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系統識別號 U0026-2108201015532400
論文名稱(中文) CCN1蛋白引發心肌細胞凋亡的訊號傳遞機制
論文名稱(英文) The Signaling Mechanism Underlying CCN1-induced Apoptosis
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 98
學期 2
出版年 99
研究生(中文) 邱靈音
研究生(英文) Ling-Yin Chiu
學號 T9697404
學位類別 碩士
語文別 中文
論文頁數 61頁
口試委員 口試委員-黃步敏
口試委員-蔣輯武
指導教授-莫凡毅
中文關鍵字 心肌細胞  CCN1 蛋白  FasL  細胞凋亡  協同作用  胞外間質蛋白 
英文關鍵字 Cardiac Muscle Cells  CCN1  FasL  Apoptosis  Synergistic Effect  Extracellular Matrix (ECM) Protein 
學科別分類
中文摘要 CCN 家族屬於胞外間質蛋白,由CCN1~6 組成。過去的研究指出,CCN1 藉由和不同的Integrin 結合來影響細胞的增殖(Proliferation)、黏附(Adhesion)、移動(Migration)、分化(Differentiation)、凋亡(Apoptosis)和生存(Survival)。當心臟受到外在傷害或在壓力過大的環境下會誘導CCN1 產生,另外,Fas/Fas Ligand (FasL)的訊號傳遞機制在心臟受損時的反應佔有重要的影響力。在本篇研究中証實CCN1 會幫助心肌細胞進行黏附,並使細胞走向凋亡,而心肌細胞凋亡的程度會隨著CCN1 濃度的增加而上升。CCN1 和FasL 個別都會使心肌細胞走向凋亡,但當兩者同時對心肌細胞作用時,出現協同作用(Synergistic Effect)。在正常的情況下,心肌細胞對FasL 反應的能力,在FasL 10 ng/ml 時已達到最大限度,但當CCN1 (2 ug/ml)同時存在的情況下,心肌細胞走向凋亡的程度隨著FasL 濃度(10 ng/ml~200 ng/ml)增加而持續上升。本篇研究進一步對CCN1 和FasL 兩者造成心肌細胞凋亡及協同作用的機轉進行探討,結果指出給予CCN1 後,心肌細胞內的Caspase 3, 9 及p38 MAPK 分子被活化的量增加; 當給予Caspase 3, 8, 9 及p38 MAPK 的抑制劑後,CCN1 及FasL 所影響的凋亡作用都會被抑制。綜合本篇結果得知,CCN1 有影響心肌細胞凋亡的能力,除此之外,還能增加心肌細胞對高濃度FasL 產生反應,並且透過Casepase 3, 8, 9 及p38 MAPK 的參予,使心肌細胞走向凋亡。
英文摘要 The CCN family consists of six secreted extracellular matrix (ECM) proteins,CCN1 ~ 6. Among them, CCN1 regulates cell proliferation, adhesion, migration,differentiation, apoptosis, survival and extracellular matrix production through binding with integrin receptors. In the heart, CCN1 is induced during ischemia and pressure overload. Fas/Fas ligand (FasL) signaling is often associated with cardiac injury. In this study, we prove that CCN1 can regulate adhesion in cardiomyocytes. We have demonstrated that CCN1 treatment induced apoptosis in rat cardiac muscle cells (H9c2s) in a does-dependent manner. Individually, either CCN1 or FasL induced low level of cell apoptosis. In combination, CCN1 was found to synergize with FasL in inducing H9c2 cell apoptosis. Apoptosis induced by FasL reached plateau at 10 ng/ml. Interestingly, CCN1(2 ug/ml) treatment sensitized the H9c2 cells to respond to increasing dosages of FasL beyond 10 ng/ml and up to 200 ng/ml (the highest dose tested) and resulted in double amount of cell death. In an attempt to study the molecular mechanism underlying the synergism between CCN1 and FasL, we found that caspase 3, caspase 8, caspase 9 and p38 MAPK were activated by CCN1 and were required for CCN1-induced apoptosis. In addition to signaling molecules involved in CCN1 actions, we are currently investigating the cause of the increase of sensitivity in H9c2 in response to FasL under CCN1 treatment. Our results suggested that cardiomyocytes are resistant to high doses of Fas/FasL-induced cell death, and only co-existence of CCN1 would sensitize the cardiomyocytes to effectively respond to FasL resulting in increasing cell death. Targeting CCN1 activities in a stressed heart may alleviate the damage caused by cardiac cell death.
論文目次 摘要 ........................... i
Abstract ............................ ii
致謝 ............................. iii
目錄 ........................... iv
圖目錄 ............................ vii
縮寫表 ........................... viii
第一章前言 ......................... 1
1-1 CCN 家族: CCN1 蛋白 ................. 1
1-2 Fas/FasL 系統..................... 4
1-2-1 Fas ..................... 4
1-2-2 FasL ................... 4
1-2-2-1 穿膜的型態(Transmembrane form) ..... 5
1-2-2-2 游離的型態(Soluble form) ............ 5
1-2-3 Fas/FasL 訊息傳遞路徑............. 5
1-3 細胞凋亡(Apoptosis) ................. 6
1-4 Caspase 家族..................... 9
1-4-1 Long-prodomain ............... 9
1-4-1-1 Caspase 8 ............... 10
1-4-1-2 Caspase 9 ............... 10
1-4-2 Short-prodomain ................ 10
1-5 Mitogen-activated protein kinase (MAPK).......... 11
第二章材料與方法 ...................... 14
2-1 材料 ......................... 14
2-1-1 化學試劑/藥品 ................ 14
2-1-2 儀器設備 ................... 15
2-2 實驗方法 ....................... 15
2-2-1 細胞株/細胞培養 ................ 16
2-2-2 細胞繼代 ................... 16
2-2-3 細胞黏附測試 ................. 16
2-2-4 心肌細胞(H9c2)對CCN1 濃度梯度的反應測試....................... 16
2-2-5 CCN1 與FasL 引發心肌細胞(H9c2)凋亡的測試.......................17
2-2-6 TUNEL 檢測 .................. 17
2-2-7 心肌細胞(H9c2)對FasL 濃度梯度的反應測試.......................18
2-2-8 流式細胞儀檢測凋亡細胞技術 .......... 18
2-2-9 抑制劑對凋亡狀況影響的測試 .......... 18
2-2-10 西方墨點法 .................. 19
2-2-10-1 蛋白質純化(此蛋白由柏全學長純化) ....... 19
2-2-10-2 西方點墨法(此Immunoblotting 來自珮蓉學姊) ....................... 19
第三章結果 .......................... 21
3-1 CCN1 蛋白促進心肌細胞(H9c2)進行細胞黏附 ......... 21
3-2 CCN1 蛋白引發心肌細胞(H9c2)進行凋亡作用 ........ 21
3-3 CCN1 與Fas Ligand 在引發心肌細胞(H9c2)凋亡之協同作用....................... 22
3-4 CCN1 活化心肌細胞(H9c2)提升對FasL 反應的飽和濃度.......................24
3-5 CCN1 和FasL 引發心肌細胞(H9c2)走向凋亡的訊息傳遞路徑....................... 25
第四章討論 ........................... 28
第五章結論 ......................... 33
第六章參考文獻 ....................... 34
第七章附錄 ........................ 47
第八章圖表 ......................... 52
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