepatoma cells. The expression of TM mRNA in DV-infected human endothelial cell line, HMEC-1 was increased as determined by RT-PCR. Immunofluorescent stain and Western blot further confirmed the expression of TM antigen was increased. However, using the construct of TM promoter with reporter gene demonstrated that DV infection of endothelial cells did not significantly alter its expression. In the present of transcription inhibitor, actinomycin D, the stability of TM mRNA was increased in DV-infected HMEC-1 cells as compared to uninfected cells. On the other hand, DV infection of HMEC-1 as well as hepatoma cell line (HepG2) increased both mRNA and protein expression of PS. PS expression of endothelial cells induced by DV infection was transcription-dependent. Taken together, DV infection of endothelial cells may increase TM and PS expresses through different mechanisms and the increased TM and PS expression may contribute to the anticoagulant properties during DV infection.

論文目次 目錄
中文摘要1
英文摘要2
誌謝3
目錄4
圖目錄7
表目錄8
緒論9
一、登革病毒
(一)前言9
(二)登革病毒的流行史及臨床表現10
(三)登革病毒的致病機轉11
二、人類凝血酶調節素(Thrombomodulin, TM)
(一)前言13
(二)人類凝血酶調節素的結構和功能14
三、S 蛋白(Protein S, PS)
(一)前言16
(二)PS的結構和功能16
研究目的與動機機18
實驗設計19
材料與方法
一、材料
(一) 儀器20
(二)試劑藥品暨耗材21
(三)登革病人檢體來源24
二、方法
(一) 利用酵素免疫分析法分析登革病毒感染病人之TM,PC,PS抗原24
(二)人類微血管內皮細胞(Human microvascular endothelial cell, HMEC-1)培養25
(三) 人類臍帶靜脈血管內皮細胞(Human umbilical vein endothelial cell,HUVEC)培養25
(四) 病毒之製備 26
(五) 定量病毒效價 26
(六) 病毒感染27
(七) 登革病毒染細胞之確認28
免疫螢光染色
(八) 登革病毒感染後相關之凝血因子mRNA表現分析
1. 萃取細胞RNA 28
2. 反轉錄反應(reverse transcription; RT) 29
3. 聚合酶連鎖反應(polymerase chain reaction; PCR) 30
(九) 利用Western bolting分析登革病毒感染後TM之表現情形
1. 硫酸十二酯鈉-聚丙烯醯氨膠電泳法(SDS-PAGE) 30
2. 西方點墨法(Western blotting) 32
(十) 以免疫螢光染色的方式檢視登革病毒感染內皮細胞(HMCE-1)之TM表現情形 33
(十一) 檢視登革病毒感染內皮細胞(HMCE-1)之表面TM表現 34
(十二)暫時性表現共同轉染分析﹙transient expression cotransfection assay﹚
1. 大量質體的萃取 34
2. 質體的轉染 35
3. 報告基因的活性分析 36
結果
ㄧ、登革病毒感染病人血清之TM、PC及PS量變化量 39
二、登革病毒對內皮細胞感染之能力 39
三、登革病毒感染後對抗凝固因子的影響
(一)mRNA的改變 39
(二)Protein的改變 40
(三)TM之分佈 40
(四)表面TM之表現 40
四、登革病毒感染人類臍帶靜脈血管內皮細胞(HUVEC)TM之表現 41
五、登革病毒感染後TM基因啟動子(promoter)轉錄 41
六、登革病毒感染後TM基因上升之調節機制 42
七、登革病毒感染後PS基因上升之調節機制 43
八、登革病毒感染後相關之凝血因子之調節
(一)登革病毒對肝細胞感染之能力 43
(二)mRNA的改 44
(三)Protein的改變 44
討論
一、登革病毒感染後引起之凝血功能缺失(coagulopathy) 45
二、登革病毒感染後造成凝血因子之改 46
三、登革病毒感染後造成凝血機制失衡之可能機轉 48
參考文獻 51
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