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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊雅倩(Ya-Chien Yang) | |
| dc.contributor.author | Ya-Lin Li | en |
| dc.contributor.author | 李雅玲 | zh_TW |
| dc.date.accessioned | 2021-06-16T06:32:07Z | - |
| dc.date.available | 2024-08-05 | |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-08-06 | |
| dc.identifier.citation | 1 Kitisin, K., and Mishra, L.: ‘Molecular biology of colorectal cancer: new targets’, Semin Oncol, 2006, 33, (6 Suppl 11), pp. S14-23
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Structure and activity of the fourth member, NDST4’, The Journal of biological chemistry, 2001, 276, (8), pp. 5876-5882 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/56970 | - |
| dc.description.abstract | 大腸直腸癌主要是由於上皮細胞不正常增值，並累積基因變異，包含致癌基因過度活化與抑癌基因失去功能。先前本實驗室利用微衛星標記，於人類第四號染色體4q26區域篩選出N-deacetylase/N-sulfotransferase (NDST4)為大腸直腸癌相關之抑癌基因。NDST4參與Heparan sulfate proteoglycans (HSPGs)合成過程，主要的功能為去乙醯化作用(N-deacetylation)和硫酸化作用(N-sulfation)，HSPGs在發育、生長、腫瘤發生、炎症反應、微生物侵襲等不同生理和病理機制皆扮演重要角色。為了探究NDST4的功能，本實驗室已製造Ndst4基因剔除小鼠，本論文即進行表現型分析。首先，我們觀察到Ndst4基因剔除並不影響其發育與繁衍。接著利用Modified-SHIRPA v1.、全血球計數、血清生化檢驗與組織學檢查進行研究。在外觀和行為分析上，野生型與Ndst4基因剔除小鼠並無顯著差異；而統計全血球計數，發現於Ndst4基因剔除母鼠，其嗜酸性白血球數目和其百分比顯著高於野生型小鼠；在血清生化檢驗結果顯示： Ndst4基因剔除公鼠之高密度脂蛋白顯著低於野生型小鼠。此外，於組織學檢查，以H&E染色觀察大腸組織並計量大腸隱窩(crypt)長度，並無顯著差異，但發現Ndst4基因剔除小鼠之大腸杯狀細胞有增加的現象，進一步以Alcian blue and Periodic Acid Schiff Staining分析，證實Ndst4基因剔除小鼠之近端與中段大腸，杯狀細胞數量皆顯著高於野生型小鼠。接著以Carbonic anhydrase I 免疫組織化學染色法檢測大腸吸收細胞，結果顯示：Ndst4基因剔除小鼠之近端與中段大腸的大腸吸收細胞皆顯著下降。進一步分析大腸道上皮之腸幹細胞與前驅細胞數量，以細胞增生標記ki-67和 5-bromo-2-deoxyuridine進行標定，則無顯著差異。此外，Ndst4基因剔除小鼠之近端與中段大腸隱窩頂端的凋亡小體顯著增加，此現象並以活化態caspase 3染色進行確認。然而，檢查其它組織和器官之形態，並未發現顯著變異。此外，我們發現Ndst4基因剔除小鼠之近端大腸Muc2基因mRNA表現量顯著增高，此結果與組織學檢查之杯狀細胞增加一致。最後，我們也檢測大腸之Ndst家族其他成員表現量，發現Ndst4基因剔除並未使Ndst1-Ndst3基因表現量顯著變化，推測Ndst4於大腸之HSPG生合成過程具有其特定功能，並在大腸道分化與生理功能扮演重要的角色。 | zh_TW |
| dc.description.abstract | Colorectal cancer (CRC) originates from abnormal proliferation of epithelial cells and accumulation of many genetic aberration, including activation of oncogenes and inactivation of tumor suppressor genes. Our previous study seaked for CRC-associated tumor suppressor genes on chromosome 4 by loss of heterozygosity study. A putative tumor suppressor gene, namely N-deacetylase/N-sulfotransferase 4 (NDST4) was found at chromosome 4q26. NDST4 participates in biosynthesis of Heparan sulfate proteoglycans (HSPGs), resulting in N-acetylglucosamine (GlcNAc) N-deacetylation and N-sulfation. HSPGs play many important roles in development, growth, tumorigenesis, inflammation and microbial invasion. To study the physiological function of NDST4, we had produced a Ndst4 knockout (Ndst4-/-) mouse strain and aimed to phenotypic characterization in the study. First, the Ndst4-/- mice were fertile and developed normally. To compare the phenotypes between Ndst4-/- and WT mice, we conducted the modified-SHIRPA v1., complete blood count, biochemistry and histological analysis. There was no significant difference in modified-SHIRPA v1. analysis. Nevertheless, the number and percentage of eosinophils were significantly increased in Ndst4-/- female mice, and the concentration of high-density lipoprotein was significantly decreased in Ndst4-/- male mice when compared with their gender-matched wild type (WT) littermates. As for histological examination, the goblet cell density is significantly higher in the proximal and middle colon of Ndst4-/- mice. Consistantly, the colonocyte density was significantly lower in the proximal and middle colon of Ndst4-/- mice. However, there was no difference in length of crypt and intestinal progenitor cell with ki-67 and 5-bromo-2-deoxyuridine staining. Moreover, Ndst4 deficiency increased the basal level of apoptosis in the colonic mucosa. Whereae, there was no obvious aberration found in other organs and tissues by histological examination. Using real-time RT-PCR analyses, Muc2 expression was increased in the proximal colon of Ndst4-/- mice compared with WT mice. The result is compatible with the histological finding of increased goblet cell. On the other hand, the gene expression levels of Ndst1-Ndst3 were not significantly different between WT and Ndst4-/- mice. Taken together, the results in the study indicate that Ndst4 deficiency may influence HS chain modification of specific HSPGs that play a pivotal role in colonic epithelial differentiation and function. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T06:32:07Z (GMT). No. of bitstreams: 1 ntu-103-R01424012-1.pdf: 10523846 bytes, checksum: 61ea448dcd312a318845ca5c35400945 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 誌謝 i
中文摘要 ii 英文摘要 iv 縮寫對照表 vi 圖目錄 xii 表目錄 xiv 一. 緒論 1 1. 研究背景 1 1.1大腸直腸癌 1 1.2抑癌基因 2 2. 相關文獻回顧 2 2.1第四號染色體基因刪除 2 2.2 NDST (N-deacetylase/N-sulfotransferase)家族與NDST4 3 2.3 HSPG與癌症 4 2.4表現型分析 6 2.5大腸分化 7 2.6 腸道黏液系統 9 3 實驗室先前研究結果 11 3.1第四號染色體之失異合性檢測 11 3.2 Ndst4基因剔除小鼠 12 二. 研究目標 13 三. 材料方法 14 1. 實驗小鼠 14 2. Ndst4基因剔除小鼠表現型分析 14 2.1 Modified-SHIRPA v1.檢測 14 2.2血液檢測 14 2.3生化檢測 15 3. 5-bromo-2-deoxyuridine(BrdU)標記實驗 15 4. 組織處理及染色 15 4.1 組織處理 15 4.2 蘇木紫-伊紅染色(Hemotoxylin and Eosin stain) 16 4.3 阿爾斯藍-過碘酸希夫氏染色(Alcian blue and Periodic Acid Schiff Staining) 16 4.4 免疫組織化學染色(Immunohistochemistry stain) 17 5. RNA表現量分析 17 5.1 採取小鼠周邊血液之白血球 17 5.2 RNA萃取 18 5.3 反轉錄合成cDNA 18 5.4 定量反轉錄聚合酶連鎖反應 19 6. 統計分析 20 7. 試劑和抗體 20 四. 實驗結果 21 1. Ndst4基因剔除小鼠發育和生育能力 21 2. Ndst4基因剔除小鼠表現型分析 21 2.1 Modified-SHIRPA v1.檢測分析 22 2.2 血液學檢測分析 22 2.3 生化學檢測分析 22 3. 組織學檢測分析 23 3.1 缺乏Ndst4，其近端大腸與中段大腸之杯狀細胞顯著多於野生型 小鼠，而遠端大腸無顯著差異 23 3.2 缺乏Ndst4，其近端大腸與中段大腸之腸吸收細胞顯著少於野生 型小鼠，而遠端大腸無顯著差異 24 3.3 缺乏Ndst4，不影響腸道隱窩下層的腸幹細胞與前趨細胞數量 24 3.4 缺乏Ndst4，其近端大腸與中段大腸之凋亡小體顯著高於野生型 小鼠，而遠端大腸則無顯著差異 25 3.5 缺乏Ndst4不影響大腸上皮之Syndecan1的表現量 26 3.6 缺乏Ndst4，其大腸以外之組織與器官的形態學分析並無顯著差 異 26 4. 基因表現分析 28 4.1 缺乏Ndst4，其近端大腸之Muc2表現量顯著高於野生型小鼠， 而遠端大腸則無顯著差異 28 4.2 缺乏Ndst4，其近端大腸與遠端大腸之Hes1、Dll1、Klf4表現 量皆無顯著差異 29 4.3 分析Ndst4於不同器官與組織之表現量 29 4.4 Ndst4缺失並不影響其他Ndst家族成員之基因表現量 30 4.5 Ndst4表現量隨著近端大腸到遠端大腸有所不同，符合組織學檢 查之結果 30 4.6 Ndst1至Ndst4在不同組織或器官其表現量不一，符合過去文獻 研究之報告 31 五. 討論 32 六. 圖 39 七. 表 72 八. 參考文獻 81 九. 附錄 93 | |
| dc.language.iso | zh-TW | |
| dc.title | Ndst4基因剔除小鼠之表現型分析 | zh_TW |
| dc.title | Phenotypic analysis of Ndst4 knockout mice | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林淑華(Shu-Wha Lin),蘇剛毅(Kang-Yi Su),林素珍(Sue-Jane Lin) | |
| dc.subject.keyword | 大腸直腸癌,NDST4,基因剔除小鼠,表現型分析, | zh_TW |
| dc.subject.keyword | Colorectal cancer,NDST4,Gene knockout mouse,Phenotyping, | en |
| dc.relation.page | 96 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-08-06 | |
| 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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