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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林琬琬(Wan-Wan Lin) | |
dc.contributor.author | Yi Cheng | en |
dc.contributor.author | 程奕 | zh_TW |
dc.date.accessioned | 2021-06-17T06:28:21Z | - |
dc.date.available | 2021-10-03 | |
dc.date.copyright | 2018-10-03 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-08-17 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72197 | - |
dc.description.abstract | C型凝集素18 (C-type lectin 18, CLEC18)是C型凝集素受體中的新型受體,並擁有結合醣類的C-type lectin-like domain (CTLD)及Sperm-coating protein (SCP)結構。一直到最近人類CLEC18A的研究才有了第一篇的報導出現。人類的CLEC18基因坐落在染色體的16q22位置中,且基因簇包含CLEC18A、CLEC18B及CLEC18C三種基因, CLEC18A-1 為一種常見的CLEC18A多樣型,結構上CLEC18A共計有三個胺基酸與CLEC18A-1不同,分別是位在SCP 位置的Val118 → Ala118,Thr151 → Met151 及位在CTLD 區域的Ser339 → Arg339 。在人類CLEC18A廣泛分布在各個器官,但與人類不同,老鼠基因只有CLEC18A,且只表現在大腦、心臟及腎臟。研究更發現Ser339 → Arg339的改變會導致CLEC18A/18A-1有不同的醣類結合能力。由於肝臟纖維化及脂肪肝為兩種主要肝癌的前期病變,故我們利用hCLEC18A knock-in (KI)及hCLEC18A-1 KI的基因轉殖小鼠作為工具,來研究CLEC18A/18A-1參與肝纖維化及脂肪肝的病理角色。在本論文的第一部份,我們發現在膽管結紮手術(bile duct ligation, BDL)後的CLEC18A KI及CLEC18A-1 KI小鼠,顯著的比WT小鼠有較緩和的肝臟纖維化病理組織變化、較低的麩丙酮酸轉胺脢(ALT)、麩草醋酸轉胺脢(AST)、膽紅素、膽固醇血清濃度及死亡率。除此之外,手術後的CLEC18A KI及CLEC18A-1 KI小鼠,-SMA、collagen 1A1、periostin、CTGF、vimentin、elastin及PDGFR等肝臟纖維化指標蛋白及其基因表現量也較WT小鼠少。除此之外,在人類肝臟星狀細胞 (human hepatic stellate cells,LX2)使用小干擾RNA (small interfering RNA, siRNA)抑制CLEC18A的表現後,可以顯著增加PDGF及TGF誘導的細胞活化及分化,包括細胞遷移及纖維化蛋白的表現。在第二部分,我們使用methionine and choline deficient (MCD)及高脂飼料(HFD)誘發脂肪肝的實驗。在MCD實驗中,只有 CLEC18A-1呈現較WT小鼠嚴重的脂肪肝病變。同時我們發現在控制組的CLEC18A-1 KI小鼠血清中,也表現較低的膽固醇、肝油三酯及低密度膽固醇。在餵食MCD後,,促進脂質形成的轉錄因子ChREBP及其調控的基因MTTP 在CLEC18A-1 KI小鼠的肝臟中有顯著的增高;同時我們也發現內質網中兩種促脂肪形成的酵素HMGCR及SOAT,在CLEC18A-1 KI的小鼠肝臟有較高的基因表現量。除此之外,在高脂飲食誘導的小鼠脂肪肝實驗中,我們也發現只有CLEC18A-1 KI小鼠發展出較嚴重的脂肪肝、胰島素抗性及葡萄糖不耐的症狀。同時促進脂質分解的轉錄因子PPAR在CLEC18A-1 KI小鼠肝臟的表現量也比WT及CLEC18A KI小鼠低。總的來說, CLEC18A 及CLEC18A-1對肝臟纖維化有保護性的角色,而這作用可能是透過抑制PDGF及TGF活化肝臟星狀細胞而來;然而, CLEC18A-1似乎較 CLEC18A對脂肪肝的病程會有較不利的影響,產生較高的疾病嚴重程度。 | zh_TW |
dc.description.abstract | CLEC18 family is a novel polymorphic C-type lectin (CLEC) containing the conserved C-type lectin-like domain (CTLD) and the sperm-coating protein (SCP)/Tpx-1/Ag5/PR-1/Sc7 (TAPS) domain, also known as the cysteine-rich secretory proteins/antigen 5/pathogenesis-related 1 proteins (CAP) domain. In general, CTLD and SCP domain recognize glycans and lipids/sterols, respectively, and exert the ligand binding functions of CLRs. Human C-type lectin 18 (clec18) gene cluster contains clec18a, clec18b and clec18c three loci and is located in human chromosome 16q22. Structurally CLEC18A contains three amino acid residues distinct from CLEC18A-1: Val(118)→Ala(118) and Thr(151)→Met(151) in SCP domain and Ser(339)→Arg(339) in CTLD. Unlike human CLEC18A which is ubiquitously expressed, mouse CELC18A is only expressed in the brain, heart, and kidney. Until now the biological functions of CLEC18s are not investigated until a recent study demonstrated that the S339R339 mutation in CTLD leads to the differential binding affinities of CLEC18A/A-1 to various types of glycans. Since liver fibrosis and steatohepatitis are two major causes of the hepatocellular carcinoma development, here we used hCLEC18A knock-in (KI) and hCLEC18A-1 KI mice to evaluate the roles of CLEC18 in liver fibrosis and steatohepatitis. In the first part of this thesis, we applied the bile duct ligation (BDL) surgery to evaluate the roles of CLEC18A/18A-1 in liver fibrosis. We found that CLEC18A KI and CLEC18A-1 KI ameliorated BDL-induced liver fibrosis (i.e. collagen deposition and bile duct hyperplasia), clinical manifestation (i.e. increased serum levels of cholesterol, AST, ALT, and bilirubin), and mice death. In the liver lysates of operated mice, protein and/or gene expressions of fibrosis markers -SMA, collagen 1A1, periostin, CTGF, vimentin, elastin and PDGFR were alleviated in CLEC18A/18A-1 KI mice compared with WT mice. In addition, silence of the CLEC18A in human LX2 hepatic stellate cell (HSC) line resulted in more severe PDGF-BB- and TGF-induced HSC activation, including cell migration and fibrosis markers expressions. In the second part of this thesis, we utilized both methionine choline-deficient (MCD) and high fat diet (HFD) models to elucidate the roles of CLEC18A/18A-1 in hepatosteatosis. In normal diet situation, the CLEC18A-1 KI mice exhibited lower serum T-Cho, TG, and LDL level compared with WT mice. After the MCD treatment, CLEC18A-1 KI but not CLEC18A KI mice exhibited more severe MCD-induced fatty change score in liver. In addition, CLEC18A-1 KI induced higher expressions of lipogenic hepatic nuclear receptor ChREBP, its target gene MTTP and ER lipogenic enzymes HMGCR and SOAT. Except for the MCD treatment, CLEC18A-1 KI mice exhibited more severe microvascular fatty changes in livers after HFD treatment. Furthermore, increased insulin resistance and glucose intolerance as well as decreased expression of lipolytic PPAR gene expression in liver were found in CLEC18A-1 KI mice after HFD treatment. In conclusion, CLEC18A and CLEC18A-1 play protective roles in the progression of liver fibrosis, which might result from the inhibition of PDGF- and TGF-induced HSC activation. Nevertheless, CLEC18A-1 might also exhibit a more significant action than CLEC18A in the development of liver steatosis. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T06:28:21Z (GMT). No. of bitstreams: 1 ntu-107-R05443001-1.pdf: 8927575 bytes, checksum: 1af6d0830ceed373a31b9e6e0143f2d6 (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | Abbreviations ...………………………………………………………... 1
Abstract ………...………………………………………………............ 4 中文摘要 ………..…………………………………………...……........ 7 Introduction ……...………………………………………………......... 9 Specific Aims ……...………………………………………….………. 20 Materials and Methods ……...………………………………...…….. 22 Results Part. I ……………………..…………………………....……...… 35 Part. II ……………………..……...………………………......…. 42 Discussions ………………………………………………………...….. 48 Figures and Legends ............................................................................. 59 References .............................................................................................. 84 Appendix ............................................................................................... 92 | |
dc.language.iso | zh-TW | |
dc.title | 探討C型凝集素18參與肝臟纖維化及脂肪肝的角色 | zh_TW |
dc.title | The roles of CLEC18 in liver fibrosis and steatohepatitis | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 謝世良(Shie-Liang Hsieh),楊鎧鍵(Kai-Chien Yang),蔡丰喬(Feng-Chiao Tsai) | |
dc.subject.keyword | C型凝集素18A,C型凝集素18A-1,肝臟纖維化,脂肪肝, | zh_TW |
dc.subject.keyword | CLEC18A,CLEC18A-1,liver fibrosis,steatohepatitis,HSC,MCD,HFD, | en |
dc.relation.page | 100 | |
dc.identifier.doi | 10.6342/NTU201803746 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2018-08-17 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥理學研究所 | zh_TW |
顯示於系所單位: | 藥理學科所 |
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