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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林亮音(Liang-In Lin) | |
dc.contributor.author | Meng-Shan Hsieh | en |
dc.contributor.author | 謝孟珊 | zh_TW |
dc.date.accessioned | 2021-06-08T02:27:25Z | - |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-17 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19924 | - |
dc.description.abstract | In the present study, taking advantages of rapid growth and transparent embryo, together with the similarity of gene sequence and hematopoiesis to mammals, zebrafish has been a good animal model to study on the development of hematopoiesis and hematologic malignancies. SOX4 (SRY sex determining region Y-box 4) is a transcription factor belonging to SOX family. Overexpression of SOX4 has been found in a variety of cancers. It is indicated that desregulated expression of SOX4 was associated with leukemogenesis in acute myeloid leukemia (AML) patients with CEBPA mutation. Therefore, SOX4 or its downstream molecules might be potential therapeutic targets for treating this subtype of AML patients. Furthermore, SOX4 has also been found to be strongly related to cell proliferation, survival, and differentiation; and overexpression of SOX4 in myeloid progenitor cells resulted in a blockage to myeloid maturation. Although these findings have provided preliminary concepts, further study is required to understand the mechanism and the impact of SOX4 on hematopoiesis or myeloid malignancies. Thus, the aim of this study is to establish a transgenic zebrafish model expressing human SOX4 under the control of myeloid specific promoter, and to explore the role of SOX4 on zebrafish hematopoiesis from embryo to adult stages. Oncomine research analysis first revealed that the expression of SOX4 is relatively increased in patients with AML compared with normal controls (p<0.0001). In addition, we confirmed that the HMG domain and TAD domain of SOX4 gene were conserved between species by phylogenetics and sequence alignment. By using Multisite Gateway system○R and Tol2 transposon technology, we established an expression vector including spi1 promoter, human SOX4 gene and EGFP. This constructed vector was then injected into zebrafish embryos. After a serious of fluorescent selection, stable transgenic SOX4 zebrafish were generated. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed that SOX4 could be detected at 20 hpf (TG1, 0.2x103 copies; TG2, 1.7x103 copies), and then increased gradually during development. At 5 dpf, level of SOX4 in TG1 and TG2 was up to 2x103 copies and 10x103 copies, respectively. However, there were no significant differences in the expression of hematopoiesis-related transcription factors, in spite of the expression of SOX4. We also found that there were no significant difference of myeloperoxidase (mpo) expression in transgenic zebrafish TG1 and TG2, compared with control fish by using whole-mount in situ hybridization (WISH) technique with p value of 0.11 and 0.89, respectively. In addition, Tg(spi1:SOX4-EGFP/cd41:EGFP) demonstrated normal development of hematopoietic stem cells; and Tg(spi1:SOX4-EGFP) zebrafish had normal granulopoiesis of myeloid cells. These results indicated that the SOX4 transgenic zebrafish had normal hematopoiesis in the larval stage. Regarding to the adult stage, 5 and 9-month-old SOX4 transgenic zebrafish were examined. At age of 5 months, out of 6 transgenic zebrafish, 4 were found to have increased myelopoiesis (M/E=2.20 to 6.42 vs. 1.70) in kidney marrow, especially immature myeloid cells; but showing normal pattern in peripheral blood (PB). At age of 9 months, out of 6 transgenic zebrafish, more increased myelopoiesis (M/E=4.88 to 9.09 vs. 3.31) and immature cells were found in kidney marrow. Intriguingly, some immature cells were found in PB smear at age of 9 months. Taken together, we proposed that continuous overexpression of SOX4 in myeloid cells would lead to an expansion of myeloid progenitors and differentiation arrest in kidney marrow as well as abnormal myeloid cells in PB from SOX4 transgenic zebrafish at adult stage. These defects resemble the blood pattern of myeloid malignancy in human beings. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:27:25Z (GMT). No. of bitstreams: 1 ntu-104-R02424013-1.pdf: 3937850 bytes, checksum: aa4ac2086543c08b98cd11b5f5e791fb (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 誌謝 I 目錄 II 縮寫表 VII 摘要 VIII Abstract X 第一章 前言 1 1.1 模式動物-斑馬魚 1 1.2 斑馬魚造血與血球發育 1 1.3 斑馬魚造血相關轉錄因子 2 1.4 SOX家族 3 1.4.1 SOX家族簡介 3 1.4.2 SOX的結構與功能 4 1.5 調控因子SOX4 5 1.5.1 SOX4簡介 5 1.5.2 SOX4結構與功能 5 1.5.3 SOX4與癌症 6 1.5.4 SOX4與血液相關癌症 6 第二章 研究目的 8 第三章 材料與方法 9 3.1 材料 9 3.1.1 儀器設備 9 3.1.2 藥品 10 3.1.3 抗體 11 3.1.4 酵素與試劑 12 3.1.5 生物試劑組 12 3.1.6 藥品與試劑配置 12 3.2 方法 14 3.2.1 斑馬魚 14 3.2.2 建立基因轉殖魚 14 3.2.3 Tol2 RNA之合成 20 3.2.4 顯微注射 21 3.2.5 基因轉殖魚之篩選 22 3.2.6 基因分析 23 3.2.7 原位雜交 25 3.2.8 血球與組織分析 28 3.2.9 統計方法 30 第四章 實驗結果 31 4.1 SOX4在急性骨髓性白血病病人中具有較高表現量 31 4.2 SOX4在不同物種具有保守性 31 4.3 轉殖基因魚型態觀察與鑑定 32 4.4 探討SOX4過度表現對於造血相關轉錄因子之影響 33 4.5 骨髓系列血球發育與分化之觀察與測定 34 4.6 SOX4在成魚造血器官中的表現 35 4.7 組織染色分析 35 4.8 血球染色分析 35 第五章 討論 38 第六章 參考文獻 41 表 50 圖 54 附圖 73 | |
dc.language.iso | zh-TW | |
dc.title | SOX4 基因轉殖斑馬魚的造血系統研究 | zh_TW |
dc.title | Hematopoietic study of SOX4 transgenic zebrafish | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 胡忠怡(Chung?Yi Hu),侯信安(Hsin-An Hou),陳曜鴻(Yau-Hung Chen),郭遠燁(Yuan-Yeh Kuo) | |
dc.subject.keyword | SOX4,基因轉殖斑馬魚,Tol2轉位子,造血,骨髓惡性血液疾病, | zh_TW |
dc.subject.keyword | SOX4,transgenic zebrafish,Tol2 transposon,hematopoiesis,myeloid malignancy, | en |
dc.relation.page | 79 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2015-08-17 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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