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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 伍安怡 | |
dc.contributor.author | Wen-Yu Chen | en |
dc.contributor.author | 陳文裕 | zh_TW |
dc.date.accessioned | 2021-06-17T06:13:07Z | - |
dc.date.available | 2024-03-05 | |
dc.date.copyright | 2019-03-05 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-10-04 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/71876 | - |
dc.description.abstract | 我們產製了人類DC-SIGN基因轉殖小鼠,其腎小管上皮細胞表現了DC-SIGN轉殖基因。本研究以靜脈注射白色念珠菌感染轉殖小鼠來研究DC-SIGN如何影響全身性念珠菌感染之致病機轉。我們發現白色念珠菌感染會導致轉殖小鼠及同窩小鼠腎臟之纖維化,而轉殖小鼠比起同窩小鼠的腎臟有較低的Acta2, Col1a2, Col3a1及Col4a1 mRNA表現量。KIM-1蛋白,一個腎臟受損的常用指標,以及Kim1, Tnf, Il6及Tgfb1 mRNA 之表現量在感染的轉殖小鼠較低,而Il10 mRNA表現量則與同窩小鼠相似。在感染的轉殖小鼠及同窩小鼠中,浸潤至腎臟的CD45+ 免疫細胞負責產生TNF, IL-6及IL-10,而表現LTL之近端腎小管上皮細胞則負責產生TGF-β1。表現DC-SIGN的腎小管上皮細胞在體外感染白色念珠菌後,會產生較低量的TGF-β1。以TGF-β中和抗體注射小鼠,我們的實驗證明了TGF-β對於白色念珠菌所誘發的腎臟損傷及纖維化之形成是非常重要的。另外,我們以免疫組織染色染腎臟組織切片觀察到感染的轉殖小鼠其腎臟的Raf-1及p38磷酸化有顯著的增加,而腎臟的ERK1/2及JNK磷酸化則是感染的同窩小鼠較轉殖小鼠明顯。值得注意的是,將感染的轉殖小鼠以Raf-1抑制劑處理後,會增加其腎臟的Tgfb1, Kim1及Acta2 mRNA表現量。以上的結果顯示DC-SIGN訊息傳遞會活化Raf-1及p38,而抑制ERK1/2及JNK磷酸化,進而降低TGF-β1產生,藉此減緩白色念珠菌所誘發的腎臟纖維化。本研究的結果首次揭露DC-SIGN對於白色念珠菌所誘發的腎臟纖維化之影響。 | zh_TW |
dc.description.abstract | We generated a human dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN) transgenic mouse in which renal tubular epithelial cells expressed DC-SIGN. Transgenic mice were infected with Candida albicans intravenously to study how DC-SIGN expression affects the pathogenesis of systemic candidiasis. We discovered that while C. albicans infection induced renal fibrosis in both transgenic and littermate control mice, the transgenic mice had significantly less Acta2, Col1a2, Col3a1 and Col4a1 transcripts compared to the controls. KIM-1, an emerging biomarker for kidney injury, along with Tnf, Il6 and Tgfb1 transcripts were lower in infected transgenic mice yet that of Il10 remained comparable to controls. While renal CD45+ infiltrating cells were the source of Tnf, Il6 and Il10, LTL+ renal proximal tubular epithelial cells were TGF-β1 producers in both infected transgenic and littermate controls. In vitro study showed that DC-SIGN-expressing primary tubular epithelial cells produced less TGF-β1 upon C. albicans infection. Employing anti-TGF-β neutralizing antibody we demonstrated that production of TGF-β was key to C. albicans-induced renal fibrosis and injury. Infection of transgenic mice induced in the kidney a marked increase of phosphorylated Raf-1 and p38. However, ERK1/2 and JNK phosphorylation was more pronounced in infected-littermate controls. Interestingly, treating infected transgenic mice with Raf-1 inhibitor increased the levels of Tgfb1, Kim1 and Acta2 transcripts. These results indicate that DC-SIGN signaling, through activating Raf-1 and p38 and suppressing JNK and ERK1/2 phosphorylation, reduces TGF-β1 production and C. albicans-induced renal fibrosis. Our study reveals for the first time the effect of DC-SIGN expression on C. albicans-induced renal fibrosis. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T06:13:07Z (GMT). No. of bitstreams: 1 ntu-107-D98449004-1.pdf: 22669989 bytes, checksum: 441f46c8113753b6a4d833261f7e926f (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii Abstract iv Table of Contents vi Chapter 1 Introduction 1 1.1 Candida albicans 2 1.2 DC-SIGN 3 1.2.1 DC-SIGN expression on immune cells 3 1.2.2 DC-SIGN interacts with a range of pathogens 4 1.2.3 DC-SIGN expression on non-immune cells 5 1.2.4 Effects of DC-SIGN on immune response 5 1.2.5 DC-SIGN-mediated signaling 6 1.3 Renal fibrosis 8 1.3.1 Myofibroblast: the key mediator of fibrosis 8 1.3.2 Factors causing fibrosis 9 Chapter 2 Materials and Methods 11 2.1 Materials 12 2.1.1 Ethics statement 12 2.1.2 Mice 12 2.1.3 Antibodies used in immunohistochemical staining, immunofluorescence staining, cell sorting and Western blotting 13 2.1.4 Buffers and culture medium 15 2.1.5 Primer sequences used in qPCR 16 2.2 Methods 18 2.2.1 RT-PCR 18 2.2.2 Immunohistochemical staining 18 2.2.3 Immunofluorescence staining 19 2.2.4 Fungus and infection 21 2.2.5 Assessment of collagen deposition in kidney 21 2.2.6 Isolation, phenotyping and sorting of renal infiltrating cells 21 2.2.7 Quantitative PCR (qPCR) 22 2.2.8 Mouse KIM-1 ELISA assay 22 2.2.9 Neutralization of TGF-β 23 2.2.10 Isolation of primary renal tubular epithelial cells 23 2.2.11 Western blotting 24 2.2.12 Mouse TGF-β1 ELISA assay 25 2.2.13 Inhibition of Raf-1 25 2.2.14 Statistics 25 Chapter 3 Results 26 3.1 Generation of hDC-SIGN transgenic mice 27 3.2 hDC-SIGN decreases C. albicans-induced collagen deposition 27 3.3 hDC-SIGN expression alleviates myofibroblast formation and renal injury in C. albicans-infected mice 28 3.4 The percentages and absolute numbers of renal infiltrating cells are comparable in C. albicans-infected hDC-SIGN transgenic mice and littermate controls. 29 3.5 The levels of chemokine and chemokine receptor transcripts in the kidneys of hDC-SIGN transgenic mice and littermate controls after C. albicans infection 30 3.6 Transgenic mouse kidneys have lower levels of TNF, IL-6 and TGF-β1 in the late phase of infection 31 3.7 Renal proximal tubular epithelial cells in transgenic mice produce less TGF-β1 after C. albicans infection 31 3.8 Neutralizing TGF-β alleviates C. albicans-induced renal fibrosis development upon infection 32 3.9 DC-SIGN-expressing renal proximal tubular epithelial cells produce less TGF-β1 after C. albicans infection 33 3.10 Raf-1 and p38 phosphorylation is prominent in the kidney of DC-SIGN transgenic mice after C. albicans infection 33 3.11 Raf-1 inhibitor increases collagen deposition, TGF-β1 expression and worsens renal injury 34 Chapter 4 Discussion 36 4.1 Modulation of DC-SIGN on non-immune cells 37 4.2 Infection-induced renal fibrosis 38 4.3 TGF-β1-producing cells 40 4.4 TGF-β as a therapeutic target 41 4.5 DC-SIGN-mediated signaling 42 4.6 Summary 44 Chapter 5 References 45 Chapter 6 Figures 57 Chapter 7 Appendix 116 | |
dc.language.iso | en | |
dc.title | DC-SIGN下游訊號藉由活化Raf-1以減緩全身性念珠菌症所引起之腎臟纖維化 | zh_TW |
dc.title | Human dendritic cell-specific ICAM-3-grabbing non-integrin downstream signaling alleviates renal fibrosis via Raf-1 activation in systemic candidiasis | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 林水龍,繆希椿,徐立中,陳宜君 | |
dc.subject.keyword | 白色念珠菌,DC-SIGN,Raf-1,腎臟纖維化,TGF-β1, | zh_TW |
dc.subject.keyword | Candida albicans,DC-SIGN,Raf-1,Renal fibrosis,TGF-β1, | en |
dc.relation.page | 119 | |
dc.identifier.doi | 10.6342/NTU201804175 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2018-10-05 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 免疫學研究所 | zh_TW |
顯示於系所單位: | 免疫學研究所 |
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