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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林泰元(Thai-Yen Ling) | |
| dc.contributor.author | Bo-Yi Yu | en |
| dc.contributor.author | 余柏毅 | zh_TW |
| dc.date.accessioned | 2021-06-15T11:37:59Z | - |
| dc.date.available | 2021-08-26 | |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-16 | |
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H., & Fabian, C. (2016). Therapeutic potential of mesenchymal stem cells for pulmonary complications associated with preterm birth. Int J Biochem Cell Biol, 74, 18-32. doi:10.1016/j.biocel.2016.02.023 26. Li, Q., Wall, S. B., Ren, C., Velten, M., Hill, C. L., Locy, M. L., . . . Tipple, T. E. (2016). Thioredoxin Reductase Inhibition Attenuates Neonatal Hyperoxic Lung Injury and Enhances Nrf2 Activation. Am J Respir Cell Mol Biol. doi:10.1165/rcmb.2015-0228OC 27. Liao, J., Kapadia, V. S., Brown, L. S., Cheong, N., Longoria, C., Mija, D., . . . Savani, R. C. (2015). The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia. Nat Commun, 6, 8977. doi:10.1038/ncomms9977 28. Luan, Y., Zhang, L., Chao, S., Liu, X., Li, K., Wang, Y., & Zhang, Z. (2016). Mesenchymal stem cells in combination with erythropoietin repair hyperoxia-induced alveoli dysplasia injury in neonatal mice via inhibition of TGF-beta1 signaling. Oncotarget. doi:10.18632/oncotarget.9314 29. Morse, D., & Choi, A. M. (2002). Heme oxygenase-1: the 'emerging molecule' has arrived. Am J Respir Cell Mol Biol, 27(1), 8-16. doi:10.1165/ajrcmb.27.1.4862 30. Nardiello, C., & Morty, R. E. (2016). MicroRNA in late lung development and bronchopulmonary dysplasia: the need to demonstrate causality. Mol Cell Pediatr, 3(1), 19. doi:10.1186/s40348-016-0047-5 31. Nordberg, J., & Arner, E. S. (2001). Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med, 31(11), 1287-1312. 32. Northway, W. H., Jr., Rosan, R. C., & Porter, D. Y. (1967). Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med, 276(7), 357-368. doi:10.1056/NEJM196702162760701 33. Olson, G. E., Whitin, J. C., Hill, K. E., Winfrey, V. P., Motley, A. K., Austin, L. M., . . . Burk, R. F. (2010). 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(2005). The transcription factor gene Nfib is essential for both lung maturation and brain development. Mol Cell Biol, 25(2), 685-698. doi:10.1128/MCB.25.2.685-698.2005 38. Syed, M. A., & Bhandari, V. (2013). Hyperoxia exacerbates postnatal inflammation-induced lung injury in neonatal BRP-39 null mutant mice promoting the M1 macrophage phenotype. Mediators Inflamm, 2013, 457189. doi:10.1155/2013/457189 39. van Haaften, T., Byrne, R., Bonnet, S., Rochefort, G. Y., Akabutu, J., Bouchentouf, M., . . . Thebaud, B. (2009). Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med, 180(11), 1131-1142. doi:10.1164/rccm.200902-0179OC 40. Vicencio, A. G., Lee, C. G., Cho, S. J., Eickelberg, O., Chuu, Y., Haddad, G. G., & Elias, J. A. (2004). Conditional overexpression of bioactive transforming growth factor-beta1 in neonatal mouse lung: a new model for bronchopulmonary dysplasia? 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J Interferon Cytokine Res, 36(3), 159-168. doi:10.1089/jir.2015.0080 49. Zelko, I. N., Mariani, T. J., & Folz, R. J. (2002). Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med, 33(3), 337-349. 50. Zhang, X., Peng, W., Zhang, S., Wang, C., He, X., Zhang, Z., . . . Feng, Z. (2011). MicroRNA expression profile in hyperoxia-exposed newborn mice during the development of bronchopulmonary dysplasia. Respir Care, 56(7), 1009-1015. doi:10.4187/respcare.01032 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49618 | - |
| dc.description.abstract | 高純度氧氣療法已被納入現今許多疾病的治療準則之中，但不可否認地它伴隨的副作用如結構損傷或發炎反應仍然遍及各種組織器官，而其中肺臟的損傷尤甚。目前關於高氧造成肺部損傷之研究多數仍集中在第二型肺泡細胞及肺臟內皮細胞的損傷模式等等，但有關於高純度氧氣如何對第一型肺泡細胞及其幹細胞造成影響，而此影響又是如何參與在肺部損傷的病理機制之中，都還尚未被廣泛討論。為了釐清高氧誘導之肺部損傷的機制並找到合適的治療方法，我們將在之前的研究中建立好的類第一型肺泡細胞之分化模型暴露於高純度氧氣的環境中，並且發現隨著老鼠肺部幹細胞分化成類第一型肺泡細胞之過程中，細胞對於高純度氧氣的抗性也會隨之上升。接著我們透過生物資訊工具分析肺部幹細胞分化過程之全基因表現資料推測第三型穀胱甘肽過氧化物酶(GPx 3)可能於此抗性中扮演關鍵的角色，因此又進行了後續的即時聚合酶鏈鎖式反應、西方墨點法，及免疫螢光細胞染色法證實了其在老鼠肺部幹細胞分化中的表現量差異。而在以藥物抑制第三型穀胱甘肽過氧化物酶的酵素作用之實驗中也再度得證了其在已分化成熟的老鼠肺部幹細胞中抵禦高純度氧氣之重要性。綜合以上實驗的結果，我們合理地推測隨著老鼠肺部幹細胞分化而增加其表現量的第三型穀胱甘肽過氧化物酶對於其獲得的抵禦高純度氧氣損傷之抗性有高度的相關性。 | zh_TW |
| dc.description.abstract | Hyperoxia-based treatment has been approved for many disease indications from long times ago, but its adverse effect such as structural damages and inflammation of tissues, especially lungs, still cannot be ignored. Numerous researches focused on endothelial cells and type 2 pneumocytes of lungs, but the role of type 1 pneumocytes and its stem cells in pathological events of hyperoxia-induced lung injuries was little discussed. To deeply understand the pathology of hyperoxia-induced lung injuries and search for its potential therapies, we applied hyperoxia treatments to a type 1-like pneumocytes differentiation model of mouse lung stem/progenitor cells (mPSCs) established in our lab in previous studies and discovered a growing resistance accompanied with differentiation. Through bioinformatics tools to analyze the whole genome gene expression data of mPSCs, we supposed the potential role of glutathione peroxidase 3 (GPx3) in the mechanism of acquired hyperoxia-resistance of mPSCs. Also, the differential expression of GPx3 was validated by the results of real-time qPCR, western blot, and immunocytochemistry and inhibition of GPx enzyme activities in cell proliferation and intracellular ROS accumulation assays further confirmed its indispensability in anti-oxidant defensing system of mPSCs. Based on the evidence of our experiments, we supposed that the growing expression of GPx3
provided the resistance to hyperoxia environment for well-differentiated mPSCs. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T11:37:59Z (GMT). No. of bitstreams: 1 ntu-105-R03443007-1.pdf: 3129790 bytes, checksum: 94ffb86623a646596ab4cef4323f276d (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 中文摘要 iv
Abstract v Abbreviation list vi Chapter 1 : Introduction 1 1.1 Hyperoxia-induced lung injury 2 1.2 Bronchopulmonary dysplasia and stem cells 3 1.3 ROS metabolism 4 1.4 Anti-oxidant defense system 5 1.5 Glutathione peroxidase (GPx) family 9 1.6 Aims of study 10 Chapter 2 : Materials and Methods 12 2.1 Primary culture of mPSCs (mouse pulmonary stem/progenitor cells) 13 2.2 mPSCs isolation and in vitro differentiation 14 2.3 WST-8 cell proliferation assay 14 2.4 TUNEL staining 15 2.5 Bioinformatics analysis 16 2.6 Real-time PCR and primers design 16 2.7 Immunocytochemistry 18 2.8 Immunohistochemistry 18 2.9 Western blotting and antibodies 19 2.10 Intracellular ROS assay 20 Chapter 3 : Results 21 3.1 mPSCs show a differential sensitivity to hyperoxia treatment during differentiation process. 22 3.2 gpx3 is a potential candidate gene involved in mPSCs anti-oxidant defense system 23 3.3 The significance of GPx3 in mPSCs anti-oxidant defense system was validated by its protein level and distribution during mPSCs differentiation. 24 3.4 GPx3 and T1 double positive cells can be observed in surface of alveolus. 26 3.5 Inhibition of GPx activity for 72 hours induces hyperoxia sensitivity of differentiated mPSCs. 27 3.6 NAC treatment doesn’t increase hyperoxia resistance of mPSCs in the early stage. 28 3.7 Cell death induced by inhibition of GPx activity is mediated by intracellular ROS accumulation in mPSCs 29 Chapter 4 : Discussion and Conclusion 30 4.1 The potential mechanism of hyperoxia-induced injuries on developing lungs: a comparison between other studies. 31 4.2 The dynamic lung stem/progenitor cells differentiation model 33 4.3 The period-related hypothesis of catalase and GPx in mPSCs differentiation model 34 4.4 The potential as a drug screening platform of mPSCs differentiation model 35 4.5 Conclusion 35 Chapter 5 : Figures and Legends 37 5.1 mPSCs show a differential sensitivity to hyperoxia treatment during differentiation 39 5.2 Hyperoxia induces cell apoptosis of mPSCs during the hyperoxia sensitive period 41 5.3 Anti-oxidant related gene expression profile of mPSCs at specific differentiation stages 43 5.4 Validation of the gene expression profile from NGS was conducted by real-time qPCR 45 5.5 GPx3 protein levels are upregulated in the differentiation process of lung stem/progenitor cells 47 5.6 GPx3 protein shows a time-related distribution pattern during the differentiation process of lung stem/progenitor cells. 49 5.7 GPx3 protein was co-localized with type I pneumocytes marker T1 on neonatal mouse alveolar slices. 51 5.8 Inhibition of GPx activity for 72 hours induces hyperoxia sensitivity of differentiated mPSCs. 53 5.9 NAC treatment doesn’t increase hyperoxia resistance of mPSCs in the early stage. 55 5.10 Inhibition of GPx activity for 24 hours induces intracellular ROS accumulation in mPSCs 57 References 59 | |
| dc.language.iso | en | |
| dc.title | 高氧誘導肺臟幹細胞損傷之機制探討 | zh_TW |
| dc.title | To study the mechanism of hyperoxia-induced injury of pulmonary stem/progenitor cells. | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳惠文(Huei-Wen Chen),符文美(Wen-Mei Fu),楊鎧鍵(Kai-Chien Yang),曹伯年(Po-Nien Tsao) | |
| dc.subject.keyword | 高氧,肺臟幹細胞,自由基,第三型穀胱甘?過氧化物?, | zh_TW |
| dc.subject.keyword | Hyperoxia,lung stem cell,ROS,GPX3, | en |
| dc.relation.page | 63 | |
| dc.identifier.doi | 10.6342/NTU201602746 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2016-08-16 | |
| 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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