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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 | Tzu-Han Lee | en |
dc.contributor.author | 李姿涵 | zh_TW |
dc.date.accessioned | 2021-06-17T07:12:14Z | - |
dc.date.available | 2021-02-23 | |
dc.date.copyright | 2021-02-23 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-12-30 | |
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Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicol Pathol 39, 916-924 (2011). 52. Larsson, J., et al. Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. EMBO J 20, 1663-1673 (2001). 53. B, B.M., et al. Animal models of fibrotic lung disease. Am J Respir Cell Mol Biol 49, 167-179 (2013). 54. Raghu, G., et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 183, 788-824 (2011). 55. Homer, R.J., Elias, J.A., Lee, C.G. Herzog, E. Modern concepts on the role of inflammation in pulmonary fibrosis. Arch Pathol Lab Med 135, 780-788 (2011). 56. Carrington, R., Jordan, S., Pitchford, S.C. Page, C.P. Use of animal models in IPF research. Pulm Pharmacol Ther 51, 73-78 (2018). 57. Hashimoto, N., et al. Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 43, 161-172 (2010). 58. Choi, S.H., et al. A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis. Clin Cancer Res 21, 3716-3726 (2015). 59. Lee, T.H., et al. Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFbeta signaling through TGFBR1 stabilization. Nat Commun 11, 4254 (2020). | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72971 | - |
dc.description.abstract | 肺纖維化可以是原發性 (idiopathic pulmonary fibrosis, IPF)或次發於其他肺部疾病,如急性呼吸窘迫症候群 (acute respiratory distress syndrome, ARDS)及嚴重特殊傳染性肺炎 (COVID-19),或其他系統性疾病,如多發性硬化症 (multiple sclerosis)及類風溼性關節炎 (rheumatoid arthritis)。肺纖維化會破壞肺泡組織結構,於間質產生嚴重結痂 (scar),導致肺泡氣體交換功能受阻及肺活量下降,進而造成血氧降低、呼吸困難及運動耐受力降低的症狀。除了呼吸系統的症狀,肺纖維化也會導致肺動脈高壓、右心衰竭,以及肺栓塞風險的增加。由於肺纖維化引起的健康影響與死亡率十分嚴重,病人被診斷為 IPF後其中位存活時間 (medium survival time)只有二到四年,盛行率也隨人口老化逐 漸攀升,是醫療與公衛上亟待解決的課題。然而,目前針對肺纖維化的治療選擇非常有 限,需要更多研究來找尋引發肺纖維化的新型因子及致病機轉,來發展治療肺纖維化的新型藥物。 我們的研究團隊先前發現一個內質網蛋白 Thioredoxin Domain Containing 5 (TXNDC5)在心臟纖維化的過程扮演重要角色。我們發現 TXNDC5在纖維化的心臟組織中表達量顯著上升,且能透過兩種不同機轉促進心肌纖維化:其一能透過增加纖維母細胞中氧化壓力,激活 JNK而使纖維母細胞活化增生,其二是能透過其protein disulfide isomerase活性來協助 ECM蛋白折疊,增加 ECM分泌的產 量。我們在小鼠進行 Txndc5基因剔除後,發現心臟受 beta-agonist刺激造成的心肌功能受損及心肌纖維化都能獲得改善。透過生物資訊學的分析,我們發現 TXNDC5在 IPF病患的肺組織中高度增加,其表現量亦與其他肺纖維化相關蛋白呈高度正相關。我們推測,TXNDC5在肺纖維化可能也具有重要角色。我們的實驗結果發現在肺纖維化可能也具有重要角色。我們的實驗結果發現IPF病病患肺組織及肺纖維母細胞中的患肺組織及肺纖維母細胞中的TXNDC5基因及蛋白表達量比正常人高。基因及蛋白表達量比正常人高。TXNDC5高度且特定表現在高度且特定表現在bleomycin誘導之小鼠肺纖維化模型中的肺纖維母細胞。誘導之小鼠肺纖維化模型中的肺纖維母細胞。TXNDC5主要透過影響肺纖維母細胞中主要透過影響肺纖維母細胞中TGFBR1的穩定性及表現量來強化的穩定性及表現量來強化TGFβ訊息傳遞路徑,造成肺纖維母細胞的大量活化增生及胞外基質堆積,引起肺纖維化。訊息傳遞路徑,造成肺纖維母細胞的大量活化增生及胞外基質堆積,引起肺纖維化。在小鼠的肺纖維化動物模型中也證實,利用誘導型在小鼠的肺纖維化動物模型中也證實,利用誘導型CRISPR/Cas9基因編輯技術敲基因編輯技術敲除纖維母細胞中除纖維母細胞中Txndc5基因表現,能有效減緩肺纖維化之進程並改善肺功能。綜基因表現,能有效減緩肺纖維化之進程並改善肺功能。綜合以上結果顯示,抑制TXNDC5活性可望能作為肺纖維化病患的新型治療藥物。 | zh_TW |
dc.description.abstract | RATIONALE: Pulmonary fibrosis (PF) has become a major and growing public health problem. PF can be idiopathic or secondary to various diseases such as acute respiratory distress syndrome and COVID-19. PF can distort pulmonary architecture and cause excessive scarring which leading to impaired lung function and alveolar gas exchange, finally resulting in hypoxemia, dyspnea and exercise intolerance. In spite of the advances in medicine, the incidence and mortality rate of PF remain high and options for PF therapeutics are very limited. There is a clear need to identify novel mediators and pathways of lung fibrosis to develop therapies to improve the outcomes of PF patients. Recently, our group has identified thioredoxin domain containing 5 (TXNDC5), a cardiac fibroblast (CF)-enriched endoplasmic reticulum (ER) protein, as a novel mediator of cardiac fibrosis. Through the bioinformatic approach, we have found that TXNDC5 was highly up-regulated and positively correlate with extracellular matrix (ECM) proteins in lung tissues from patients with idiopathic pulmonary fibrosis (IPF). Based on these findings, we hypothesize that TXNDC5 could also contribute to the development of lung fibrosis. METHODS: To investigate the role of TXNDC5 in vivo, WT, Txndc5-/- and fibroblasts-specific Txndc5 deletion (Col1a2-Cre/ERT2*Txndc5fl/fl) mice were subjected to intratracheal bleomycin (BLM, 3mg/kg) treatment. The extent and functional consequences of pulmonary fibrosis were evaluated using histological study, immunofluorescence, pulmonary function test, and transcript analysis. To determine the molecular mechanisms by which TXNDC5 regulates lung fibroblasts in vitro, lentiviral vectors was used to knockdown or overexpress TXNDC5 in primary human pulmonary fibroblasts (HPF-a). Primary mouse lung fibroblasts isolated from WT and Txndc5-/- mice were used for mechanistic investigations. RESULTS: Here we show that TXNDC5 is highly upregulated in the lung fibroblasts from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 significantly reduces the extent of PF and preserves lung function in mice treated with BLM. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGF 1 canonical and non-canonical signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGF 1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Furthermore, inducing fibroblast-specific deletion of Txndc5 lessons the progression of BLM-induced PF and lung function deterioration. CONCLUSIONS: The present study revealed a novel role for TXNDC5 in the development of PF. TXNDC5 increases in fibrotic lungs and promotes pulmonary fibroblast activation, proliferation and ECM production by enhancing TGFBR1 expression and stabilization. Targeted deletion of Txndc5 protects against bleomycin-induced PF and lung dysfunction. Therefore, targeting TXNDC5 could be a novel therapeutic approach against PF. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T07:12:14Z (GMT). No. of bitstreams: 1 U0001-2912202013220600.pdf: 6347309 bytes, checksum: e3aaab4e89495066dcfaa5f92b47533f (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | 口試委員審定書...................................................................... i 中文摘要.......................................................................... ii ABSTRACT.......................................................................... iv CONTENTS.......................................................................... vi LIST OF FIGURES.................................................................... x Chapter 1 Introduction............................................................. 1 1.1 Pulmonary fibrosis............................................................. 1 1.1.1 Idiopathic pulmonary fibrosis (IPF).......................................... 2 1.2 Mechanism underlying pulmonary fibrosis........................................ 4 1.2.1 The activation of TGFb in pulmonary fibrosis................................. 5 1.2.2 TGFb signaling pathway....................................................... 6 1.2.3 Endoplasmic Reticulum (ER) stress and pulmonary fibrosis..................... 7 1.3 Limitation in treating pulmonary fibrosis...................................... 9 1.4 TXNDC5........................................................................ 10 1.4.1 TXNDC5 in pathology......................................................... 10 1.5 Aim of the study.............................................................. 11 Chapter 2 Materials and Methods................................................... 12 2.1 Human lung tissues............................................................ 12 2.2 Txndc5-/-, Txndc5fl/fl and cell type-specific Txndc5cKO mice.................. 12 2.3 Reporter mouse models......................................................... 14 2.4 Bleomycin-induced lung fibrosis model......................................... 15 2.5 in vivo microCT scanning...................................................... 15 2.6 ex vivo microCT scanning...................................................... 15 2.7 Lung function tests........................................................... 16 2.8 Bronchoalveolar lavage........................................................ 16 2.9 Hydroxyproline assay.......................................................... 17 2.10 Histology.................................................................... 17 2.11 Immunohistochemical staining................................................. 17 2.12 Immunofluorescence........................................................... 18 2.13 Human pulmonary fibroblasts (HPF) culture.................................... 19 2.14 NIH-3T3 mouse fibroblasts culture............................................ 19 2.15 Murine primary lung fibroblasts (MLF) isolation.............................. 19 2.16 TGFb 1 stimulation in fibroblasts............................................ 20 2.17 Viral transduction for gene knockdown and overexpression..................... 20 2.18 siRNA for EIF2A knockdown in HPF............................................. 21 2.19 RNA extraction and qRT-PCR................................................... 21 2.20 Immunoblot analysis.......................................................... 21 2.21 Fibroblast proliferation assay............................................... 22 2.22 Protein stability assay...................................................... 23 2.23 TXNDC5 promoter luciferase activity assay.................................... 23 2.24 Generation of TXNDC5 AAA mutant lacking PDI activity......................... 23 2.25 In situ proximity ligation assay (PLA)....................................... 24 2.26 Co-immunoprecipitation (Co-IP)............................................... 25 2.27 Apoptosis detection.......................................................... 25 2.28 Multiphoton microscopy and SHG imaging....................................... 25 2.29 Statistics analysis.......................................................... 26 Chapter 3 Results................................................................. 27 3.1 TXNDC5 was highly upregulated in human IPF lungs/lung fibroblasts and correlated with fibrogenic protein genes..................................................... 27 3.2 TXNDC5 was also markedly upregulated in fibrotic mouse lungs induced by bleomycin treatment and showed strong enrichment in lung fibroblasts........................ 28 3.3 Global deletion of Txndc5 attenuated PF and lung function impairment induced by BLM............................................................................... 29 3.4 Knocking out Txndc5 did not alter inflammatory response following BLM treatment......................................................................... 30 3.5 TXNDC5 is essential and sufficient to promote lung fibroblast activation, proliferation and ECM production.................................................. 31 3.6 TXNDC5 promotes fibrogenesis by augmenting TGFb signaling activity via increased TGFBR1 expression levels.......................................................... 32 3.7 TXNDC5 increases TGFBR1 expression by enhancing TGFBR1 protein folding and stability......................................................................... 33 3.8 TGFβ1 induces TXNDC5 expression via ER stress and activating transcription factor 6 (ATF6)-dependent transcriptional regulation in HPF.............................. 35 3.9 Fibroblast-specific deletion of Txndc5 significantly lessened the progression of established pulmonary fibrosis and lung dysfunction induced by BLM in mice........ 36 3.10 The unique pathogenic role of TXNDC5 among the PDI family.................... 38 Chapter 4 Discussion.............................................................. 39 4.1 TXNDC5 as a novel target for pulmonary fibrosis............................... 39 4.2 Therapeutic potential of targeting TXNDC5..................................... 40 4.3 TXNDC5 in inflammatory response in the lung tissue............................ 41 4.4 Clinical perspective of targeting TXNDC5...................................... 41 4.5 The possibility of endothelial TXNDC5 contributing to lung fibrogenesis....... 42 4.6 What this study adds to the field of pulmonary fibrosis....................... 43 REFERENCE......................................................................... 44 FIGURES AND TABLES................................................................ 47 Fig. i Alveolar damage and pulmonary fibrosis2..................................... 1 Fig. ii The comprehensive management of patients with IPF9......................... 3 Fig. iii Proposed mechanism of pulmonary fibrosis15................................ 4 Fig. iv The process of TGFb activation20........................................... 5 Fig. v The regulation of TGFb signaling pathway22.................................. 6 Fig. vi The three branches of ER stress downstream pathway24....................... 7 Fig. vii Mainly clinical trials in patients with idiopathic pulmonary fibrosis3.... 9 Fig. viii The structure of TXNDC532............................................... 10 Fig. 1 TXNDC5 was upregulated in IPF lungs/lung fibroblasts and correlated with fibrogenic genes59................................................................ 47 Fig. 2 TXNDC5 was upregulated in BLM-induced PF and enriched in lung fibroblasts in vivo59............................................................................ 49 Fig. 3 TXNDC5 was co-localized with active myofibroblasts in the mouse lungs59.... 51 Fig. 4 Knockout of Txndc5 markedly reduced the severity of pulmonary fibrosis induced by BLM59.......................................................................... 53 Fig. 5 Loss of Txndc5 ameliorates BLM-induced pulmonary fibrosis59................ 55 Fig. 6 Global deletion of Txndc5 did not alter inflammatory response to BLM treatment59....................................................................... 56 Fig. 7 Inflammatory responses in WT and Txndc5-/- mouse lungs59................... 58 Fig. 8 TXNDC5 is both essential and sufficient for HPF activation, proliferation and ECM production59...................................................................... 60 Fig. 9 TXNDC5 is required for TGFβ1-induced MLF activation and proliferation59.... 62 Fig. 10 TXNDC5 triggers canonical and non-canonical TGFβ1 signaling pathway59..... 63 Fig. 11 TXNDC5 modulates TGFBR1 expression in human lung fibroblasts and mouse lungs59........................................................................... 65 Fig. 12 TXNDC5-induced pulmonary fibroblast activation and ECM production requires TGFBR159.......................................................................... 67 Fig. 13 TXNDC5 promotes fibrogenesis by enhancing TGFBR1 protein stability via its PDI activity59.................................................................... 69 Fig. 14 TXNDC5 interacted with TGFBR159........................................... 71 Fig. 15 TGFβ1 induces TXNDC5 expression in HPF through ER stress-dependent ATF6 activation59...................................................................... 72 Fig. 16 TGFb 1 treatment triggered increased ER stress in HPF59................... 74 Fig. 17 TGFb 1-induced TXNDC5 upregulation was independent of XBP1 and EIF2A59.... 75 Fig. 18 Fibroblasts-specific Txndc5 deletion lessened the progression of pulmonary fibrosis59........................................................................ 76 Fig. 19 Fibroblasts-specific deletion of Txndc5 attenuated the extent of PF59..... 78 Fig. 20 Txndc5 was the only PDI family gene upregulated in the lung fibroblasts59. 79 Fig. 21 Deletion of Txndc5 did not lead to increased ER stress or apoptosis59..... 80 Supplementary Fig. 1 Design of CRISPR/Cas9-mediated creation of floxed TXNDC5 allele59.......................................................................... 82 Supplementary Fig. 2 Original Western blots59..................................... 91 Table 1 Primer lists59............................................................ 92 | |
dc.language.iso | zh-TW | |
dc.title | 內質網蛋白TXNDC5穩定肺纖維母細胞TGFBR1蛋白表現以促進TGFβ訊息傳遞進而引起肺纖維化 | zh_TW |
dc.title | Endoplasmic Reticulum Protein TXNDC5 Promotes Pulmonary Fibrosis by Augmenting TGFβ Signaling via Post-translational Stabilization of TGFBR1 in Lung Fibroblasts | en |
dc.type | Thesis | |
dc.date.schoolyear | 109-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 林建煌(Chien-Huang Lin),林頌然(Sung-Jan Lin),施金元(Jin-Yuan Shih),曹伯年(Po-Nien Tsao) | |
dc.subject.keyword | 肺纖維化,肺纖維母細胞,肺功能, | zh_TW |
dc.subject.keyword | pulmonary fibrosisoblast,TXNDC5,lung function,TGFBR1,pulmonary fibroblast, | en |
dc.relation.page | 93 | |
dc.identifier.doi | 10.6342/NTU202004476 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2020-12-30 | |
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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