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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 周祖述 | zh_TW |
| dc.contributor.advisor | Tzuu-Shuh Jou | en |
| dc.contributor.author | 許展彰 | zh_TW |
| dc.contributor.author | Jhan-Jhang Syu | en |
| dc.date.accessioned | 2023-09-05T16:08:15Z | - |
| dc.date.available | 2023-11-09 | - |
| dc.date.copyright | 2023-09-05 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-08-04 | - |
| dc.identifier.citation | 1. Satir P and Christensen ST (2007) Overview of structure and function of mammalian cilia. Annu Rev Physiol 69:377-400. https://doi.org/10.1146/annurev.physiol.69.040705.141236
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89213 | - |
| dc.description.abstract | 在細胞分化後的頂端區域有著一個特殊的胞器稱為初級纖毛。在之前的研究中發現，初級纖毛有別於運動用的纖毛是屬於靜態的、能感知和傳遞環境訊息的胞器，初級纖毛的生成及長度受到各種機制的嚴格調控，例如纖毛的生成及伸長會受到物質在鞭毛內輸送蛋白運輸的頻率或大小來控制，這些輸送蛋白運送材料也包含纖毛生長所必需的微管蛋白和訊息分子等。在本次研究中，我們發現在初級纖毛的細胞膜上被唾液酸聚醣修飾的蛋白質或是脂質與半乳糖凝集素8的交互作用會調控初級纖毛的生長。在細胞進行極化的過程中，我們觀察到分泌到細胞頂端區域外部的半乳糖凝集素8會隨著時間增加，同時這些細胞外的半乳糖凝集素8會結合到初級纖毛及初級纖毛根部的過度區，根據我們的觀察，這樣的結合會使初級纖毛出現快速生長的現象。透過實驗分析，我們發現半乳糖凝集素8會和脂筏的組成分子有一定程度的交互關係，如：神經節苷脂和小窩蛋白1等，這個結果可以支持我們的假說，即半乳糖凝集素8會結合在初級纖毛及初級纖毛根部的過度區。此外我們觀察到半乳糖凝集素8結合在初級纖毛後會擾亂初級纖毛過渡區的屏障功能，促使初級纖毛的快速生長。我們的研究還發現，初級纖毛過渡區的屏障功能是否健全取決於初級纖毛過度區中脂筏結構的完整性，在小窩蛋白1基因敲除和脂筏的藥理學抑制實驗均表現出類似於頂端添加重組半乳糖凝集素8的效果，即初級纖毛快速生長和初級纖毛過度區屏障功能受損，因此我們推論半乳糖凝集素8在初級纖毛短期快速生長上扮演一個重要的角色。後續，我們透過轉錄組分析和蛋白質組分析也發現，半乳糖凝集素8會和胰島素樣生長因子1受體有高度的親和性，同時胰島素樣生長因子1受體下游的蛋白激酶B被活化、Myc的訊號路徑活化和Myc蛋白質表現量增加，這些都暗示著半乳糖凝集素8和初級纖毛的交互作用會誘導細胞重新進入有絲分裂的循環週期。 | zh_TW |
| dc.description.abstract | Primary cilium is a specialized sensory organelle that transmits environmental information into cells. Its length is tightly controlled by various mechanisms such as the frequency or the cargo size of the intraflagellar transport trains which deliver the building materials such as tubulin subunits essential for the growing cilia. Here we show the sialoglycan interacting galectin 8 regulates the process of primary ciliogenesis. As the epithelia become polarized, there are more galectin 8 being apically secreted and these extracellular galectin 8 molecules apparently bind to a lipid raft enriched domain at the base of the primary cilia through interacting with lipid raft components ganglioside and caveolin 1. Furthermore, the binding of galectin 8 at this critical region triggers rapid growth of primary cilia by perturbing the barrier function of transition zone. Our study also demonstrates the functionality of this barrier depends on intact organization of lipid rafts at the cilia as genetically knockout of Cav1 and pharmacologically inhibition of lipid raft both phenocopy the effect of apical addition of recombinant galectin 8; i.e., rapid elongation of primary cilia and redistribution of cilial proteins from transition zone to the growing cilial trunk. We also investigated the cellular response after galectin 8 interacted with primary cilia through transcriptome and proteome analysis. The proteomics analysis implied Gal8 might interact with insulin-like growth factor 1 receptor (IGF1R) while the transcriptomic analysis showed Myc signaling pathway was up-regulated. Moreover, the protein kinase B (AKT) which had been reported as a downstream target of IGF1R was activated and the Myc protein level was increased. Our results imply that the interaction of galectin 8 with primary cilia induces cell entry into the cell cycle. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-05T16:08:15Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-09-05T16:08:15Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 論文審定書 I
中文摘要 II ABSTRACT III CONTENT 1 BBREVIATION 4 INTRODUCTION 5 Primary cilia structure and ciliogenesis 5 The function of transition zone on primary cilia 6 The galectin 8 and galectin protein families 7 The cell signaling on primary cilia 8 METHODS AND MATERIALS 11 Cell Culture 11 Antibodies and chemicals 11 Plasmids construction and recombinant protein purification 12 Generation of a MDCK clone stably expressing Arl13B-mCherry 13 GST fused Gal8 pull-down assay and Western blot 14 Immunoprecipitation of Gal8 secreted in the culture medium 14 Lipid-binding assay 15 Lipid floatation assay 15 Immunofluorescence staining and microscopy 15 Surface biotinylation and mass spectrometry 16 Lipid raft labeling with Cholera toxin subunit B 17 The lipid raft perturbation treatment 18 CRISPR/Cas9 knockout Cav1 18 Transcriptomic analysis and next-generation sequencing (NGS) 18 EdU staining and cell proliferation rate assay 19 Quantification of primary cilia length and statistical analyses 19 RESULTS 20 PART I. Galectin 8 promoted primary cilia elongation 20 Extracellular galectin 8 interacted with primary cilia membrane and promoted cilia elongation in polarized MDCK monolayer. 20 Apical domain Gal8 increased in vitro MDCK cell culture and in vivo murine developing renal tubules during the course of cilia lengthening. 22 Gal8 interacted with membranous ganglioside to promote primary cilia elongation. 22 Gal8 perturbed a lipid raft based barrier to promote primary cilia elongation. 24 Cav1 organized a lipid raft barrier on transition zone to restrict primary cilia growth 25 PART II. Extracellular galectin 8 promoted cell proliferation 27 Apical Gal8 interacted with primary cilia would induce AKT-Myc signaling activation 27 DISCUSSION AND PROSPECTIVES 29 FIGURES 33 Fig. 1 Knockdown endogenous Gal8 reduced ciliogenesis. 33 Fig. 2 Endogenous Gal8 was localized on primary cilia. 34 Fig. 3 Extracellular Gal8 interacted with primary cilia membrane. 35 Fig. 4 Extracellular Gal8 interacted with primary cilia membrane and regulated ciliogenesis. 36 Fig. 5 Extracellular Gal8 interacted with primary cilia membrane on apical domain. 37 Fig. 6 Recombinant Gal8 facilitated primary cilia lengthening in a dose-dependent manner. 38 Fig. 7 Recombinant Gal8 facilitated primary cilia lengthening through transient intermediate tubulin based structures. 39 Fig. 8 Recombinant Gal8 facilitated primary cilia lengthening in NIH3T3 and IMCD3 cells. 40 Fig. 9 Primary cilia resorption followed after recombinant Gal8 was removed. 41 Fig. 10 Gal8 was secreted to apical domain during epithelial polarization. 42 Fig. 11 Both the primary cilia length and the number of ciliated cells increased during epithelial polarization. 43 Fig. 12 Gal8 was secreted to the apical domain during mouse kidney development. 44 Fig. 13 Gal8 interacted with the primary cilia and this interaction contributed to the cilia-elongating effect of Gal8. 45 Fig. 14 Recombinant Gal8 specifically interacted with ganglioside-GD3. 46 Fig. 15 Ganglioside-GD3 was localized on the primary cilia base. 47 Fig. 16 Several gangliosides were localized on the primary cilia. 48 Fig. 17 Gal8 interacted with gangliosides on the primary cilia and this interaction contributed to the cilia-elongating effect of Gal8. 49 Fig. 18. Scheme of the strategy used to identify apical interactome for galectin 8. 50 Fig. 19 The apical Gal8-interacting plasma membrane candidates were identified by mass spectrometry analysis. 51 Fig. 20 Gal8 interacted and co-migrated with lipid raft scaffold proteins 52 Fig. 21 Gal8 interacted with lipid raft on primary cilia. 53 Fig. 22 Gal8 interacted with primary cilia at the transition zone. 54 Fig. 23 Lipid raft disruption induced primary cilia elongation and caveolin 1 translocation. 55 Fig. 24 Caveolin 1 is localized on primary cilia. 56 Fig. 25 Caveolin 1 depletion induced primary cilia elongation. 57 Fig. 26 Transcriptomic analysis of MDCK cells after Gal8 treatment. 58 Fig. 27 Gal8 promote cell proliferation at early stage. 59 Fig. 28 Both of phosphorylated AKT and Myc protein levels were increased after Gal8 treatment. 60 TABLES 61 Table 1. Candidate list for apical interacting partners of galectin 8 61 Table 2. Candidate list for gene expression induced by galectin 8 65 RFERENCES 66 | - |
| dc.language.iso | en | - |
| dc.subject | 神經節苷脂 | zh_TW |
| dc.subject | 脂筏 | zh_TW |
| dc.subject | 初級纖毛過渡區 | zh_TW |
| dc.subject | 初級纖毛 | zh_TW |
| dc.subject | 小窩蛋白1 | zh_TW |
| dc.subject | 半乳糖凝集素8 | zh_TW |
| dc.subject | ganglioside | en |
| dc.subject | lipid raft | en |
| dc.subject | transition zone | en |
| dc.subject | primary cilia | en |
| dc.subject | galectin 8 | en |
| dc.subject | caveolin 1 | en |
| dc.title | 與脂筏交互作用的Galectin8調控初級纖毛生長之研究 | zh_TW |
| dc.title | Lipid raft interacting galectin 8 regulates primary ciliogenesis | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 蔡欣祐;鄭永銘;葉秀慧;陳佑宗 | zh_TW |
| dc.contributor.oralexamcommittee | Hsin-Yue Tsai;Yung-Ming Jeng;Shiou-Hwei Yeh;You-Tzung Chen | en |
| dc.subject.keyword | 初級纖毛,初級纖毛過渡區,脂筏,神經節苷脂,半乳糖凝集素8,小窩蛋白1, | zh_TW |
| dc.subject.keyword | primary cilia,transition zone,lipid raft,ganglioside,galectin 8,caveolin 1, | en |
| dc.relation.page | 72 | - |
| dc.identifier.doi | 10.6342/NTU202302590 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2023-08-04 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 分子醫學研究所 | - |
| Appears in Collections: | 分子醫學研究所 | |
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| File | Size | Format | |
|---|---|---|---|
| ntu-111-2.pdf | 4.79 MB | Adobe PDF | View/Open |
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