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系統識別號 U0026-1712201811082400
論文名稱(中文) 在血管窄化與氯化鈣共同處理所誘發的大鼠腹主動脈血管重塑中內質網壓力的變化
論文名稱(英文) ER stress in the coarctation and calcium chloride cotreatment-induced rat abdominal aortic remodeling
校院名稱 成功大學
系所名稱(中) 細胞生物與解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 107
學期 1
出版年 107
研究生(中文) 張詠琦
研究生(英文) Yong-Ci Jhang
學號 T96041041
學位類別 碩士
語文別 中文
論文頁數 50頁
口試委員 指導教授-江美治
口試委員-吳佳慶
口試委員-林寶彥
中文關鍵字 腹主動脈瘤  腹主動脈窄化  氯化鈣  內質網壓力  未摺疊蛋白反應路徑 
英文關鍵字 Abdominal aortic aneurysm  abdominal aorta coarctation  CaCl2 ER stress  UPR pathway 
學科別分類
中文摘要 動脈瘤是動脈管壁的局部擴張而造成的疾病。在所有的動脈瘤當中,以腹主動脈瘤最為常見,而腹主動脈瘤的好發位置在腎動脈以及髂總動脈分枝處之間。腹主動脈瘤經常沒有明顯的症狀,但一旦破裂,其致死率高達90%,是目前臨床上重要的問題。目前為止,沒有任何藥物可治療腹主動脈瘤。由於在手術當中獲得的腹主動脈瘤的組織是晚期的腹主動脈瘤,因此需要建立動物模式來釐清腹主動脈瘤的發病機制。我們實驗室之前的研究指出,長時間窄化蘭嶼迷你豬腎動脈離心端的腹主動脈十二週後,會在窄化區域的離心端誘發腹主動脈瘤的形成。為了發展出容易操作的小動物模式,我們嘗試在大鼠以窄化誘導腹主動脈瘤。可惜的是,單純窄化腹主動脈無法誘導腹主動脈瘤的生成。先前的研究指出,在大鼠的腎動脈下方的腹主動脈處理低濃度的氯化鈣,會誘發長期的彈性蛋白降解和鈣化的情形。因此我們提出一個假設,在大鼠腹主動脈進行窄化以及氯化鈣處理後,內質網壓力以及未摺疊蛋白反應路徑(簡稱UPR路徑)的活化會加速腹主動脈瘤的生成。根據此假說,我們進行了兩組實驗。在第一組實驗中,我們把大鼠分成三組: 對照組、0.15 M 氯化鈣以及0.15 M氯化鈣和動脈窄化的共同處理組。我們用GRP78偵測內質網壓力,並分別以eIF2α磷酸化(p-eIF2α)及活化的ATF6偵測兩條UPR路徑。在處理後10-12週用免疫組織化學染色偵測遠端腹主動脈中內質網壓力、p-eIF2α及活化態的ATF6。結果顯示,GRP78表現量在各組間沒有差異,但在動脈中層產生鈣化及彈性纖維薄層降解的區域則有增加。此外,在各組並未偵測到eIF2α的活化,而活化態的ATF6在各組的遠端腹主動脈之間沒有差異。在第二組實驗中,我們探討處理0.5 M氯化鈣及0.5 M氯化鈣和腹主動脈窄化共同處理10週後對遠端腹主動脈的影響。利用Verhoeff's van Gieson (EVG)法染彈性纖維,在0.5 M氯化鈣及共同處理組的遠端腹主動脈中,動脈管腔周長及彈性纖維薄層降解均有增加,在共同處理組有更明顯的變化。此外,在共同處理組中偵測到DNA氧化性損傷增加,而在0.5M氯化鈣處理組中蛋白質氧化性損傷和巨噬細胞浸潤有增加的趨勢。在免疫墨點的實驗結果顯示,在共同處理組中GRP78表現量有增加的趨勢。此外,eIF2α在兩個處理組中都被活化,而活化態的ATF6則沒有變化。這些結果顯示,腹主動脈窄化及0.5 M氯化鈣共同處理,誘發彈性纖維薄層降解和DNA氧化性損傷伴隨內質網壓力和eIF2α的UPR路徑的活化,可能因而促進腹主動脈瘤的形成。
英文摘要 Animal models are needed to unravel AAA pathogenesis. This study tested the hypothesis that endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR) pathways promote AAA formation induced by the co-treatment of infrarenal abdominal aorta (AA) coarctation and calcium chloride using rat as a model. ER stress was probed with GRP78 expression and activation of two UPR pathways was assessed with activation of eIF2α (p-eIF2α) and ATF6, respectively. In the first set of experiments, rats were divided into sham, 0.15 M CaCl2 treatment, and AA coarctation-0.15 M CaCl2 co-treatment groups. GRP78 expression only increased in the aortic media exhibiting calcification and elastic lamella degradation; p-eIF2α was not detected whereas ATF6 activation did not change in the distal AA of treatment groups. In the second experiment, the effects of 0.5 M CaCl2 treatment and 0.5 M CaCl2–AA coarctation co-treatment were examined. At 10 weeks post-treatment, lumen perimeter and elastic lamella degradation increased in the distal AA of 0.5 M CaCl2-treated and co-treatment groups with co-treatment generating more pronounced changes. Increased oxidative DNA damages were apparent in the co-treatment group, whereas oxidative protein damage and macrophage infiltration tended to increase in 0.5 M CaCl2-treated group. GRP78 protein expression tended to increase in the co-treatment group with apparent increases in p-eIF2α and no change in ATF6 in both experimental groups. These results suggest that AA coarctation-0.5 M CaCl2 co-treatment induces oxidative and structural damages with concomitant ER stress and activation of UPR pathway involving eIF2α, which may promote AAA formation.
論文目次 中文摘要 I
英文摘要 III
致謝 VI
緒論 1
研究動機 6
材料 7
方法 15
實驗結果 20
討論 24
參考文獻 28
圖表 36
附錄 48
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