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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16319完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃銓珍(Chang-Jen?Huang) | |
| dc.contributor.author | Chih-Ting Shih | en |
| dc.contributor.author | 施繼庭 | zh_TW |
| dc.date.accessioned | 2021-06-07T18:09:37Z | - |
| dc.date.copyright | 2012-07-19 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-07-10 | |
| dc.identifier.citation | Arber, S., Halder, G., and Caroni, P. (1994). Muscle LIM protein, a novel essential regulator of myogenesis, promotes myogenic differentiation. Cell 79, 221-231.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16319 | - |
| dc.description.abstract | Four-and-a-half LIM domains(FHL) 蛋白家族在真核生物中具有很高的保守性，其結構是由四又二分之一個LIM domain所組成。LIM domain為一蛋白質交互作用motif，因此FHL蛋白能夠和許多蛋白質進行作用，包括structural proteins、kinases以及許多transcription factors，因此參與、調控了許多細胞內的活動，包括細胞存活、轉錄調控及訊息傳遞。其組織特異性的表現模式主要在骨骼肌及心肌中，因此FHL蛋白家族在體內扮演的角色主要是調控肌肉及心血管的發育及功能。
本實驗中，我們首先比較了人類、老鼠及斑馬魚的FHL蛋白胺基酸序列，顯示了高度的保守性。接著，由斑馬魚的whole mount in situ hybridization實驗所得到的結果顯示，FHL蛋白在心臟及部分肌肉皆有表現，意味著其在心臟的重要性。為了探討FHL蛋白家族對於班馬魚胚胎時期的心臟發育及功能之影響，利用實驗室所選殖出的三種FHL基因，包括FHL1、FHL2、FHL5，藉由心臟專一性表現之啟動子cmlc2過量表現於斑馬魚胚胎心臟中，並同時表達綠色螢光蛋白以利於觀察。結果發現，FHL蛋白過量表現之基因轉殖魚部分螢光斑馬魚子代產生心律不整、心跳減緩的情形，顯示FHL蛋白參與了心肌節律，調控心跳。為了嘗試治療心律不整之病症並進一步釐清FHL蛋白家族是否透過和β-adrenergic receptor signaling pathway產生作用而調控心跳，將表現不同組合FHL 蛋白之斑馬魚品系以isoprenaline此一強心劑進行處理，將5~6dpf的魚苗浸泡、飼養在不同濃度(0.01μg/μl、0.0075μg/μl、0.005μg/μl、0.001μg/μl)的isoprenaline中，並持續觀察。我們的研究結果發現，經由isoprenaline處理將可以有效地改善過表現FHL 蛋白所造成的心律不整。然而，在長時間處理之下，過表現FHL 蛋白的斑馬魚品系心律不整的情形將會復發，並且有顯著的死亡率上升。我們仍需更進一步實驗來探討此現象。 藉由本實驗，我們更清楚地瞭解FHL蛋白在心臟中之作用，以及其在心臟疾病中的角色，而我們的成果也成功地以斑馬魚建立了心律不整的生物模式，有利於將來相關藥物的篩選及開發。 | zh_TW |
| dc.description.abstract | In eukaryotes, Four-and-a-half LIM domains (FHL) protein family is highly conserved. Structurally, the FHL proteins are composed of four closely connected LIM domains arranged in tandem, which are cysteine-rich double zinc finger motifs; and an N-terminal half LIM domain, which has one zinc finger motif. The LIM domain is known for mediating protein-protein interaction. Based on its protein-protein interaction properties, FHL protein family can interact with many proteins. Such like structural proteins, kinases and many transcription factors. The presence of multiple LIM domains, suggests that FHL protein family may involve in many cellular mechanisms. Including cellular survival, transcription regulation and signal transduction. The tissue-specific expression pattern of FHL protein family is mainly at cardiac muscular and skeletal muscle. Therefore the FHL protein family plays an important role in muscle and cardiovascular differentiation and the function maintenance.
In our study, by alignment of the FHL protein sequences in human, mouse and zebrafish and the results of whole mount in situ hybridization assay. Our results shows that FHL protein family are highly conserved and mainly expressed in heart and some part of skeletal muscle, suggest the importance of FHL protein family in the cardiomyocyte. We further analysed the role of FHL protein in the heart development by overexpressed several FHL proteins fused GFP including FHL1, FHL2 and FHL5, in zebrafish heart by a cardiac-specific promoter; cmlc2. The results turned out that a certain number of the FHL-GFP-positive offspring of transgenic line had arrhythmia. This indicates that FHL protein plays a role in regulation of heart rhythm. Next, we intend to rescue the phenotype of arrhythmia. Transgenic zebrafish which overexpressed different combination of FHL proteins, were treated with isoprenaline, a cardiac stimulant. Different FHL transgenic zebrafish embryos of 5-6dpf were immersed with different concentration of isoprenaline and heart beat were recorded daily. Our results demonstrated that isoprenaline could significantly rescue arrhythmia phenotype. However, long-term treatment had resulted in dramatic drop of survival rate and the recurring of irregular heart beat of FHL overexpressed transgenic line. Therefore further studies may be required to decipher the mechanism in the future. Taken together, our studies provide more understandings about the function of FHL protein in heart, the role in the cardiac disease, and established a zebrafish arrhythmia model for cardiovascular drug selection. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-07T18:09:37Z (GMT). No. of bitstreams: 1 ntu-101-R99B46020-1.pdf: 2573153 bytes, checksum: 6f13063399a9e47eed27a249fac3ba6e (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 章節目錄
誌謝 I 章節目錄 II 圖表目錄 IV 摘要 VI Abstract VIII 壹、序言 一、LIM domain and Four-and-a-half LIM (FHL) domains protein - 1 - I. FHL1 - 3 - II. FHL2 - 6 - III. FHL5 - 8 - 二、FHL 蛋白在人類肌肉疾病中之角色 - 9 - 三、以斑馬魚作為功能性基因體分析之實驗動物的優點 - 13 - 四、研究目的及策略 - 14 - 貳、實驗材料與方法 一、實驗材料 - 16 - 二、實驗方法 - 17 - I. FHL表現載體於斑馬魚胚胎之顯微注射 - 17 - II. 斑馬魚 FHL domains protein mRNA在早期胚胎發育之表現：RNA全胚胎原位雜交 (RNA whole-mount in situ hybridization) - 20 - III. 基因轉殖魚之Genotyping - 27 - IV. 基因轉殖魚之型態觀察、心律統計及照相、錄影 - 28 - V. β-adrenergic receptor agonist (isoprenalin)藥物處理 - 30 - 参、實驗結果 一、斑馬魚FHL蛋白家族基因序列分析 - 31 - 二、斑馬魚FHL蛋白家族基因在不同胚胎發育時期的表現位置 - 32 - 三、斑馬魚FHL 蛋白家族影響心臟之功能 - 35 - 四、利用FHL基因轉殖魚進行β2-adrenergic receptor agonist藥物測試 - 38 - 肆、討論 一、過量表現班馬魚FHL蛋白和心律不整之間的關係 - 41 - 二、FHL2過量表現之基因轉殖魚作為心律不整之藥物篩選模式生物 - 44 - 三、FHL5之功能預測 - 45 - 伍、參考文獻 - 47 - 六、備註 - 53 - 圖表目錄 圖1-1、FHL1蛋白在人類、老鼠和斑馬魚之胺基酸序列比對 - 55 - 圖1-2、FHL2蛋白在人類、老鼠和斑馬魚之胺基酸序列比對 - 56 - 圖1-3、FHL5蛋白在人類、老鼠和斑馬魚之胺基酸序列比對 - 57 - 圖2、原位雜合分析斑馬魚FHL1 mRNA在胚胎發育時期的分佈表現 - 58 - 圖3、原位雜合分析斑馬魚FHL2 mRNA在胚胎發育時期的分佈表現 - 59 - 圖4、原位雜合分析斑馬魚FHL5 mRNA在胚胎發育時期的分佈表現 - 60 - 圖5、心臟專一性啟動子cmlc2表現不同組合之FHL基因轉殖魚螢光樣式圖 - 61 - 圖6、Geno-typing分析各基因轉殖魚FHL基因是否嵌入斑馬魚染色體中，PCR電泳跑膠圖 - 62 - 圖7-1、原位雜合分析斑馬魚FHL蛋白在野生型斑馬魚與基因轉殖魚中之表現差異 - 63 - 圖7-2、原位雜合分析斑馬魚FHL蛋白在野生型斑馬魚與基因轉殖魚中之表現差異 - 64 - 圖8、心律不整與正常心律之影片截圖比較 - 66 - 圖9、各基因轉殖魚子代出現心律不整之比例分布 - 67 - 圖10、以Isoprenaline對過量表現不同組合FHL蛋白之基因轉殖魚進行藥物處理之心律不整比例觀察記錄圖 - 68 - 圖11、以Isoprenaline分別對過量表現FHL2及FHL5之基因轉殖魚進行藥物處理之心律不整比例觀察記錄圖 - 69 - 圖12、以Isoprenaline分別對過量表現FHL2及FHL5之基因轉殖魚進行藥物處理之存活率觀察記錄圖 - 70 - 表1、製備全覆性原位雜合之探針所用之引子序列 - 71 - 表2、以全覆性原位雜合法偵測FHL蛋白基因在不同胚胎發育時期之表現位置整理表 - 71 - 表3、表現不同FHL蛋白組合之基因轉殖魚列表(表現質體列表) - 72 - 表4、Geno-typing所使用之引子序列 - 72 - 表5、已知能與FHL1作用之蛋白質 - 75 - 表6、已知能與FHL2作用之蛋白質 - 79 - | |
| dc.language.iso | zh-TW | |
| dc.subject | isoprenaline | zh_TW |
| dc.subject | Four-and-a-half LIM domains(FHL) 蛋白家族 | zh_TW |
| dc.subject | LIM domain | zh_TW |
| dc.subject | cmlc2 | zh_TW |
| dc.subject | 心律不整 | zh_TW |
| dc.subject | arrhythmia | en |
| dc.subject | isoprenaline | en |
| dc.subject | Four-and-a-half LIM domains (FHL) protein | en |
| dc.subject | LIM domain | en |
| dc.subject | zinc finger motif | en |
| dc.subject | cmlc2 | en |
| dc.title | 螢光蛋白基因轉殖魚在心臟疾病之研究 | zh_TW |
| dc.title | Application of transgenic zebrafish expressing four-and-a-half LIM(FHL) domains proteins to the study of heart disease | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳建璋(Chien-Chang Chen),廖永豐(Yung-Feng Liao) | |
| dc.subject.keyword | Four-and-a-half LIM domains(FHL) 蛋白家族,LIM domain,cmlc2,心律不整,isoprenaline, | zh_TW |
| dc.subject.keyword | Four-and-a-half LIM domains (FHL) protein,LIM domain,zinc finger motif,cmlc2,arrhythmia,isoprenaline, | en |
| dc.relation.page | 79 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2012-07-10 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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