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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/80661完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊鎧鍵(Kai-Chien Yang) | |
| dc.contributor.author | Chen-Ting Hung | en |
| dc.contributor.author | 洪振庭 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:12:07Z | - |
| dc.date.available | 2022-02-16 | |
| dc.date.available | 2022-11-24T03:12:07Z | - |
| dc.date.copyright | 2022-02-16 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-02-08 | |
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TGF-beta/SMAD Pathway and Its Regulation in Hepatic Fibrosis. J Histochem Cytochem 64, 157-167 (2016). 34. Xu, M.Y., et al. Stat3 signaling activation crosslinking of TGF-beta1 in hepatic stellate cell exacerbates liver injury and fibrosis. Biochim Biophys Acta 1842, 2237-2245 (2014). 35. Weston, C.R. Davis, R.J. The JNK signal transduction pathway. Curr Opin Cell Biol 19, 142-149 (2007). 36. Bataller, R., et al. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 112, 1383-1394 (2003). 37. Novo, E., et al. Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells. J Hepatol 54, 964-974 (2011). 38. Kluwe, J., et al. Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. Gastroenterology 138, 347-359 (2010). 39. Carballo, M., et al. 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STAT3: A key regulator in liver fibrosis. Ann Hepatol 21, 100224 (2020). 69. Wegrzyn, J., et al. Function of mitochondrial Stat3 in cellular respiration. Science 323, 793-797 (2009). 70. Danial, N.N. Rothman, P. JAK-STAT signaling activated by Abl oncogenes. Oncogene 19, 2523-2531 (2000). 71. Butturini, E., Carcereri de Prati, A. Mariotto, S. Redox Regulation of STAT1 and STAT3 Signaling. Int J Mol Sci 21(2020). 72. Li, L. Shaw, P.E. A STAT3 dimer formed by inter-chain disulphide bridging during oxidative stress. Biochem Biophys Res Commun 322, 1005-1011 (2004). 73. Xie, Y., Kole, S., Precht, P., Pazin, M.J. Bernier, M. S-glutathionylation impairs signal transducer and activator of transcription 3 activation and signaling. Endocrinology 150, 1122-1131 (2009). 74. Liu, Y., et al. Transforming growth factor-beta (TGF-beta)-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires Stat3 signaling activation. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/80661 | - |
| dc.description.abstract | "背景及目的 肝臟纖維化 (Liver fibrosis, LF) 常發生於肝臟受到長期的損傷像是病毒性肝炎及過度飲酒。然而，至今尚無有效治療肝纖維化的治療方式。 先前，本實驗室找到一個內質網蛋白thioredoxin domain containing 5 (TXNDC5)，亦是蛋白質雙硫鍵異構酶家族的一員，其被證實為造成心臟、肺臟及腎臟纖維化的重要媒介。本實驗中，我們以探討TXNDC5是否也具有潛力作為治療肝纖維化的標的蛋白為目標。 方法 利用組織學及轉錄組分析肝硬化病人肝臟。Col1a1-GFPTg, Alb-Cre;Rosa26-tdTomato 及 Tie2-Cre/ERT2;Rosa26-tdTomato 老鼠被應用於確認肝損傷後TXNDC5於肝臟中各細胞類型中的蛋白表現量。 同時，應用人類肝星狀細胞株中進行體外實驗研究。利用Col1a2-Cre/ERT2;Txndc5fl/fl (Txndc5cKO)及Alb-cre;Txndc5fl/fl (Txndc5Hep-cKO) 老鼠分別在肝星狀細胞(HSC)及肝細胞(Hepatocytes)剔除TXNDC5 基因。於實驗老鼠給予四氯化碳(Carbon tetrachloride, CCl4) 及膽管結紮(Bile duct ligation, BDL) 手術誘導其肝臟纖維化。利用組織染色, second harmonic generation (SHG) 影像以及轉錄/蛋白質分析定量肝臟纖維化程度。 結果 在人類及老鼠纖維化肝臟，TXNDC5顯著地被表現在病灶中，特別是活化態肝星狀細胞。在肝星狀細胞中，TXNDC5媒介TGFβ1刺激造成纖維化反應，包括細胞活化, 增生, 存活及細胞外基質生成。此外，過度表達TXNDC5也足以造成其細胞活化等促纖維化反應。於機制上， TGFβ1 誘導內質網壓力 (ER stress)增加及ATF6媒介的轉錄調節來誘導TXNDC5的表現。 另外，TXNDC5透過自身PDI活性調控下游相關的JNK及STAT3訊號，同時，透過此機制促進肝星狀細胞活化及賦予其抗凋亡能力。專一性地剔除肝纖維化老鼠中肝星狀細胞的TXNDC5可以回復肝臟纖維化。 結語 內質網蛋白TXNDC5透過自身氧化還原相關能力促使肝星狀細胞活化, 增生以及細胞外基質生成，進而導致肝臟纖維化。因此，針對TXNDC5來減緩肝臟纖維化可作為具潛力的治療方針。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T03:12:07Z (GMT). No. of bitstreams: 1 U0001-0802202211472800.pdf: 120166928 bytes, checksum: fc8cf707af3dcdeef64c777b343f013a (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | "Chapter 1 Introduction 1 1.1 Epidemiology of liver fibrosis 1 1.2 Hepatic stellate cell (HSC) is a major origin of myofibroblast upon liver fibrogenesis 1 1.3 Canonical and noncanonical TGFβ signaling in HSCs 2 1.4 Endoplasmic Reticulum stress-related liver fibrogenesis 4 1.5 Origin of reactive oxygen species (ROS) in HSCs 6 1.6 Redox-sensitive molecules: JNK and STAT3 8 1.7 Physiology and pathology of TXNDC5 9 1.8 Current therapeutic limitation in liver fibrosis 9 1.9 Aim of the study 10 Chapter 2 Materials and Methods 11 2.1 Study subjects of liver sample 11 2.2 LX-2 human hepatic stellate cell (LX-2 HSC) and primary human hepatic stellate (primary human HSC) culture 11 2.3 TGF1 stimulation in LX-2 HSCs and primary human HSCs 12 2.4 Pharmacological agent treatment in LX-2 HSCs 12 2.5 Lentiviral transduction in LX-2 HSCs and primary human HSCs 13 2.6 TXNDC5 promoter luciferase reporter activity assay 13 2.7 Cell viability assay 14 2.8 Cell apoptosis assay 14 2.9 Proliferation assay 15 2.10 Colony formation assay 15 2.11 Cellular and extracellular ROS detection assay 16 2.12 Electrophoretic mobility shift assay (EMSA) 17 2.13 Generation of experimental animals 17 2.14 Carbon tetrachloride (CCl4)-induced liver fibrosis 19 2.15 Bile duct ligation (BDL)-induced liver fibrosis 19 2.16 Blood biochemistry studies 19 2.17 Multiphoton microscopy and second-harmonic generation (SHG) imaging 20 2.18 Histological staining 20 2.19 Immunohistochemical (IHC) staining 21 2.20 Immunofluorescence (IF) staining 21 2.21 Immunoblot analysis 22 2.22 RNA isolation and quantitative real-time PCR (qPCR) 23 2.23 Statistical analyses 23 Chapter 3 Results 24 3.1 TXNDC5 is markedly upregulated in fibrotic human and mouse liver and plays a causal role in the development of LF 24 3.2 TXNDC5, enriched in activated HSCs at the fibrotic foci, is both essential and sufficient to trigger HSC activation, proliferation and ECM production 27 3.3 TXNDC5 triggers fibrogenic responses in HSCs through SMAD3-independent, non-canonical JNK signaling downstream of TGFβ pathway 28 3.4 TXNDC5 renders HSCs resistant to apoptosis by augmenting STAT3 signaling. 29 3.5 TXNDC5 promotes redox-dependent JNK and STAT3 activation in HSCs through its PDI activity 31 3.6 TGFβ1 triggers TXNDC5 expression via ER stress and activating transcription factor 6 (ATF6)-dependent transcriptional regulation 33 3.7 Targeted deletion of Txndc5 in HSCs ameliorates liver fibrosis 34 Chapter 4 Discussion 37 4.1 TXNDC5 as a novel target for liver fibrosis 37 4.2 TGF regulates canonical and noncanonical signaling at different time-point in HSCs 37 4.3 TGF induces activated ATF6 branches of ER stress pathway in HSCs 38 4.4 Thioredoxin domains (TRX) of TXNDC5 regulates downstream signaling pathway through its redox activity in HSCs 39 4.5 The causal relationship between TXNDC5, STAT3 and JNK in HSCs 40 4.6 Targeting TXNDC5 does not result in discernible adverse effect in vital organs 41 4.7 The deletion of TXNDC5 in HSC mitigates liver damage 42 4.8 The novel target for anti-fibrotic liver 43 REFERENCE 44 FIGURES AND TABLES 49" | |
| dc.language.iso | zh-TW | |
| dc.subject | TXNDC5 | zh_TW |
| dc.subject | 肝纖維化 | zh_TW |
| dc.subject | STAT3 | zh_TW |
| dc.subject | 內質網 | zh_TW |
| dc.subject | JNK | zh_TW |
| dc.subject | liver fibrosis | en |
| dc.subject | TXNDC5 | en |
| dc.subject | ER | en |
| dc.subject | JNK | en |
| dc.subject | STAT3 | en |
| dc.title | 靶向肝臟星狀細胞之內質網蛋白TXNDC5抑制非典型乙型轉化生長因子訊號以延緩肝臟纖維化 | zh_TW |
| dc.title | Targeting Endoplasmic Reticulum Protein TXNDC5 in Hepatic Stellate Cells Mitigates Liver Fibrogenesis by Repressing Non-Canonical Transforming Growth Factor-β Signaling | en |
| dc.date.schoolyear | 110-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 劉俊人(Cheng-Fu Chou),楊宏志(Ming-Yang Chih),蘇東弘(Meng-Hsiang Hsu),蔡丰喬(Ching-Chun Huang),許書豪 | |
| dc.subject.keyword | TXNDC5,肝纖維化,內質網,STAT3,JNK, | zh_TW |
| dc.subject.keyword | TXNDC5,liver fibrosis,ER,STAT3,JNK, | en |
| dc.relation.page | 92 | |
| dc.identifier.doi | 10.6342/NTU202200366 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2022-02-09 | |
| 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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