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系統識別號 U0026-2701201015521100
論文名稱(中文) 探討細胞質內鈣離子誘導細胞死亡之過程:自噬作用所扮演的角色
論文名稱(英文) Deciphering Cytosolic Calcium-Induced Cell Death: Involvement of Autophagy
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 98
學期 1
出版年 99
研究生(中文) 黃彥錦
研究生(英文) Yen-Chin Huang
學號 s3696405
學位類別 碩士
語文別 英文
論文頁數 54頁
口試委員 指導教授-湯銘哲
口試委員-沈孟儒
口試委員-劉校生
中文關鍵字 鈣離子  自噬作用  細胞死亡  Calpain 
英文關鍵字 Ca2+  Autophagy  Cell death  Calpain 
學科別分類
中文摘要 本研究的目的即是去探討細胞質內鈣離子誘導之自噬作用於細胞死亡過程中所扮演的角色。首先,我們在腎臟上皮細胞建立了細胞質內鈣離子濃度和細胞死亡之間的關係。由實驗結果可以發現,利用ionomycin的給予,可以使細胞隨著ionomycin濃度越高,細胞質內鈣離子的濃度越高而細胞的生存率越低。0.5 M Ionomycin可以誘導細胞質內鈣離子溫和地上升且維持在200±50 nM,但在12小時內僅降低細胞20 %的生存率;然而,更高的ionomycin的濃度,則會致使細胞質內鈣離子持續性地增加超過200 nM,造成巨量的細胞死亡,這暗示著細胞質內鈣離子濃度200 nM可能是鈣離子誘導細胞死亡的閾值。不過,這些由ionomycin所造成的細胞死亡可透過給予EGTA而被抑制。接下來,為了進一步地去釐清細胞質內鈣離子濃度與自噬作用之間的關係,我們透過送入LC3-GFP於細胞內,以評估在ionomycin處理後自噬作用的形成。藉由結果顯示,自噬作用形成的多寡是依照給予ionomycin的濃度而定;且該現象可以被EGTA所抑制。0.5 M 和1.0 M ionomycin分別可於8小時內誘發20-40%或60-70% 的自噬作用生成。進一步地利用自噬作用的抑制劑-3-methyladenine去抑制自噬作用的形成,可以發現將會顯著地降低細胞的生存率,這個結果暗示著細胞質內鈣離子誘導之自噬作用具有維持細胞存活的功能。另一方面,我們去觀察和鈣離子有關的訊息路徑發現,calpain將隨著ionomycin的濃度增加會有不同程度的活化;而投予calpain之抑制劑-calpeptin時,先前由ionomycin所誘發細胞壞死的比例則會顯著地降低,但是卻不影響由細胞質內鈣離子所誘導之自噬作用的生成。因此,總結我的研究,我們提出了細胞質內鈣離子濃度閾值200 nM可能是決定細胞生死的檢查點;自噬作用則是扮演著可以抑制鈣離子所誘導的細胞凋亡,但是卻不能避免因大量鈣離子所引發的細胞壞死的角色。
英文摘要 Current study focuses on the role of cytosolic Ca2+-induced autophagy formation in cell death. We first established the relationship between the level of cytosolic Ca2+ ([Ca2+]cyt) and cell death in MDCK cells. Ionomycin increased [Ca2+]cyt and decreased cell viability in a dose-dependent manner. Ionomycin (0.5 M) induced mild but sustained increase in [Ca2+]cyt to 200±50 nM. This elevated [Ca2+]cyt reduced cell viability by 20% within 12 hours. Higher doses of ionomycin induced persistent increase in [Ca2+]cyt to greater than 200 nM which triggered severe cell death, suggesting that [Ca2+]cyt of 200 nM is the threshold for Ca2+-induced cell death. EGTA alleviated ionomycin-induced cell death. To delineate the relationship between [Ca2+]cyt and formation of autophagy, we introduced LC3-GFP into the cells and observed LC3-degradation punctate formation after treatment. The results showed that ionomycin dose-dependently induced autophagy formation, which was inhibited by EGTA. Ionomycin at 0.5 M or 1 M triggered autophagy formation of 20-40% or 60-70% within 1-8 hours, respectively. Treatment of 3-methyladenine, an inhibitor of autophagy, markedly reduced cell viability, indicating that cytosolic Ca2+ -induced autophagy is required for cell survival. On the other hand, ionomycin also triggered activation of calpain in a dose-dependent manner. Treatment of calpain inhibitor calpeptin significantly reduced ionomycin-induced necrotic cell death, but could not prevent cytosolic Ca2+-induced autophagy formation. Taken together, we conclude that a threshold of [Ca2+]cyt of 200 nM represents for the check point of cell life and death. Although autophagy leads to the prevention of [Ca2+]cyt elevation-induced apoptosis, it dose not prevent [Ca2+]cyt elevation-induced necrosis.
論文目次 Abstract...............................Ⅰ
Chinese abstract.......................Ⅱ
Acknowledgement........................Ⅲ
Contents...............................Ⅴ
Figure contents .......................Ⅵ
Abbreviation list......................Ⅶ
Introduction ...........................1
Materials and methods..................10
Results................................15
Discussion.............................23
References.............................30
Figures................................42
Curriculum vitae ......................54
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