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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51745完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林辰栖(Chen-Si Lin) | |
| dc.contributor.author | Hui-Yu Chen | en |
| dc.contributor.author | 陳薈宇 | zh_TW |
| dc.date.accessioned | 2021-06-15T13:47:30Z | - |
| dc.date.available | 2020-11-23 | |
| dc.date.copyright | 2015-11-23 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-11-16 | |
| dc.identifier.citation | 1. Lee CJ. Retrospective Survey of Canine Neoplasm in the National Taiwan University Veterinary Hospital: 1999-2003. Master thesis. Taiper, Taiwan: National Taiwan university; 2005.
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Monoclonal antibodies. In: Antibodies: A laboratory manual Cold spring habor laboratory, New York, 139-244, 1988. 137. Eisenberg D. Three-dimensional structure of membrane and surface proteins. Annu Rev Biochem 53:595-623, 1984. 138. Amaral M, Levy C, Heyes DJ, Lafite P, Outeiro TF, Giorgini F, Leys D, Scrutton NS. Structural basis of kynurenine 3-monooxygenase inhibition. Nature 496:382-385, 2013. 139. Otting G, Liepinsh E, Wuthrich K. Protein hydration in aqueous solution. Science 254:974-980, 1991. 140. Smith SM. Strategies for the purification of membrane proteins. In: Walls D, Loughran ST, ed. Protein Chromatography. Humana Press, New Jersey, 485-496, 2011. 141. Goffart S, Martinsson P, Malka F, Rojo M, Spelbrink JN. The Mitochondria of Cultured Mammalian cells. In: Leister D, Herrmann JM, ed. Mitochondria. Humana Press, New Jersey, 17-32, 2007. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51745 | - |
| dc.description.abstract | The kynurenine pathway is a major route for tryptophan metabolism where several metabolites have been linked to the pathogenesis of neurodegenerative disease, as well as tumor formation. Our previous studies showed that the expression level of kynurenine 3-monooxygenase (KMO), an outer mitochondrial membrane enzyme and central to the kynurenine pathway, was positively correlated with the canine mammary tumor (CMT) malignancy. So far the study of KMO involved in caner research has been ignored and lacked for species-specific molecular tool. In this study, we successful expressed the canine KMO (cKMO) protein by using baculovirus-insect cell (Sf9 cell) and characterized the sequence by software analysis. The purified recombinant proteins were used as the antigen for developing anti-KMO antibodies to select the most suitable antibody for CMT research. The comparison of KMO amino acid sequence among canine, human and mice shown that three conserved motifs folded in the interior of predicted protein structure, which might be acted as the binding site of cofactor FAD or NADPH. These structures belong to the family of NADPH-dependent flavin monooxygenase. Canine KMO gene was inserted into baculoviral genome by transposon located on the expression vector and the full-length cKMO can be detected on the mitochondria of Sf9 cells infected with these recombinant baculovirus. The best expression conditions have been optimized including 1) baculovirus passage (P3), 2) multiplicity of infection (MOI~1.5) and 3) infection time (72-96 hours). Canine KMO, a mitochondrial membrane protein, was purified using Ni-NTA affinity column under denaturing condition. A yield of 2 mg protein can be generated from 2×108 baculovirus infected Sf9 cells. Furthermore, three mice were immunized with this recombinant protein for antibody production. Hybridoma development will be conducted while the serum antibody titers of mice are elevated. In addition, the expression of KMO could be detected on the surface of CMT cell lines by using flow cytometry. We hope that the specific anti-cKMO antibodies can contribute to theranostic application of CMT in the future. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T13:47:30Z (GMT). No. of bitstreams: 1 ntu-104-R02629006-1.pdf: 3634527 bytes, checksum: 94d49917fec933664f7581ab2c26981f (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 口試委員審定書 I
誌謝 II 中文摘要 IV Abstract V Abbreviation VII Contents X Chapter 1. Introduction 1 Chapter 2. Background and literature review 3 2.1 Canine mammary tumor 3 2.1.1 Epidemiology 3 2.1.2 Treatment 4 2.1.3 Prognostic factors 7 2.1.3.1 Clinical prognostic factors 7 2.1.3.2 Histopathologic prognostic factors 7 2.1.3.3 Biomarkers on human breast cancer and canine mammary tumor 8 2.2 Kynurenine pathway 10 2.2.1 Function of kynurenine pathway metabolites in central nervous system 10 2.2.2 Effects of kynurenine pathway metabolites on tumor growth 13 2.2.3 Kynurenine 3-monooxygenase, KMO 17 2.2.3.1 Overview of KMO 17 2.2.3.2 The role of KMO in CMTs 19 2.3 Baculovirus-insect cell expression system 20 2.4 Targeting intracellular tumor antigen with antibody 22 2.5 Conclusion 24 Chapter 3. Materials and methods 26 3.1 Cell culture 26 3.1.1 Culturing insect cell line 26 3.1.2 Culturing CMT cell lines 26 3.2 Amino acid sequence analysis and prediction of cKMO 27 3.2.1 DNAstar megalign 27 3.2.2 DNAstar protean 27 3.2.3 SWISS-MODEL 27 3.3 Construction of the recombinant cKMO (Flow chart show in Fig. 2) 28 3.3.1 Restriction enzyme digestion 28 3.3.2 Ligation 29 3.3.3 DH5α E.coli Transformation 29 3.4 Production of recombinant cKMO-baculovirus (Flow chart show in Fig. 3) 31 3.4.1 DH10Bac E. coli Transformation 31 3.4.2 Transformants analysis by Polymerase chain reaction (PCR) 31 3.4.3 Transfection of Sf9 cells 32 3.4.4 Amplification of baculoviral stock 33 3.4.5 Determination of baculoviral stock titer 34 3.5 Recombinant canine KMO protein expression 35 3.5.1 Small-scale protein expression 35 3.5.1.1 RT-PCR for measuring mRNA expression 35 3.5.1.2 SDS-PAGE and western blotting analysis for measuring protein expression 37 3.5.1.3 Subcellular location of recombinant cKMO in Sf9 cells 39 3.5.2 Large-scale protein expression 40 3.6 Recombinant canine KMO protein purification 40 3.6.1 Ni-NTA column preparation 40 3.6.2 Cell lysate preparation 41 3.6.3 Denaturing purification 41 3.6.4 Protein concentration and urea removal 43 3.7 Anti-canine KMO antibodies production 44 3.8 Flow cytometry analysis of KMO expression in CMT cell lines 44 Chapter 4. Results 46 4.1 Canine KMO characterization 46 4.2 Recombinant baculovirus generation 47 4.3 Recombinant canine KMO protein expression 48 4.4 Recombinant canine KMO protein purification 49 4.5 Anti-canine KMO antibodies production 50 4.6 Flow cytometry analysis of KMO expression in CMT cell lines 51 Chapter 5. Discussion 52 Tables 60 Table 1. Modified clinical staging system of canine mammary tumors 60 Table 2. Histologic classification of canine mammary tumors 61 Table 3. Criteria of histologic grading of canine mammary tumor 63 Table 4. Tumor grade according to histologic score in canine mammary tumor 63 Table 5. Three conserved motifs present in NAD(P)H dependent flavin monooxygenase and the relative position of sequence in cKMO 64 Table 6. Sequence of oligonucleotide primers and predicted PCR product size of cKMO and GAPDH 65 Table 7. The P3 baculoviral stocks titer determined using endpoint dilution assay 66 Table 8. An overview of comparison among expression systems 67 Figures 68 Fig. 1. Schematic overview of the kynurenine pathway of the tryptophan metabolism and the target receptor 68 Fig. 2. An illustration showing the procedure in constructing recombinant vector KMO/pFastBac HT A. 69 Fig. 3. A diagram of the generation of recombinant baculovirus using Bac-to-BacR Baculovirus Expression System 70 Fig. 4. Immune program for anti-cKMO antibodies product 71 Fig. 5. A multiple amino acid sequence alignment from canine, human, mice and swine KMO (continued) 73 Fig. 6. A predicted secondary structure characterization of canine KMO protein 74 Fig. 7. A predicted 3D protein structure of canine KMO protein 75 Fig. 8. Restriction enzyme digestion of canine KMO/pcDNA3.1 and pFastBac HT A with BamHI and XbaI 76 Fig. 9. Three transformants of KMO/pFastBac HT A/DH5α is checked by restriction enzyme digestion with BamHI and XbaI. 77 Fig. 10. KMO/bacmid transformants from white colonies were checked by PCR 79 Fig. 11. Optimization of expression condition of cKMO in Sf9 cells 80 Fig. 12. The morphological changes of Sf9 cell after 72 hours post-infection with recombinant P3 cKMO-baculovirus. 81 Fig. 13. The mRNA and protein expression of recombinant cKMO in Sf9 cells 82 Fig. 14. Subcellular location of recombinant cKMO in Sf9 cells 83 Fig. 15. Purification of recombinant cKMO protein under denaturing condition 84 Fig. 16. The amino acid sequence of canine KMO from purified protein. 86 Fig. 17. Serum antibody titers of cKMO immunized mice have been elevated 87 Fig. 18. The expression of KMO in CMT cells (MPG) observed by IFA with serum antibodies from recombinant cKMO immunized mouse 88 Fig. 19. Flow cytometry analysis of KMO expression in CMT cell lines 89 References 91 | |
| dc.language.iso | en | |
| dc.subject | 犬尿胺酸代謝途徑 | zh_TW |
| dc.subject | 桿狀病毒表現系統 | zh_TW |
| dc.subject | 犬尿胺酸 3-單氧化? | zh_TW |
| dc.subject | 犬乳房腫瘤 | zh_TW |
| dc.subject | 粒線體膜蛋白 | zh_TW |
| dc.subject | mitochondrial membrane protein | en |
| dc.subject | canine mammary tumor | en |
| dc.subject | baculovirus expression system | en |
| dc.subject | kynurenine pathway | en |
| dc.subject | kynurenine 3-monooxygenase | en |
| dc.title | 以桿狀病毒表現犬尿胺酸3-單氧化酶並探討其在犬乳房腫瘤診斷之應用 | zh_TW |
| dc.title | Expression of Canine Kynurenine 3-monooxygenase by Baculovirus for the Diagnostic Application in Canine Mammary Tumor | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 廖泰慶(Tai-Ching Liao),廖光文(Kuang-Wen Liao),王愈善(Yu-Shan Wang),詹昆衛(Kun-Wei Chan) | |
| dc.subject.keyword | 犬尿胺酸 3-單氧化?,犬尿胺酸代謝途徑,桿狀病毒表現系統,粒線體膜蛋白,犬乳房腫瘤, | zh_TW |
| dc.subject.keyword | kynurenine 3-monooxygenase,kynurenine pathway,baculovirus expression system,mitochondrial membrane protein,canine mammary tumor, | en |
| dc.relation.page | 103 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-11-17 | |
| dc.contributor.author-college | 獸醫專業學院 | zh_TW |
| dc.contributor.author-dept | 獸醫學研究所 | zh_TW |
| 顯示於系所單位： | 獸醫學系 | |
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