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系統識別號 U0026-0812200911585241
論文名稱(中文) 探討在心肌梗塞處理後WOX1和細胞凋亡蛋白在心肌組織中的表現情形及可能的調控機制
論文名稱(英文) The expressions and reactions of WOX1 and stress-induced apoptotic proteins in the heart after myocardial infarction
校院名稱 成功大學
系所名稱(中) 細胞生物及解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 94
學期 2
出版年 95
研究生(中文) 洪純瑛
研究生(英文) Chung-Ying Hong
學號 t9693402
學位類別 碩士
語文別 中文
論文頁數 83頁
口試委員 口試委員-李宜堅
口試委員-江美治
指導教授-陳淑姿
口試委員-徐麗君
中文關鍵字 心肌梗塞  WOX1  轉錄因子 
英文關鍵字 myocardial infarction  transcription factor  WOX1 
學科別分類
中文摘要 人類的WWOX (全名為WW domain-containing oxidoreductase) 基因位於容易斷裂的第十六對染色體長臂23.3-24.1的位置,經轉譯產生WWOX蛋白,又可稱為WOX1或FOR。在多種癌症中常發現此斷裂基因造成異質染色體的缺失,因此WWOX基因被定義為腫瘤抑制基因。近年來有研究指出,當細胞受到刺激,WOX1蛋白上Try33的位置會被磷酸化變成活化態,進入細胞核中,進而調控細胞凋亡,因此,WOX1被認為是一個前凋亡蛋白。先前我們實驗室發現WOX1大量表現在發育的心臟中,相反的,在成鼠的心臟中,WOX1的表現量下降。所以,WOX1是前凋亡蛋白還是調節心肌發育或具有其他功能,目前還有待釐清。已有不少研究發現,心肌梗塞會造成心肌細胞凋亡。而經由壓力刺激下產生的轉錄因子ATF-3對於心臟疾病的發生扮演著重要角色。與內質網壓力相關的CHOP在心肌梗塞的處理下被誘導出來,造成細胞的凋亡。抑癌因子p53在長時間的低氧刺激下,在心肌細胞中扮演細胞凋亡因子的角色。所以,我的研究主要是探討當大白鼠遭受血管阻塞手術引發之心肌梗塞後,WOX1和細胞凋亡蛋白在心肌組織中的表現情形及可能的調控機制。結果顯示,心肌梗塞會造成心臟組織形態上的改變。利用組織免疫化學染色法觀察到,在心肌梗塞三十分鐘後,梗塞區域中就有WOX1和WOX1蛋白磷酸化 (p-WOX1) 的表現情形。利用西方墨點法發現,WOX1和p-WOX1在梗塞區域的心肌細胞質中大量表現,細胞核中則無顯著差異。另外,相似的檢測結果中也發現,ATF-3和WOX1/p-WOX1的表現模式很類似,而且利用雙重免疫染色法及電子顯微鏡觀察到,ATF-3和WOX1有共存的現象。然而,心肌梗塞的刺激並不影響CHOP的表現情形,在電子顯微鏡的觀察下僅發現非常少數的CHOP免疫標定的金顆粒和WOX1有共存現象。另外,利用組織免疫化學染色法測試,發現在心肌梗塞刺激後,心肌細胞中並無p53的表現。综合以上的結果得知,在心肌梗塞後WOX1的表現,可能參與轉錄因子ATF-3表現的調節,但是可能並沒有參與CHOP或p53所調控的細胞凋亡路徑。

英文摘要 The human WWOX gene, encoding the WW domain-containing oxidoreductase WOX1 protein (also known as WWOX or FOR), is located on a chromosomal fragile site ch16q23.3-24.1. High frequency of loss of heterozygosity (LOH) of this gene has been shown in multiple cancer, indicating that WWOX is a putative tumor suppressor gene. Recent studies indicated that activated WOX1 induced apoptosis under stress stimuli by Tyr33 phosphorylation and nuclear translocation. Therefore, WOX1 is considered as a proapoptotic protein. In the developing rat heart, WOX1 is highly expressed in the cardiomyocytes, but downregulated as adults. There is still an argument of the exact role of WOX1, being an anti-apoptotic or proapoptotic protein. Myocardial infarction (MI) was showed to lead to apoptosis in cardiomyocytes. The induction of activating transcription factor-3 (ATF-3) by stress plays a role in pathogenesis of stress-associated cardiac disease. C/EBP homologous protein (CHOP), an ER stress-related protein, was induced responsible for apoptotic cell death under MI. Tumor suppressor p53 was reported to be an apoptotic factor in cardiomyocytes exposed to prolonged hypoxia. In this study, we investigate the expressions and reactions of WOX1 and stress-induced apoptotic proteins in the heart after myocardial infarction. The treatment of MI resulted in the pathological change of myocardial tissue. By immunohistochemistry, the expressions of WOX1 and phosphorylated WOX1 (p-WOX1) were increased in the infarct area thirty minutes after MI. The expressions of WOX1 and p-WOX1 were increased in the cytosol of injured cardiomyocytes. However, compared with the control, there is no significant difference in the nuclei of infarct area after acute injury by Western blotting. The degree of expression of ATF-3 was compatible with that of WOX1/p-WOX1 in the heart after MI by immunohistochemistry and Western blotting. Further, ATF-3 was colocalized with WOX1 after acute MI by double labeling and electron microscopical immunohistochemistry. Although CHOP expression was observed after MI, only very few immunolabeled gold particles for WOX1 and CHOP were colocalized in the MI tissue. None or few immunoreactivity for p53 was observed in the hearts after MI. Taken together, these findings indicate that WOX1 expression may be involved in the regulation of ATF-3 expression after MI. However, WOX1 might not be involved in CHOP- or p53-mediated apoptosis.

論文目次 目錄
頁數
圖表索引 3
中文摘要 4
英文摘要 7
第一章 緒論 10
1-1 心臟的簡介與功能 11
1-2 心肌梗塞 12
1-3 壓力刺激下誘導產生的蛋白 15
I. ATF-3 15
II. CHOP 16
III. p53 18
1-4 WWOX的簡介與功能 19
1-5 在心肌梗塞的心臟中WOX1的潛在角色 21
第二章 實驗材料及方法 23
2-1 實驗材料 24
2-2 方法 24
第一節 心肌梗塞老鼠動物模式 24
第二節 心臟切片之製備 25
第三節 一般染色及組織免疫化學染色 27
頁數
第四節 電子顯微鏡免疫細胞化學技術 28
第五節 西方墨點法 30
第六節 統計分析 36
第三章 實驗結果 37
3-1 心肌梗塞造成心肌組織形態的改變 38
3-2 心肌梗塞造成心肌組織中WOX1表現量增加 39
3-3 心肌梗塞後p- WOX1的表現情形 41
3-4 心肌梗塞會造成心肌組織表現ATF-3 42
3-5 WOX1和ATF-3有共存的現象 44
3-6 WOX1和CHOP沒有共存的現象 45
3-7 心肌梗塞後p53的表現情形 47
第四章 討論 54
第五章 圖表 73
第六章 參考文獻 76
附錄 82
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