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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 | 陳宏文 | |
dc.contributor.author | Liang-Jie Wang | en |
dc.contributor.author | 王亮傑 | zh_TW |
dc.date.accessioned | 2021-06-16T17:40:40Z | - |
dc.date.available | 2012-08-19 | |
dc.date.copyright | 2012-08-19 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-08-14 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64322 | - |
dc.description.abstract | 細胞融合和細胞入侵在胎盤發育的過程扮演重要且不可或缺的角色。絨毛膜絨毛(chorionic villi)上的滋養葉胞層細胞 (cytotrophoblast)可透過細胞融合分化成多核的滋養葉融合層細胞 (syncytiotrophoblast),進而幫助養份和氣體的交換,另一方面,滋養葉胞層細胞透過分化形成外絨毛滋養細胞 (extravillous trophoblast),促使滋養細胞入侵到子宮組織,幫助母體和胎兒血液循環系統的交通。在我們過去的研究中發現,人類胎盤特殊轉錄因子GCM1 (Glial cells missing homolog 1)可透過控制融合蛋白syncytin-1和syncytin-2的基因表現來調控胎盤滋養葉細胞的細胞融合。值得一題的是,GCM1和syncytin-1蛋白都會在外絨毛滋養細胞中表現,然而,我們卻不知道它們在生理上的功能。為了探討此一問題,我們首先在胎盤細胞中證實GCM1具有促進胎盤細胞入侵的功能。我們進一步利用染色質免疫沉澱技術結合晶片分析(ChIP-chip analysis),鑑定發現HtrA4 (high temperature requirement A4)是GCM1獨特的標的基因,HtrA4蛋白具有絲氨酸蛋白酶的活性,透過切割fibronectin可幫助胎盤細胞的入侵功能。重要的是,透過免疫組織染色方法偵測到HtrA4蛋白位於胎盤和子宮的接觸面,並且發現HtrA4蛋白在缺氧環境的細胞和子癇先兆症病患的胎盤表現量明顯減少,顯示缺氧環境下HtrA4蛋白的減少可能造成外絨毛滋養細胞淺層入侵子宮組織,進而導致子癇先兆症。我們更進一步證實,HtrA4蛋白可直接和syncytin-1蛋白的SU區域結合,達到抑制細胞融合的功能。因此,HtrA4蛋白可能透過抑制細胞融合和促進細胞入侵的雙重角色,完成調控外絨毛滋養細胞分化的功能。在我們的研究中揭露了GCM1和HtrA4蛋白的新功能,具有調控外絨毛滋養細胞入侵的能力,並且證實異常HtrA4蛋白的表現可能導致子癇先兆症的形成。 | zh_TW |
dc.description.abstract | Cell-cell fusion and cell invasion are essential for placental development. Human cytotrophoblasts in the chorionic villi may undergo cell-cell fusion to form syncytiotrophoblast to facilitate nutrient-gas exchange or differentiate into extravillous trophoblasts (EVTs) to facilitate maternal-fetal circulation. In our previous studies, the placental transcription factor, glial cell missing 1 (GCM1), regulates syncytin-1 and -2 expression to mediate trophoblast fusion. Interestingly, GCM1 and syncytin-1 are also expressed in EVTs with unknown physiological functions. We firstly demonstrated that GCM1 promote placental cells invasion. We also performed ChIP-chip analysis and identify high temperature requirement A4 (HtrA4) as a GCM1 novel target gene, which encodes a serine protease facilitating cleavage of fibronectin and invasion of placental cells. Importantly, HtrA4 is immunolocalized in EVTs at the maternal-fetal interface and its expression is decreased by hypoxia and in preeclampsia, a pregnancy complication associated with placental hypoxia and shallow trophoblast invasion. We further demonstrate that HtrA4 interacts with SU domain of syncytin-1 and suppresses cell-cell fusion. Therefore, HtrA4 may be crucial for EVT differentiation by playing a dual role in prevention of cell-cell fusion of EVTs and promotion of their invasion into the uterus. Our study reveals a novel function of GCM1 and HtrA4 in regulation of trophoblast invasion and that abnormal HrtA4 expression may contribute to shallow trophoblast invasion in preeclampsia. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T17:40:40Z (GMT). No. of bitstreams: 1 ntu-101-D94442006-1.pdf: 1995081 bytes, checksum: 29257f0dbba18250864164bf2d396ec9 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | Table of Contents
Chinese abstract ………………………………………………………………………………………………….1 English abstract …………………………………………………………………………………………………..2 Chapter I: General Introduction …………………………………………………………………………..3 1. Extravillous differentiation …………………………………………………………………………4 2. Preeclampsia ……………………………………………………………………………………………..4 3. Factors involved in trophoblast invasion …………………………………………………...5 3.1 Matrix metalloproteinase ………………………………………………………………….5 3.2 Hormones and Growth factors …………………………………………………………..6 3.3 Rho family of the small guanosine triphosphatase …………………………….7 3.4 Transcription factors ………………………………………………………………………….7 4. Glial cells missing-1 (GCM1) ……………………………………………………………………….8 5. HtrA family ……..…………………………………………………………………………………………9 Experimental rationals and specific aims ……………………………………………………….11 Chapter II: Materials and Methods ……………………………………………………………………12 1. Plasmid constructs …………………………………………………………………………………..13 2. Cell culture, transfection, and lentivirus transduction ……………………………..13 3. Chromatin immunoprecipitation-on-chip (ChIP-chip) analysis …………………14 4. Cell invasion assay ……………………………………………………………………………………15 5. Immunohistochemistry, flow cytometry analysis, and single cell RT-PCR ..15 6. Preparation of GST fusion protein and HtrA4 recombinant protein …………17 7. Cell-cell fusion analysis and analysis of surface syncytin-1 ……………………….17 Chapter III: Results …………………………………………………………………………………………….19 1. GCM1 regulates placental cell invasion …………………………………………………….20 2. HtrA4 is a GCM1 target gene ……………………………………………………………………20 3. Expression of HtrA4 in human placenta ……………………………………………………22 4. Regulation of placental cell invasion by HtrA4 …………………………………………23 5. Decreased expression of HtrA4 by hypoxia and in preeclamptic placentas …………………………………………………………………………………………………24 6. HtrA4 suppresses cell-cell fusion mediated by syncytin-1 ………………………..25 Chapter IV: Discussion ………………………………………………………………………………………27 Figures ………………………………………………………………………………………………………………31 References ………………………………………………………………………………………………………..52 List of Figures Figure 1. GCM1 regulates placental cell invasion ……………………………………………….32 Figure 2. Flow chat of ChIP-chip …………………………………………………………………………35 Figure 3. Characterization of HtrA4 antibody …………………………………………………….36 Figure 4. Regulation of HtrA4 expression by GCM1 ……………………………………………37 Figure 5. Coexpression of GCM1 and HtrA4 in the interstitial EVTs of human placenta ……………………………………………………………………………………………..40 Figure 6. HtrA4 regulates placental cell invasion ………………………………………………..43 Figure 7. HtrA4 expression under hypoxia and in preeclampsia …………………………46 Figure 8. Regulation of syncytin-1-mediated cell-cell fusion by HtrA4 ……………….49 Figure 9. Model of regulation of EVT differentiation by GCM1 …………………………..51 | |
dc.language.iso | en | |
dc.title | GCM1標的基因high temperature requirement A4 (HtrA4)調控胎盤細胞融合及入侵的機制 | zh_TW |
dc.title | A novel GCM1 target gene, high temperature requirement A4 (HtrA4), regulates placental cell fusion and invasion. | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 張震東,李明亭,張功耀,張茂山 | |
dc.subject.keyword | 胎盤細胞融合,胎盤細胞入侵, | zh_TW |
dc.subject.keyword | GCM1,HtrA4,trophoblast, | en |
dc.relation.page | 60 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-08-15 | |
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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