臺灣博碩士論文加值系統

Thioacetamide (TAA)已證實可透過活性氧分子造成斑馬魚胚胎發育時期心包膜水腫（edema in pericardial sac；eps），體節畸型甚至死亡等現象，其細胞與分子機制須進一步驗證，且是否可藉由過表現人類錳型超氧歧化酶(manganese superoxide dismutase ；Mn-SOD) 抑制TAA所造成的胚胎氧化傷害亦值得進一步研究。首先我們探討TAA影響胚胎發育的哪個時期造成eps 的產生？結果發現從胚胎受精後14 hpf 開始處理32 mM TAA至36 hpf，結果造成心臟跳動速率變慢50－60％，以及心臟狹窄細長的畸型，這些症狀類似心臟衰竭(Heart Failure；HF) ，且也觀察到eps的現象。接著利用轉基因技術建立活體肝臟專一性即時動態分析活性氧分子(ROS) 的模式斑馬魚，結果證實TAA可促進胚胎內superoxide及H2O2大量產生，並且經由誘導TNF- α的表現，使SOD 活性被抑制。我們利用Tol2轉位子系統建立肝臟專一性過表現Mn-SOD的轉基因魚，其mRNA 表現增加約2倍，蛋白質表現增加約3倍，且活性增加約1.3－1.5倍。轉基因魚F1世代胚胎經32mM TAA處理後，結果發現TNF- α表現量降低為1.5倍，而SOD 的活性也回復。再來我們利用免疫組織化學方法，以anti-human MC tryptase 為抗體，結果再次證實TAA造成胚胎心包膜附近聚集許多已活化的肥大細胞，若過表現Mn-SOD則可見到Mast cells聚集在心包膜附近的數量減少，且蛋白質氧化傷害也減少大約4倍，eps 的發生機率也降低到10 ~ 20％，最後胚胎的死亡率也顯著降低。我們的研究結果表明，TAA誘導胚胎發育過程中eps 的形成是由於增強ROS的產生和誘發Mast cell活化。若過表現人類Mn-SOD能降低細胞內ROS和氧化損傷，以及抑制Mast cell活化，且抑制TAA誘導的eps形成。

Thioacetamide (TAA) is a hepatotoxin that can cause hepatocellular carcinoma in mice and zebrafish, but little is known about its toxic effect on embryonic development. In the previous study, we have showed TAA can enhanced ROS generation and induced the edema in pericardial sac (eps) formation, but the cellular mechanism was still unclear. In this study, we try to identify the cells which involved in TAA induced eps formation, and overexpression of manganese superoxide dismutase (Mn-SOD) to reduce eps formation in TAA treatment. First, we test that the toxicological mechanism of TAA on eps formation, and we treated with 32mM TAA of zebrafish embryos between 14 –36 hpf. The result show the heart beat rate 50-60%, and a narrow elongated heart malformations, these symptoms similar to heart failure, and also observed eps formation. We use of transgenic technology to build real-time in vivo dynamic analysis of ROS in liver specificity at zebrafish model, the results confirm the embryo can promote superoxide and H2O2 generated after 32 mM TAA treatment, and 32 mM TAA treatment zebrafish embryos can induction of TNF-α highly expressed and the SOD activity was inhibited. Overexpress Mn-SOD transgenic fish by Tol2 transposon system were generated and confirmed by RT-PCR, Western blotting and enzyme activity assay. The result obviously show the Mn-SOD mRNA expression increased approximately 2 fold, protein expression increased approximately 3 fold, and the activity increased approximately 1.3-1.5 fold. The transgenic F1 transgenic fish embryos were treated with TAA, the results showed that TNF-α expression is reduced to 1.5 fold, and the activity can rescue of SOD. We use antibody of anti-human MC tryptase to Immunohistochemistry, we found the mast cells were congregate and degranulate at the pericardial sac, and overexpression of Mn-SOD decrease amount of the mast cells in the pericardial sac in the number and protein oxidative damage is reduced by approximately 4 fold, the eps formation rate was reduced to about 10-20%. Our results showed TAA induced eps/heart failure-like syndrome are due to enhanced ROS generation, and induced mast cells activation during embryonic development. To overexpress Mn-SOD can reduce intracellular ROS, Mast cells numbers, and oxidative damages, and can partially rescue TAA induced embryo toxicity.

中文摘要 I
English Abstract III
誌謝 V
縮寫表 VI
目錄 VII
第一章 、前言 1
第一節、肝毒性物質硫代乙醯胺 (Thioacetamide, TAA） 1
1-1-1. TAA的介紹 1
1-1-2. TAA導致肝癌的機制 2
1-1-3. TAA對於胚胎的影響 3
第二節、心臟衰竭 (Heart Failure) 4
1-2-1. 心臟衰竭的介紹及原因 4
1-2-2. 心臟衰竭的疾病分級 5
第三節、TAA造成Mast Cell活化形成edema in pericardial sac (eps) 6
第四節、活性氧分子 (ROS) 在生物體的調控 7
1-4-1. 活性氧分子及自由基介紹 7
1-4-2. 抗氧化防禦機制 8
第五節、錳型超氧歧化酶 (Manganese Superoxide Dismutase；Mn-SOD) 9
1-5-1. 錳型超氧歧化酶之介紹 9
1-5-2. 錳型超氧歧化酶之基因組成與調節方面的研究 9
1-5-3. 錳型超氧歧化酶基因的剔除與心臟疾病的關係 10
1-5-4. TAA 影響抗氧化酵素的活性 10
第六節、活體內（in vivo）偵測ROS的系統 10
1-6-1. 活體內（in vivo）偵測粒線體Superoxide的系統 10
1-6-2. 活體內（in vivo）偵測Hydrogen peroxide的系統 12
第七節、研究動機 13
第二章、實驗材料 14
2-1. 材料 14
2-2. 載體 14
2-2-1. 選殖載體 (Cloning vector) 14
2-2-2.表現載體 (Expression vector ) 14
2-3. 宿主 ( host ) 14
2-4. 培養基 ( 含抗生素 ) 14
2-4-1. 液態 Luria-Bertani (LB) 15
2-4-2. Luria-Bertani （LB） Agar medium（固態） 15
2-5. 抗生素 15
2-6. DNA marker 15
2-7. DNA 內染劑 15
2-8. Protein marker 16
2-9. 5×蛋白質樣品染劑 (5×Protein staining sample dye) 16
2-10. SDS-PAGE 緩衝溶液 16
2-11. 蛋白質染色劑與退染劑 17
2-12. 溶液 17
2-13. 抗體與轉漬膜 17
2-14. Kit 組 18
2-15. 實驗藥品 20
2-16. 實驗儀器及設備 21
2-17. primer sequences 22
第三章、實驗步驟 25
3-1藥物處理斑馬魚胚胎 25
3-1-1. 斑馬魚飼養與孵魚準備 25
3-1-2. TAA處理Wild Type斑馬魚胚胎及BMP4：EGFP基因轉殖魚胚胎 25
3-2基因選殖人類Mn-SOD 、Mito.-cpYFP 及roGFP2-Orp1 25
3-2-1. 重組人類Mn-SOD的質體 25
3-2-2. 重組人類Mito.-cpYFP的質體 29
3-3 顯微注射 (Microinjection) 35
3-3-1. 斑馬魚飼養與孵魚準備 35
3-3-2. Microinjection 拉針與磨針之製備 35
3-3-3. Microinjection Plate之製備 36
3-3-4. Microinjection Tol2 transposase mRNA之合成製備 36
3-3-5. Human Mn-SOD、Mito.-cpYFP 、roGFP2-Orp1表現載體之顯微注射 37
3-4. 萃取 Genomic DNA 38
3-5 Reverse Transcriptase PCR ( RT-PCR ) 39
3-5-1. RNA之萃取 39
3-5-2. 反轉錄酶反應(Reverse Transcriptase, RT) 39
3-6 西方點漬法( Western blot) 40
3-6-1. 蛋白質電泳製備 40
3-6-2. 蛋白質製備 41
3-6-3. 蛋白質定量 42
3-6-4. 西方點漬法 42
3-7 Mast Cell Tryptase Immunohistochemistry 43
3-7-1. 斑馬魚飼養與孵魚準備 43
3-7-2. Thioacetamide ( TAA ) 處理 43
3-7-3. 組織包埋 43
3-7-4. 組織切片 44
3-7-5. Immunohistochemistry 44
3-8 Whole Mount In situ Hybridization 45
3-8-1. 勝任細胞的製備與轉型作用 45
3-8-2. 抽取微量質體 46
3-8-3. 確認質體 46
3-8-4. 探針合成 46
3-8-5. 胚胎前處理 48
3-8-6. 前處理 48
3-8-7. 探針雜交及清洗 49
3-8-8. 抗體雜交及呈色 50
3-8-9. 固定及退染 50
3-9 細胞內分子氧化程度測定 51
3-9-1. L-012 Assay 51
3-9-2. DCFH-DA Assay 51
3-10細胞內分子氧化傷害測定 52
3-10-1. protein carbonyl 分析 52
3-11 細胞內Superoxide Dismutase (SOD) 活性測定 53
3-11-1. SOD標準曲線(Superoxide Dismutase (SOD) standard curve) 53
3-11-2.細胞內SOD活性測定 54
第四章 、結果 55
第一節、TAA 影響胚胎發育的時間點分析 55
第二節、TAA誘導類心臟衰竭症狀 (Heart Failure like syndrome；HF) 56
第三節、 TAA造成心包膜水腫 (edema in pericardial sac；eps) 是經由Mast Cell活化引起的 57
第四節、建立活體內（in vivo）偵測ROS的系統以確定TAA誘導胚胎內產生ROS 58
4-4-1. 建立mito-cpYFP 基因轉殖魚 58
4-4-2. 建立roGFP2-Orp1 基因轉殖魚 59
第五節、過表現人類錳型超氧歧化酶 (Human Manganese Superoxide Dismutase；H-MnSOD) 減緩TAA所造成的胚胎毒性 60
4-5-1. 建立H-MnSOD基因轉殖魚 60
第六節、 TAA誘導胚胎TNF-α大量表現抑制抗氧化酵素SOD的活性 61
第七節、過表現H-MnSOD 抑制Mast Cells 活化及減緩eps 發生的機率 62
第八節、 過表現H-MnSOD 抑制TAA導致的氧化傷害 63
第九節、 過表現H-MnSOD 抑制TAA誘導仔魚死亡 63
第十節、 結論 64
第五章 討論 65
第一節、肝毒性物質TAA對Wild type 斑馬魚胚胎造成Edema in pericardial sac (eps) 之分析 65
5-1-1. TAA對Wild type 斑馬魚胚胎型態與發育時間點之影響 65
5-1-2. TAA誘發心臟衰竭併發症 66
5-1-3. TAA 誘導Mast Cells聚集在pericardial sac造成eps之分析 67
5-1-4. TAA 對Wild type 斑馬魚胚胎誘導ROS 之分析 68
第二節、人類錳型超氧歧化酵素(Human Manganese Superoxide Dismutase；H-MnSOD)之基因選殖 69
第三節、TAA 對Mn-SOD轉基因魚胚胎的Tumor necrosis factor alpha (TNF-α) mRNA 表現量的影響 70
第四節、TAA 對Mn-SOD轉基因魚胚胎的SOD 抗氧化酵素活性的影響 71
第五節、TAA 對Mn-SOD轉基因魚胚胎的Mast cell聚集在pericardial sac造成eps之分析 72
第六節、TAA 對Mn-SOD轉基因魚胚胎內的氧化傷害的影響 72
第七節、TAA 對Mn-SOD轉基因魚胚胎的eps 發生率及致死率之影響 73
第八節 未來展望 74
第六章、參考文獻 75
第七章、圖表 82
第八章、附錄 107

圖目錄
圖1、TAA 影響胚胎發育的時間點分析...82
圖2、TAA 影響斑馬魚胚胎的心跳速率.83
圖3、TAA影響斑馬魚胚胎心臟的型態.84
圖4、TAA影響BMP4：EGFP基因轉殖魚心臟的型態 86
圖5、TAA活化肥大細胞(Mast cells) 聚集在心包膜(pericardial sac) 附近 87
圖6、構築mito-cpYFP的基因轉殖魚 .88
圖7、mito-cpYFP基因轉殖魚的表現 .89
圖8、mito-cpYFP基因轉殖魚可以偵測Superoxide 90
圖9、構築roGFP2-Orp1 的基因轉殖魚 91
圖10、roGFP2-Orp1基因轉殖魚的表現 92
圖11、roGFP2-Orp1 基因轉殖魚可以偵測Hydrogen Peroxide 93
圖12、構築人類錳型超氧歧化酶(H-MnSOD) 的基因轉殖 94
圖13、人類錳型基因超氧歧化酶(H-MnSOD) 基因轉殖魚的表現 95
圖14、在組織專一性表現H-MnSOD 的基因轉殖魚 96
圖15、分析H-MnSOD 基因轉殖魚之SOD的活性 97
圖16、原位雜交(whole mount in situ hybridization) 分析在0-120 小時之前H-MnSOD 基因轉殖魚之基因分布情形 98
圖17、過表現H-MnSOD 可抑制TNF- α 的mRNA 表現量 99
圖18、過量表現H-MnSOD 可補救TAA 抑制SOD的活性 100
圖19、過表現H-MnSOD 抑制TAA活化Mast cells聚集在pericardial sac.102
圖20、過表現H-MnSOD減緩eps 發生的機率 103
圖21、過表現H-MnSOD抑制TAA導致的蛋白質過氧化 104
圖22、過表現H-MnSOD 抑制TAA誘導仔魚死亡 105
圖23、過表現錳型超氧歧化酶減緩Thioacetamide誘導斑馬魚胚胎類心臟衰竭併發症 106

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