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系統識別號 U0026-2108201323344200
論文名稱(中文) 研究銀杏毒誘發的癲癇對斑馬魚胚胎代謝及發育的影響
論文名稱(英文) Characterizing the impact of Ginkgotoxin-induced seizure to the metabolism and development of zebrafish
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 101
學期 2
出版年 102
研究生(中文) 蔡怡雯
研究生(英文) Yi-Wen Tsai
學號 T36001031
學位類別 碩士
語文別 英文
論文頁數 68頁
口試委員 指導教授-傅子芳
口試委員-楊孔嘉
口試委員-蔡振寧
中文關鍵字 銀杏毒素  癲癇  維他命B6  瘦體素b 
英文關鍵字 Ginkgotoxin  Epilepsy  Vitamin B6  leptin-b 
學科別分類
中文摘要 無故復發的癲癇發作是癲癇很重要的症狀,因為癲癇發作不只影響了患者的行為也深深地影響患者的生理功能。然而,目前癲癇所引起的個人健康的影響及詳細的機制仍然是不清楚的。因此了解癲癇對於生理的影響以及相關的機制將可促進藥物的發展及治療方法。先前,我們已經利用銀杏種子和葉子中所發現的一種神經性毒素,稱為銀杏毒素(Gingkgotoxin),在斑馬魚建立一個癲癇發作的動物模式。銀杏毒素的結構上類似於維生素B6,它會抑制吡哆醛激酶(Pyridoxl kinase)的活性,這種酶催化形成具有生理活性的磷酸吡哆醛(pyridoxal5-phosphate)。出乎意料的,浸泡過銀杏毒素的斑馬魚幼苗增加了對於吡哆醇(Pyridoxine)毒性的敏感性。吡哆醇是一般人或是神經相關患者補充營養以及攝取維他命B6的主要形式。這篇研究的目的是探討為什麼曝露銀杏毒素的斑馬魚胚胎會增加對吡哆醇毒性的敏感性。我們假設銀杏毒素改變了斑馬魚胚胎的基因表達而導致對吡哆醇毒性的敏感性增加。利用DNA微陣列(microarray)分析銀杏毒素浸泡兩小時的五天大胚胎發現瘦體素b mRNA表現量增加了九倍。利用常作為誘發癲癇動物模式的藥物戊四唑(Pentylenetetrazol)進一步確認瘦體素b的增加和癲癇發作是相關的。在胚胎中過度表現瘦體素b也增加了暴露吡哆醇後的死亡率,因此更支持了瘦體素b會增加對吡哆醇毒性的敏感性。我們將斑馬魚的瘦體素b選殖出來並在活體進行分析。 RT-PCR和Whole mount in situ hybridization的結果顯示瘦體素b在胚胎發育過程中的表現和時間及特定部位相關,瘦體素b的表現在三天大前的胚胎最多而且主要集中在頭部區域。利用morpholino oligonucleotides降低瘦體素b的表現後,我們在第九天發現脂質的沉積減少,而同樣的現象也出現在銀杏毒素處理的10天大胚胎。雖然這些結果和我們預期的不同,但是支持了瘦體素b參與了脂質代謝的可能性。最後,我們發現,過度表達瘦體素減緩了戊四唑所誘發的癲癇,因此支持了瘦體素b對於神經疾病具有保護作用。我們得到的結論是癲癇發作誘發瘦體素b的增加會改變胚胎脂質沉積和增加對吡哆醇毒性的感受性。我們的研究結果還支持了利用斑馬魚來作為研究瘦體素b相關脂質代謝和癲癇發病的可能性。
英文摘要 Recurrent and unprovoked seizure is important symptoms of epilepsy since they affect patient’s physiological functions profoundly besides behavioral impact. However, the impact induced by seizure to the health of affected individuals and the mechanism underlying remain elusive. Identification of the physiological impact and the mechanism underlying caused by seizure will facilitate the development of drug and therapeutic regimen for seizure. Previously, we had established a seizure model in zebrafish larvae using ginkgotoxin, a neurotoxin found in the seeds and leaves of ginkgo biloba. Ginkgotoxin is structurally similar to vitamin B6 and inhibits the activity of pyridoxal kinase, the enzyme catalyzing the formation of pyridoxal 5-phosphate, the physiologically active form of B6. Unexpectedly, larvae exposed to ginkgotoxin displayed increased susceptibility to pyridoxine toxicity. Pyridoxine is the form of B6 in nutrition supplement and most commonly ingested by general population and patients with neuropathy. The aim of this study is to investigate why pre-exposure to ginkgotoxin increase embryonic sensitivity to pyridoxine toxicity. We hypothesized that ginkgotoxin altered the gene expression profile of ginkgotoxin-exposed embryos, leading to increased susceptibility to pyridoxine toxicity. Microarray analysis on 5 dpf embryos pre-exposed to ginkgotoxin for 2 hours revealed a 9-fold increase in leptin-b mRNA level. Zebrafish leptin-b was cloned and the expression of the gene was characterized both in vitro and in vivo. The results of RT-PCR and whole mount in-situ hybridization revealed a stage- and spatial-dependent expression of leptin-b during embryogenesis, where the leptin-b transcripts were more abundant in the stages before 3 dpf and focused in the anterior part of embryos, especially head region. Overexpressing leptin-b in embryos increased the mortality of embryos after exposed to pyridoxine, supporting the role of leptin-b in the elevated sensitivity to pyridoxine toxicity. However, incubating embryos in pentylenetetrazol, a seizure inducer commonly used in experimental animal, also increased embryonic susceptibility to pyridoxine toxicity, suggested that the up-regulation of leptin-b was most likely due to seizure. Unexpectedly, knocking down leptin-b decreased lipid deposition in morphants when observed at 9 dpf, which was also observed in ginkgotoxin-treated embryos. These results, although contradicted to our expectation, further strengthen the involvement of leptin-b in lipid metabolism. Finally, we found that overexpressing leptin-b in embryos alleviated the subsequent severity of pentylenetetraol-induced seizure, supporting the protective role of leptin-b against neuropathogenesis. We concluded that seizure-induced up-regulation of leptin-b altered embryonic lipid deposition and increased susceptibility to pyridoxine toxicity. Our results also suggest the possibility of using zebrafish for studying leptin-b related lipid metabolism and seizure pathogenesis.
論文目次 Table of Contents
摘要 I
Abstract II
Acknowledgement III
Table of Contents IV
Content of Figures VI
Contents of Tables VII
Abbreviations VIII
Ⅰ.Introduction 1
1.1 Vitamin B6 1
1.2 The biological significances of vitamin B6 1
1.3 Gingkgotoxin (4'-O-methylpyridoxine) 2
1.4 Leptin 2
1.5 The functions of leptin 3
1.6 Epilepsy 3
1.7 Zebrafish (Danio rerio) 4
1.8 Zebrafish as a seizure animal model 5
Ⅱ. Rational 6
Ⅲ. Specific aim 7
Ⅳ. Materials and Methods 8
3.1 Fish (Danio rerio) care and maintenance 8
3.2 Chemical exposure experiment 8
3.3 RNA isolation 8
3.4 Preparation of microarray 9
3.5 TUNEL assay (terminal transferase mediated dUTP nick end-labeling) 10
3.6 Embryonic protein extraction and Western blotting 10
3.7 Trypan blue 11
3.8 Reverse transcription-PCR, RT-PCR 11
3.9 leptin-b cloning and mRNA synthesis 11
3.10 Leptin-b knockdown and leptin-b mRNA overexpression 12
3.11 leptin-b probe synthesis 12
3.12 Whole mount in situ hybridization (WISH) 13
3.13 Nile red stain 14
3.14 Oil Red O Staining 14
3.15 Seizure level assay 15
3.16 Cell culture 15
3.17 Real-time PCR 16
3.18 Statistical Analyses 16
Ⅴ. Results 17
Ⅵ. Conclusion 25
Ⅶ. Discussions 26
Ⅷ Figures 31
Ⅸ. Tables 47
Ⅹ. Supplemetary Data 51
ⅩⅠ. References 55
ⅩⅡ. Appendixes 61

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