臺灣博碩士論文加值系統

腎臟纖維化特徵為腎臟結構和功能發生變化，受損腎臟細胞仍能行使部分原有功能，同時纖維化為組織病理指標與引起臨床疾病原因，最終導致細胞功能障礙，引發末期腎臟疾病或器官衰竭，其治療方式僅血液透析、腹膜透析和腎臟移植，所費不貲，造成社會與經濟成本沉重負擔。因此尋找減緩、阻止、甚至逆轉組織纖維化發生進展方法，使受損細胞向正常細胞逆轉而恢復原來功能，對腎病康復和腎衰竭逆轉具有非常重要意義。腎損傷或發炎會使腎結構被細胞外基質蛋白不正常堆積，造成腎細胞氧化壓力與第一型乙型轉型生長因子（Transforming growth factor beta, TGF-β1）增加，造成腎臟細胞發炎與粒線體生合成失去平衡等，而近來關注發炎因子胸腺基質淋巴生成素（Thymic stromal lymphopoietin, TSLP）然，沒有文獻指出TSLP所誘導發炎反應與纖維化有關。而調節粒線體功能關鍵轉錄因子第一型核呼吸因子（Nuclear respiratory factor 1, NRF-1），能活化粒線體相關基因啟動因子，進一步調控粒線體DNA複製與轉錄。為釐清發炎因子、粒線體生合成與纖維化相關性，本論文將探討TSLP與NRF-1於腎臟纖維母細胞 （NRK-49F）纖維化中角色。
文獻指出細胞激素與生長因子失衡參與腎纖維化病理機制，本論文首度發現TSLP刺激腎臟纖維母細胞造成纖維化指標纖維蛋白增加，運用TGF-β1刺激腎細胞纖維化同時也發現細胞內外TSLP隨著TGF-β1劑量增加而上升，而加入外源性TSLP（1, 10, 100 ng/mL）劑量刺激下，不僅誘導纖維蛋白增加，也刺激TGF-β1下游Smads路徑活化。為證明TSLP於纖維化角色，運用胸腺基質淋巴生成素靜默載體（TSLP shRNA）探討纖維化抑制可行性，透過TGF-β1誘導腎細胞纖維化過程，運用TSLP shRNA載體讓細胞TSLP表現降低並逆轉細胞內外纖維蛋白，同時逆轉纖維化Smads路徑活化，證實TSLP shRNA載體抗腎纖維化作用機轉；而TGF-β1刺激纖維化過程，不僅發炎因子增加，同時造成氧化壓力（Reactive oxygen species，ROS）增加使粒線體生合成降低造成粒轉錄因子NRF-1減少，當抑制氧化壓力能調控粒線體轉錄因子NRF-1，足以證明腎纖維化過程中NRF-1表現顯著不足，並且透過轉殖表現載體pcDNA-NRF-1（2g/mL）顯著逆轉腎細胞纖維化的發生（p<0.01，中華民國專利I527589），也能逆轉TGF-β1刺激下游Smads路徑活化與上皮間質轉換的路徑。為了反向證實，細胞轉殖NRF-1靜默載體shRNA-NRF-1（2g/mL）可顯著增加腎細胞纖維化，證明NRF-1具有正向調節腎纖維化角色。
透過以上結果，瞭解發炎因子TSLP與粒線體生合成因子NRF-1於腎纖維化過程所扮演重要角色，透過shRNA與pcDNA轉殖技術，深入探討發炎因子與轉錄因子的角色，本論文首度證實TSLP shRNA抗腎纖維化作用機轉，並且轉殖pcDNA-NRF-1可顯著逆轉腎細胞纖維化的發生，透過調控TGF-β1下游Smads路徑與EMT路徑，本篇研究將提供出腎纖維化控制全新治療策略為腎纖維化病變與創新治療思維上做出具體的貢獻。

One of the important features of ESRD is renal interstitial fibrosis. Fibrosis is an indication and cause of numerous severe diseases, which will eventually result in cellular dysfunction and organ failure. Although there is an alteration in the structure, the remaining renal cells could still perform a partial function. Hence, it is imperative to develop an effective approach to attenuate or even reverse the progression of renal interstitial fibrosis. Injury or inflammation in the kidney will initiate a cellular and molecular cascade that leads to fibrosis, and it is well-known that elevation of TGF-β1 is implicated in fibrogenesis. The upregulation of TGF-β1 will cause the excessive deposition of extracellular matrix, increased inflammation, and oxidative stress as well as dysfunction of mitochondrial biogenesis. Recently, TSLP has gained increasing attention as it is tightly associated with inflammatory diseases. However, there is still a lack of evidence that shows TSLP-induced inflammation is related to renal fibrosis. On the other hand, NRF-1 has been found to be a key transcription factor to activate several genes that regulate the DNA replication and transcription in mitochondria, thereby modulating the mitochondria biogenesis and function. In order to elucidate the connection between inflammation factor, mitochondria biogenesis and renal fibrosis, we sought to investigate the effects of TSLP and NRF-1 on the transdifferentiation of NRK-49F.
The current study showed that treatment of NRK-49F with TSLP increased the expression of fibronectin and activation of Smads. Moreover, we observed an elevation of TSLP when using TGF-β stimulation to induce the transdifferentiation of NRK-49F. Additionally, we showed that utilization of TSLP shRNA was able to reduce the extra- and intracellular expression of fibronectin and the activation of Smads, suggesting that the TGF-β-increased TSLP was critical to the upregulation of fibronectin and phosphorylation of Smads. In addition to inflammation, we also found that the reactive oxygen species was increased in response to TGF-β stimulation. Our results showed that the mitochondria biogenesis was downregulated and the expression of NRF-1 was inhibited during fibrogenesis, while these phenomena were all prevented when using the antagonist of ROS. In an effort to investigate the functional role of NRF-1 in fibrosis, we examined the effect of overexpression and inhibition of NRF-1 on NRK-49F activation. First, we utilized the pcDNA-NRF-1 to overexpress NRF-1 and showed that the transdifferentiation of NRK-49F was blocked（Taiwan Patent # I527589）. Subsequently, shRNA-NRF-1 was employed to inhibit the expression of NRF-1 and we found an increase in the transdifferentiation of NRK-49F.
Altogether, these results demonstrated that TSLP and NRF-1 both play important roles in renal fibrosis. We shall be able to contribute to the development of proper strategies for clinical usage of renal fibrosis treatment.

目 錄
論文審定書………….……………………………………………............I
誌謝………………………………………………………………...........II
中文摘要…………………………………………………….….......III、IV
英文摘要…………………………………………..…...……………...…..V、VI
第一章 緒論…………………………………………………................1
一、 糖尿病腎病變之盛行率................................................................2
二、 糖尿病腎臟纖維化之致病與機轉................................................2
（一） 第一階段：纖維化形成與進展的可逆階段..........................3
（二） 第二階段：纖維形成階段......................................................4
三、 纖維化與上皮間質轉換相關性....................................................6
四、 纖維化與活性氧化物質相關性....................................................8
五、 TGF-β1在糖尿病腎病變纖維化之角色......................................9
六、 纖維化之TGF-β訊息傳導路徑.................................................10
七、 胸腺基質淋巴生成素（TSLP）簡介 ..........................................11
八、 氧化壓力與粒線體生合成關聯.................................................12
九、 核呼吸因子（Nuclear respiratory factor 1，NRF-1）簡介............14
第二章 研究目的…………...........................……......……….....……16
一、具體目標....................................................................................................17
二、各階段執行目標.......................................................................................18
目標一、探討發炎因子胸腺基質淋巴生成素TSLP...............................19
目標二、探討粒線體生合成和調節粒線體生合成功能的關鍵轉錄因子
NRF1.......................................................................................20
第三章 材料與方法................................................................................21
一、 試劑與材料 ........................................................................22-23
二、 細胞培養 ...................................................................................24
三、 繼代細胞 ...................................................................................24
四、 細胞的保存 ...............................................................................24
五、 細胞計數 ...................................................................................25
六、 細胞冰凍與解凍 .......................................................................25
七、 細胞轉殖試驗 ...........................................................................25
八、 蛋白質電泳及西方墨點法 .......................................................26
九、 蛋白轉漬 ...................................................................................26
十、 西方墨點法 ...............................................................................27
十一、 酵素連結免疫吸附分析 ...........................................................27
十二、 免疫螢光分析法.........................................................................28
十三、 粒線體生合成測定.....................................................................28
十四、 氧化壓力測定.............................................................................29
十五、 統計分析 ...................................................................................29
第四章 實驗結果....................................................................................30
一、 TSLP誘導纖維化之生物效應...................................................31
二、 TGF-β1誘導腎纖維母細胞TSLP的表現 ................................31
三、 TSLP對TGF-β1之影響 ............................................................32
四、 TSLP於TGF-β1訊息Smad途徑...............................................32
五、 TSLP靜默載體轉殖腎細胞讓TSLP靜默表現.........................32
六、 TSLP靜默載體（TSLP shRNA）減少TGF-β1誘導纖維蛋白
之表現..........................................................................................33

七、 TSLP靜默載體（TSLP shRNA）調控TGF-β1受器
與Smad傳導路徑........................................................................33
八、 TSLP調控TGF-β1受器訊息誘導Smad傳導路徑.................34
九、 TGF-β1能顯著促進腎臟纖維母細胞纖維蛋白表現...............34
十、 探討纖維化狀態下，是否調控氧化壓力的表現.......................35
十一、 探討纖維化的狀態下，粒線體生合成的表現...........................35
十二、 探討纖維化狀態，粒線體轉錄因子NRF-1表現...................... 35
十三、 TGF-β1刺激纖維化狀況下， 纖維蛋白與NRF-1表現............35
十四、 NRF-1是否透過氧化壓力調控纖維化......................................36
十五、 NRF-1靜默載體（shRNA-NRF1）增加TGF-β1誘導
纖維蛋白表現.............................................................................37
十六、 NRF-1表現載體（pcDNA-NRF1）減少TGF-β1誘導
纖維蛋白之表現........................................................................ 37
十七、 NRF-1表現載體（pcDNA-NRF1）減少TGF-β1受器................37
十八、 NRF-1表現載體（pcDNA-NRF1）減少TGF-β1誘導
Smad訊息之表現.......................................................................38
十九、 NRF-1表現載體（pcDNA-NRF1）減少TGF-β1誘導上皮間質轉換之表現.....................................................................................37
二十、 NRF-1表現載體（pcDNA-NRF1）調控TGF-β1刺激
細胞纖維化.................................................................................38
第五章 討論............................................................................................39
討論一、TSLP於誘導腎纖維母細胞纖維化...............................................40
討論二、NRF-1表現載體（pcDNA-NRF1）減少TGF-β1誘導
纖維化...........................................................................................42
第六章 圖表............................................................................................44
圖一、TSLP誘導腎纖維母細胞纖維化之生物效應........................................45
圖二、TGF-β1誘導TSLP的表現......................................................................46
圖三、TSLP對TGF-β1之影響.........................................................................47
圖四、TSLP於TGF-β1訊息Smad途徑..........................................................48
圖五、運用TSLP靜默載體轉殖細胞中之TSLP靜默表現...............................49
圖六、TSLP靜默載體（TSLP shRNA）減少TGF-β1訊息
誘導纖維蛋白表現.................................................................................50
圖七、TSLP靜默載體（TSLP shRNA）調控TGF-β1受器訊息
誘導Smad傳導路徑 .............................................................................51
圖八、TSLP調控TGF-β1受器訊息誘導Smad傳導路徑.................................52
圖九、TGF-β1顯著促進腎臟纖維母細胞纖維蛋白表現........................53、54
圖十、探討纖維化狀態下，調控氧化壓力的表現.............................................55
圖十一、探討纖維化的狀態下，粒線體生合成的表現.....................................56
圖十二、探討纖維化下粒線體轉錄因子核呼吸因子（NRF-1）的表現............57
圖十三、TGF-β1刺激纖維化時，纖維蛋白與NRF-1表現................................58
圖十四、NRF-1是否透過氧化壓力調控纖維化................................................59
圖十五、NRF-1靜默載體（shRNA-NRF1）增加TGF-β1誘導
纖維蛋白之表現...............................................................................60
圖十六、NRF-1表現載體（pcDNA-NRF1）減少TGF-β1誘導
纖維蛋白之表現..................................................................................61
圖十七、NRF-1表現載體（pcDNA-NRF1）減少TGF-β1誘導
受器之表現.........................................................................................62
圖十八、NRF-1表現載體（pcDNA-NRF1）減少TGF-β1誘導
Smad路徑之表現........................................................................63、64
圖十九、NRF-1表現載體（pcDNA-NRF1）減少TGF-β1誘導上皮間質
轉換之表現.......................................................................................65
圖二十、NRF-1調控TGF-β1刺激細胞纖維化..................................................66
第七章 結論............................................................................................67
一、纖維化狀態下.............................................................................................68
二、運用載體處理下.........................................................................................69
第八章 參考文獻……..………………….........................................70-78
第九章 附錄（以發表兩篇SCI期刊與一篇專利）.................................79

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