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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林淑華(Shu-Wha Lin) | |
| dc.contributor.author | Shu-Jhu Yang | en |
| dc.contributor.author | 楊淑筑 | zh_TW |
| dc.date.accessioned | 2021-06-15T04:47:23Z | - |
| dc.date.available | 2016-10-07 | |
| dc.date.copyright | 2011-10-07 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-08-18 | |
| dc.identifier.citation | Autin L, Miteva MA, Lee WH, Mertens K, Radtke KP, Villoutreix BO (2005) Molecular models of the procoagulant factor VIIIa-factor IXa complex. J Thromb Haemost 3: 2044-2056
Bajaj SP (1999) Region of factor IXa protease domain that interacts with factor VIIIa: analysis of select hemophilia B mutants. Thromb Haemost 82: 218-225 Biere-Rafi S, Baarslag MA, Peters M, Kruip MJ, Kraaijenhagen RA, den Heijer M, Buller HR, Kamphuisen PW (2010) Cardiovascular risk assessment in haemophilia patients. Thromb Haemost 105 Butenas S, Mann KG (2002) Blood coagulation. Biochemistry (Mosc) 67: 3-12 Chang J, Jin J, Lollar P, Bode W, Brandstetter H, Hamaguchi N, Straight DL, Stafford DW (1998) Changing residue 338 in human factor IX from arginine to alanine causes an increase in catalytic activity. J Biol Chem 273: 12089-12094 Chang JY, Monroe DM, Stafford DW, Brinkhous KM, Roberts HR (1997) Replacing the first epidermal growth factor-like domain of factor IX with that of factor VII enhances activity in vitro and in canine hemophilia B. J Clin Invest 100: 886-892 Chang YJ, Wu HL, Hamaguchi N, Hsu YC, Lin SW (2002) Identification of functionally important residues of the epidermal growth factor-2 domain of factor IX by alanine-scanning mutagenesis. Residues Asn(89)-Gly(93) are critical for binding factor VIIIa. J Biol Chem 277: 25393-25399 Chang YJ, Wu HL, Hsu YC, Hamaguchi N, Shi GY, Shen MC, Lin SW (2003) Discontinuous residues of factor IX constitute a surface for binding the anti-factor IX monoclonal antibody A-5. Thromb Res 111: 293-299 Decker K, Chan CAK, Seroski W, Bissonnette D, Floros G, Lacasse L, Laudenbach L, Paradis E, Purcell S, Stain AM (2010) All about Hemophilia, A Guide for Families: instructor's manual for health professionals in hemophilia care. Haemophilia 16: 54-54 Di Scipio RG, Kurachi K, Davie EW (1978) Activation of human factor IX (Christmas factor). J Clin Invest 61: 1528-1538 Finn JD, Simioni P, Jacobelli N, Zhou SZ, Nichols TC, High KA, Arruda VR (2009) FIX-R338L (FIX Padua) as a Successful Alternative for the Treatment of Canine Severe Hemophilia B. Blood 114: 290-291 Freedman SJ, Furie BC, Furie B, Baleja JD (1995) Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX. Biochemistry 34: 12126-12137 Girolami A, Scandellari R, Zanon E, Sartori R, Girolami B (2006) Non-catheter associated venous thrombosis in hemophilia A and B. A critical review of all reported cases. J Thromb Thrombolysis 21: 279-284 Green P (2010) The 'Royal disease'. J Thromb Haemost 8: 2214-2215 Hamaguchi N, Roberts H, Stafford DW (1993) Mutations in the catalytic domain of factor IX that are related to the subclass hemophilia Bm. Biochemistry 32: 6324-6329 Hasbrouck NC, High KA (2008) AAV-mediated gene transfer for the treatment of hemophilia B: problems and prospects. Gene Ther 15: 870-875 Herzog RW, Arruda VR, Fisher TH, Read MS, Nichols TC, High KA (2000) Absence of circulating factor IX antigen in hemophilia B dogs of the UNC-Chapel Hill colony. Thromb Haemost 84: 352-354 Hoffman R. (2005) Hematology : basic principles and practice. Elsevier Churchill Livingstone, Philadelphia, Pa., pp. xxix, 2821 p. Jin DY, Zhang TP, Gui T, Stafford DW, Monahan PE (2004) Creation of a mouse expressing defective human factor IX. Blood 104: 1733-1739 Kirchhofer D, Eigenbrot C, Lipari MT, Moran P, Peek M, Kelley RF (2001) The tissue factor region that interacts with factor Xa in the activation of factor VII. Biochemistry 40: 675-682 Kirchhofer D, Lipari MT, Moran P, Eigenbrot C, Kelley RF (2000) The tissue factor region that interacts with substrates factor IX and Factor X. Biochemistry 39: 7380-7387 Lannoy N, Hermans C (2010) The 'royal disease'--haemophilia A or B? A haematological mystery is finally solved. Haemophilia 16: 843-847 Larson PJ, Stanfield-Oakley SA, VanDusen WJ, Kasper CK, Smith KJ, Monroe DM, High KA (1996) Structural integrity of the gamma-carboxyglutamic acid domain of human blood coagulation factor IXa Is required for its binding to cofactor VIIIa. J Biol Chem 271: 3869-3876 Lin CN, Kao CY, Miao CH, Hamaguchi N, Wu HL, Shi GY, Liu YL, High KA, Lin SW (2010) Generation of a novel factor IX with augmented clotting activities in vitro and in vivo. J Thromb Haemost 8: 1773-1783 Lin HF, Maeda N, Smithies O, Straight DL, Stafford DW (1997) A coagulation factor IX-deficient mouse model for human hemophilia B. Blood 90: 3962-3966 Lozier J (2004) Gene therapy of the hemophilias. Semin Hematol 41: 287-296 Mann KG (1999) Biochemistry and physiology of blood coagulation. Thromb Haemost 82: 165-174 Mathur A, Zhong D, Sabharwal AK, Smith KJ, Bajaj SP (1997) Interaction of factor IXa with factor VIIIa. Effects of protease domain Ca2+ binding site, proteolysis in the autolysis loop, phospholipid, and factor X. J Biol Chem 272: 23418-23426 Metzner HJ, Weimer T, Kronthaler U, Lang W, Schulte S (2009) Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost 102: 634-644 Monahan PE, Di Paola J (2010) Recombinant Factor IX for Clinical and Research Use. Semin Thromb Hemost 36: 498-509 Monroe DM, Hoffman M, Roberts HR (2002) Platelets and thrombin generation. Arterioscler Thromb Vasc Biol 22: 1381-1389 Nelsestuen GL, Broderius M, Martin G (1976) Role of gamma-carboxyglutamic acid. Cation specificity of prothrombin and factor X-phospholipid binding. J Biol Chem 251: 6886-6893 Peters RT, Low SC, Kamphaus GD, Dumont JA, Amari JV, Lu Q, Zarbis-Papastoitsis G, Reidy TJ, Merricks EP, Nichols TC, Bitonti AJ (2010) Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood 115: 2057-2064 Petrus I, Chuah M, VandenDriessche T (2010) Gene therapy strategies for hemophilia: benefits versus risks. J Gene Med 12: 797-809 Pipe SW (2005) The promise and challenges of bioengineered recombinant clotting factors. J Thromb Haemost 3: 1692-1701 Ravanat C, Freund M, Dol F, Cadroy Y, Roussi J, Incardona F, Maffrand JP, Boneu B, Drouet L, Legrand C, et al. (1995) Cross-reactivity of human molecular markers for detection of prethrombotic states in various animal species. Blood Coagul Fibrinolysis 6: 446-455 Schmidt AE, Stewart JE, Mathur A, Krishnaswamy S, Bajaj SP (2005) Na+ site in blood coagulation factor IXa: effect on catalysis and factor VIIIa binding. J Mol Biol 350: 78-91 Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR (2009) X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med 361: 1671-1675 White GC, 2nd, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J (2001) Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 85: 560 Yan SC, Razzano P, Chao YB, Walls JD, Berg DT, McClure DB, Grinnell BW (1990) Characterization and novel purification of recombinant human protein C from three mammalian cell lines. Biotechnology (N Y) 8: 655-661 Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi K (1985) Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry 24: 3736-3750 張育嘉 (1998) 人類凝血第九因子EGF-2區域之功能性探討. 碩士 Thesis, 醫事技術學系, 國立台灣大學, 台北市 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45853 | - |
| dc.description.abstract | B型血友病是一種性聯遺傳的出血性疾病，病人主要由於缺乏第九凝血因子的功能所造成。目前B型血友病的治療方式多採用替代性療法，即病人接受注射自血漿純化或重組合成的第九因子。本實驗室研發出一個具有三個單點突變(V86A/E277A/R338A)的第九因子Factor IX-Triple (簡稱FIX-Triple)，FIX-Triple在in vitro比野生型第九因子高出13倍專一活性。先前文獻報導一位靜脈血栓病人具有第九凝血因子的單點突變(R338L)，導致雖然第九凝血因子的表現量正常，但凝血活性卻高出正常人8倍(Simioni et al, 2009)。本論文的研究目標是希望顯示具338L變異型的高活性第九因子可能造成的病症，與比較FIX-Triple與338L的差異及病理機制。
初步我建構兩種表現質體，其一是胺基酸第338位置單點突變(FIX-338L)，而另一是將FIX-Triple 胺基酸第338位置的精胺酸(Arginine, R)置換成白胺酸(Leucine, L)，命名為FIX-TripleL (V86A/E277A/R338L)。純化的FIX-TripleL具有比野生型第九因子(FIX-WT)高的專一活性，FIX-338L為8倍，FIX-TripleL為15倍，且FIX-TripleL的内源凝血酶生成能力(Endogenous Thrombin Potential)也是野生型的1.7倍，透過血栓彈力圖(TEG)分析儀發現FIX-TripleL具有最快速的血栓形成速率。而在第九因子輸注至血友病小鼠體內評估治療狀況的實驗，發現FIX-TripleL在小鼠體內具有比野生型高8倍的活性，FIX-338L及FIX-Triple為4倍。當使用腺病毒相關病毒載體(AAV)，感染血友病小鼠與野生型小鼠(C57BL/6)，發現接受FIX-TripleL的血友病小鼠測得第九因子專一活性是接受FIX-WT的小鼠的14倍，又帶有FIX-TripleL腺病毒相關病毒載體感染野生型小鼠初步評估並無提高血栓風險。使用抗凝血酶III (Antithrombin III)定量活化態凝血第九因子時發現，當338位置突變成白胺酸(L)時，第九因子較不受抗凝血酶III抑制，且此情形與肝素(Heparin)存在與否無相關性。而變異型與野生型的第九因子皆能結合TFPI (Tissue factor pathway inhibitor)。 總結本論文的研究可發現，就補充第九因子蛋白及基因療法策略而言，FIX-TripleL的確能有效提高凝血能力及血纖維蛋白(Fibrin)形成速率。而在血栓風險探討結果發現FIX-TripleL可與抗凝血酶III形成複合體，且在FIX-TripleL治療組小鼠發現凝血酶/抗凝血酶複合物偵測結果上是安全的，且不影響與組織因子路徑抑制因子結合能力。因此上述結果支持FIX-TripleL具有臨床治療血友病的應用潛力。 | zh_TW |
| dc.description.abstract | Hemophilia B is an X-linked bleeding disorder that results from a deficiency or dysfunction of factor IX (FIX). Conventional treatment involves the replacement of the deficient factor. We previously reported a FIX variant containing three point mutations (V86A/E277A/R338A, FIX-Triple) with 13-fold higher specific clotting activity compared with FIX wild-type (FIX-WT). Simioni et al. reported a case of thrombophilia associated with a substitution of leucine for arginine at position 338 (R338L) with 8-fold higher specific clotting activity than FIX-WT. This thesis compared differences between 338L and the FIX-Triple as well as investigated the pathological mechanism of 338L.
To this end, I generated novel FIX variants with leucine replacement at the 338 residue of FIX-Triple and of FIX-WT. These Variants are designated FIX-TripleL and FIX-338L, respectively. Purified FIX-R338L and FIX-TripleL proteins revealed 8 and 15-fold higher specific clotting activity than FIX-WT. Furthermore, FIX-TripleL had the greatest improvement of endogenous thrombin potential and maximum rate of thrombus generation among the FIX variants assessed by the calibrated automated thrombogram and thromboelastography. In protein replacement therapy for hemophilia B mice, FIX-TripleL respectively resulted in 8-fold greater clotting activity than FIX-WT. Additionally, HB mice treated with AAV particle expressing either FIX-R338L, FIX-Triple, or FIX-TripleL exhibited a respective 7, 9, and 14-fold higher specific clotting activity than FIX-WT. C57BL/6 mice injected with different doses of virus particles carrying FIX-WT, FIX-R338L, FIX-Triple, or FIX-TripleL did not show increased risk of thrombosis compared with FIX-WT. The results indicate that the FIX-TripleL variant exhibits significantly enhanced clotting activity relative to FIX-WT and the other gain-of-function FIX variants studied in this work. FIX-TripleL neither showed thrombogenic with the mouse models nor effected binding ability with TFPI. These data support the potential for therapeutic use of FIX-TripleL for treating HB. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T04:47:23Z (GMT). No. of bitstreams: 1 ntu-100-R98424026-1.pdf: 42851977 bytes, checksum: 1ad39bd012470f9c142da5bec3a2cafa (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
致謝 ii 中文摘要 iii Abstract v 縮寫表 vii 圖目錄 ix 表目錄 ix 附錄表 ix 文獻回顧 1 實驗材料及方法 7 實驗結果 17 實驗討論 21 參考文獻 40 附錄 45 | |
| dc.language.iso | zh-TW | |
| dc.subject | 小鼠模式 | zh_TW |
| dc.subject | B型血友病 | zh_TW |
| dc.subject | 第九凝血因子 | zh_TW |
| dc.subject | 基因治療 | zh_TW |
| dc.subject | 蛋白補充治療 | zh_TW |
| dc.subject | Gene therapy | en |
| dc.subject | Mouse model | en |
| dc.subject | Hemophilia B | en |
| dc.subject | Coagulation Factor IX | en |
| dc.subject | Protein infusion therapy | en |
| dc.title | 探討重組人類凝血第九因子338L及TripleL之功能 | zh_TW |
| dc.title | Functional Characterization of Human Coagulation Factor IX-338L and Factor IX-TripleL | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 吳華林(Hua-Lin Wu),高照村(Jau-Tsuen Kao),紀威光(Wei-Kuang Chi) | |
| dc.subject.keyword | B型血友病,第九凝血因子,基因治療,蛋白補充治療,小鼠模式, | zh_TW |
| dc.subject.keyword | Hemophilia B,Coagulation Factor IX,Gene therapy,Protein infusion therapy,Mouse model, | en |
| dc.relation.page | 48 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-08-18 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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