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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 莊雅惠 | |
dc.contributor.author | Ming-Hung Hung | en |
dc.contributor.author | 洪明宏 | zh_TW |
dc.date.accessioned | 2021-06-16T13:18:16Z | - |
dc.date.available | 2018-09-24 | |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-07-27 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/61909 | - |
dc.description.abstract | Cullin 4B (Cul4B)屬於Cullin 4B-RING E3 ubiquitin ligase (CRL4B) complex中的骨架蛋白,可以將細胞內蛋白質泛素化(ubiquitination)使其被proteasome降解或執行其他功能。Cul4B調控的蛋白質包括調節細胞週期與DNA複製相關的蛋白質。人類的Cul4B基因突變時會罹患X-linked intellectual disability (XLID),這類病人的周邊血液中單核球增加,表示Cul4B突變可能導致單核球增生。有研究發現以shRNA調降巨噬細胞株(RAW264.7)中Cul4B的表現後,在LPS刺激下巨噬細胞株產生的TNF-α減少。綜合以上結果表示Cul4B可能會影響單核球或巨噬細胞的發育及免疫功能。然而,單核球與巨噬細胞對於先天性免疫十分的重要,在此我們製造出骨髓性特異性Cul4B缺失(LysMCreKI/KI Cul4bf/y or f/f; CKO)小鼠來研究Cul4B缺失對於先天性免疫的影響。首先,我們確認CKO小鼠的Cul4B的確特異性缺失於骨髓性白血球中,與正常小鼠比較,CKO小鼠的骨髓細胞數與周邊血全血球計數上也無明顯的差異,表示CKO小鼠沒有明顯血球發育問題。然而我們將LPS注射入小鼠腹腔引起急性腹膜炎後,CKO小鼠體重下降幅度較正常小鼠大,並且在腹腔當中有較多的免疫細胞。但單一免疫細胞分泌發炎細胞激素(TNF-α, IL-6)的能力較差。而在體外細胞實驗中證實缺少Cul4B的巨噬細胞經LPS刺激後所分泌TNF-α及IL-6較少,但CKO的巨噬細胞比起正常小鼠較易進行DNA複製而加快細胞週期而使增生速率加快。因此,骨髓特異性Cul4B缺失小鼠在LPS誘發腹膜炎的反應會比較嚴重。而在細胞實驗中發現Cul4B的缺失影響巨噬細胞DNA複製進而使其加速增生與抑制其分泌發炎細胞激素。我們的研究成果發現Cul4B或可能其他Cullin家族的成員在免疫反應中亦扮演角色。 | zh_TW |
dc.description.abstract | Cullin 4B (Cul4B), one member of cullin family, is a scaffold protein of Cullin4B-RING-E3 ligase complex which ubiquitinate intracellular protein. The targets for cul4B include cell cycle regulation proteins and some DNA replication-related molecules. Patients with defect or mutation of Cul4B have increased frequency and numbers of peripheral monocytes. In addition, RAW264.7 macrophages with knockdown of cul4B expression by shRNA secrete lower level of TNF-α. These results indicated that Cul4B would affect the development and immune function of monocytes/macrophages which are very important for innate immunity. In this study, we generated a myeloid-specific Cul4B deficient mice (LysMCreKI/KI Cul4bf/y or f/f; CKO) to investigate the influence of Cul4B defect on innate immunity. At first, we confirmed that Cul4B gene was deleted in only myeloid cells of CKO mice. We found the number of bone marrow cells and complete blood count and differential count of peripheral blood were no difference in CKO and control mice, suggesting that Cul4B defect on myeloid cells did not affect the development of blood cells. However, after an intraperitoneal injection of LPS, significantly decreased in the body weight and increased immune cells in peritoneal cavity of CKO mice were observed. Surprisingly, each peritoneal exudate cell in LPS injected CKO mice produced fewer proinflammatory cytokines TNF-α and IL-6 than control mice. Furthermore, bone marrow derived macrophages from CKO mice secreted fewer TNF-α and IL-6 upon LPS stimulation but proliferated faster due to the cell cycle acceleration. Given our findings, myeloid-specific Cul4b deficiency worsened LPS induced acute peritonitis. In macrophages, Cul4B deficiency enhanced DNA replication and proliferation but decreased production of proinflammatory cytokines. Our data highlights the new role of Cul4B and maybe other members of cullin family in the immune responses. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T13:18:16Z (GMT). No. of bitstreams: 1 ntu-102-R00424020-1.pdf: 3960262 bytes, checksum: 71c7c7ac6f988f66f35cdbaeb0dd3cf4 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 摘要 i
Abstract ii 縮寫對照表 iv 目錄 v 表目錄 viii 圖目錄 ix 第一章 研究背景 1 1.1 Cullin family之研究 1 1.2 Cul4B之研究 1 1.3 Cre-lox基因重組系統 2 1.4 條件式基因剔除小鼠 3 1.5 骨髓特異性基因剔除小鼠 4 1.6 先天性免疫 4 1.7 Toll like receptors (TLRs) 5 1.8 巨噬細胞 6 1.9 Macrophage colony stimulating factor (MCSF) 6 1.10 細胞週期 7 1.11 研究目的 7 第二章 材料與方法 9 2.1 實驗用小鼠 9 2.2 抽取小鼠尾巴DNA 9 2.3 腹膜滲出細胞收集 9 2.4 腹膜滲出細胞中顆粒球純化 10 2.5 L929 conditioned medium製備 10 2.6 由骨髓細胞分化之巨噬細胞(Bone marrow derived macrophage;BMMs)培養流程 10 2.7 細胞抹片製作 11 2.8 脾臟細胞製備 11 2.9 Genomic DNA萃取 11 2.10 LysMCre基因定型 12 2.11 Multiplex PCR材料與反應條件 12 2.12 小鼠基因型(Genotype)判讀 12 2.13 細胞RNA萃取 13 2.14 RNA反轉錄 13 2.15 cDNA PCR 13 2.16 以即時定量反轉錄聚合酶連鎖反應偵測TNF-α與IL-6之mRNA的表現量 14 2.17 流式細胞儀(Flow cytometry)分析細胞表面抗原 14 2.18 周邊血白血球分類計數 15 2.19 細胞吞噬能力試驗(Phagocytosis test) 15 2.20 [3H]-thymidine incorporation細胞增生實驗 15 2.21 細胞週期分析 16 2.21.1 準備樣本 16 2.21.2 PI(Propidium iodide)染色 16 2.21.3 FACS (fluorescence-activated cell sorting)分析 16 2.22 以LPS誘發小鼠腹膜炎 17 2.23 LPS刺激巨噬細胞 17 2.24 細胞激素測定 17 2.25 繪圖及統計分析 17 第三章 實驗結果 18 3.1 確認CKO小鼠為骨髓性特性缺失Cul4B小鼠 18 3.2 骨髓性特異性缺失Cul4B的小鼠無明顯之先天性缺陷及血球發育問題 18 3.3 在thioglycollate誘發腹膜炎之CKO小鼠腹腔內顆粒球數增加。 19 3.4 在LPS誘發腹膜炎之CKO小鼠腹腔內腹膜滲出細胞增加但單一顆細胞分泌較少的TNF-α及IL-6。 19 3.5 Cul4B 缺失使巨噬細胞分泌TNF-α及IL-6的能力下降但不影響TLR-4的表現 21 3.6 Cul4B 缺失促使巨噬細胞增生 22 3.7 缺乏Cul4B會使巨噬細胞加快進行DNA複製以利細胞增生,但不影響其細胞凋亡。 23 3.8 Cul4B 缺失不影響巨噬細胞之吞噬功能 24 第四章 討論 26 附表 30 附圖 33 參考文獻 47 附錄 57 | |
dc.language.iso | zh-TW | |
dc.title | 以條件式基因剔除小鼠探討Cullin 4B缺失對於先天性免疫反應之影響 | zh_TW |
dc.title | Study on the influence of Cullin 4B defect on the innate response of the conditional knock-out mice | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林淑華,徐立中,陳俊任 | |
dc.subject.keyword | 先天性免疫反應,骨髓特異性缺失小鼠,腹膜炎小鼠模式,Cul4B,巨噬細胞, | zh_TW |
dc.subject.keyword | innate immune response,LysMCre,myeloid-specific knockout mice,experimental peritonitis mouse model,Cul4B,macrophage, | en |
dc.relation.page | 59 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2013-07-29 | |
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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