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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45238完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃德富 | |
| dc.contributor.author | Kang-lin Hsieh | en |
| dc.contributor.author | 謝岡霖 | zh_TW |
| dc.date.accessioned | 2021-06-15T04:10:14Z | - |
| dc.date.available | 2011-03-12 | |
| dc.date.copyright | 2010-03-12 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-02-01 | |
| dc.identifier.citation | Andrews, R.K., Gardiner, E.E., Shen, Y., and Berndt, M.C. (2003a). Structure-activity relationships of snake toxins targeting platelet receptors, glycoprotein Ib-IX-V and glycoprotein VI. Curr Med Chem Cardiovasc Hematol Agents 1, 143-149.
Andrews, R.K., Gardiner, E.E., Shen, Y., Whisstock, J.C., and Berndt, M.C. (2003b). Glycoprotein Ib-IX-V. Int J Biochem Cell Biol 35, 1170-1174. Andrews, R.K., Shen, Y., Gardiner, E.E., Dong, J.F., Lopez, J.A., and Berndt, M.C. (1999). The glycoprotein Ib-IX-V complex in platelet adhesion and signaling. Thromb Haemost 82, 357-364. Baglia, F.A., Badellino, K.O., Li, C.Q., Lopez, J.A., and Walsh, P.N. (2002). Factor XI binding to the platelet glycoprotein Ib-IX-V complex promotes factor XI activation by thrombin. J Biol Chem 277, 1662-1668. Bellinger, D.A., Nichols, T.C., Read, M.S., Reddick, R.L., Lamb, M.A., Brinkhous, K.M., Evatt, B.L., and Griggs, T.R. (1987). Prevention of occlusive coronary artery thrombosis by a murine monoclonal antibody to porcine von Willebrand factor. Proc Natl Acad Sci U S A 84, 8100-8104. Chang, C.H., Chung, C.H., Kuo, H.L., Hsu, C.C., and Huang, T.F. (2008). The highly specific platelet glycoprotein (GP) VI agonist trowaglerix impaired collagen-induced platelet aggregation ex vivo through matrix metalloproteinase-dependent GPVI shedding. J Thromb Haemost 6, 669-676. Chen, Y.L., and Tsai, I.H. (1995). Functional and sequence characterization of agkicetin, a new glycoprotein Ib antagonist isolated from Agkistrodon acutus venom. offf2p4. Biochem Biophys Res Commun 210, 472-477. Chung, C.H., Peng, H.C., and Huang, T.F. (2001). Aggretin, a C-type lectin protein, induces platelet aggregation via integrin alpha(2)beta(1) and GPIb in a phosphatidylinositol 3-kinase independent pathway. Biochem Biophys Res Commun 285, 689-695. Cranmer, S.L., Ulsemer, P., Cooke, B.M., Salem, H.H., de la Salle, C., Lanza, F., and Jackson, S.P. (1999). Glycoprotein (GP) Ib-IX-transfected cells roll on a von Willebrand factor matrix under flow. Importance of the GPib/actin-binding protein (ABP-280) interaction in maintaining adhesion under high shear. J Biol Chem 274, 6097-6106. De Marco, L., Mazzucato, M., Masotti, A., and Ruggeri, Z.M. (1994). Localization and characterization of an alpha-thrombin-binding site on platelet glycoprotein Ib alpha. J Biol Chem 269, 6478-6484. Dong, J.F., Li, C.Q., Sae-Tung, G., Hyun, W., Afshar-Kharghan, V., and Lopez, J.A. (1997). The cytoplasmic domain of glycoprotein (GP) Ibalpha constrains the lateral diffusion of the GP Ib-IX complex and modulates von Willebrand factor binding. Biochemistry 36, 12421-12427. Favaloro, E.J., Henniker, A., Facey, D., and Hertzberg, M. (2000). Discrimination of von Willebrands disease (VWD) subtypes: direct comparison of von Willebrand factor:collagen binding assay (VWF:CBA) with monoclonal antibody (MAB) based VWF-capture systems. Thromb Haemost 84, 541-547. Fox, J.W., and Serrano, S.M. (2008). Insights into and speculations about snake venom metalloproteinase (SVMP) synthesis, folding and disulfide bond formation and their contribution to venom complexity. FEBS J 275, 3016-3030. Francischetti, I.M., Saliou, B., Leduc, M., Carlini, C.R., Hatmi, M., Randon, J., Faili, A., and Bon, C. (1997). Convulxin, a potent platelet-aggregating protein from Crotalus durissus terrificus venom, specifically binds to platelets. Toxicon 35, 1217-1228. Furlan, M. (1996). Von Willebrand factor: molecular size and functional activity. Ann Hematol 72, 341-348. Gardiner, E.E., Arthur, J.F., Kahn, M.L., Berndt, M.C., and Andrews, R.K. (2004). Regulation of platelet membrane levels of glycoprotein VI by a platelet-derived metalloproteinase. Blood 104, 3611-3617. Gu, M., Xi, X., Englund, G.D., Berndt, M.C., and Du, X. (1999). Analysis of the roles of 14-3-3 in the platelet glycoprotein Ib-IX-mediated activation of integrin alpha(IIb)beta(3) using a reconstituted mammalian cell expression model. J Cell Biol 147, 1085-1096. Ikeda, Y., Handa, M., Kamata, T., Kawano, K., Kawai, Y., Watanabe, K., Kawakami, K., Sakai, K., Fukuyama, M., Itagaki, I., et al. (1993). Transmembrane calcium influx associated with von Willebrand factor binding to GP Ib in the initiation of shear-induced platelet aggregation. Thromb Haemost 69, 496-502. Jackson, J.E. (2003). Pathogen inactivation of platelet concentrates and fresh frozen plasma. Br J Biomed Sci 60, 227-232. Kanaji, S., Kanaji, T., Furihata, K., Kato, K., Ware, J.L., and Kunicki, T.J. (2003). Convulxin binds to native, human glycoprotein Ib alpha. J Biol Chem 278, 39452-39460. Kiefer, T.L., and Becker, R.C. (2009). Inhibitors of platelet adhesion. Circulation 120, 2488-2495. Li, C.Q., Vindigni, A., Sadler, J.E., and Wardell, M.R. (2001). Platelet glycoprotein Ib alpha binds to thrombin anion-binding exosite II inducing allosteric changes in the activity of thrombin. J Biol Chem 276, 6161-6168. Manea, M., and Karpman, D. (2009). Molecular basis of ADAMTS13 dysfunction in thrombotic thrombocytopenic purpura. Pediatr Nephrol 24, 447-458. Mangin, P., Yuan, Y., Goncalves, I., Eckly, A., Freund, M., Cazenave, J.P., Gachet, C., Jackson, S.P., and Lanza, F. (2003). Signaling role for phospholipase C gamma 2 in platelet glycoprotein Ib alpha calcium flux and cytoskeletal reorganization. Involvement of a pathway distinct from FcR gamma chain and Fc gamma RIIA. J Biol Chem 278, 32880-32891. Matsuzaki, R., Yoshiara, E., Yamada, M., Shima, K., Atoda, H., and Morita, T. (1996). cDNA cloning of IX/X-BP, a heterogeneous two-chain anticoagulant protein from snake venom. Biochem Biophys Res Commun 220, 382-387. Navdaev, A., and Clemetson, K.J. (2002). Glycoprotein Ib cross-linking/ligation on echicetin-coated surfaces or echicetin-IgMkappa in stirred suspension activates platelets by cytoskeleton modulated calcium release. J Biol Chem 277, 45928-45934. Nicholson, N.S., Panzer-Knodle, S.G., Salyers, A.K., Taite, B.B., Szalony, J.A., Haas, N.F., King, L.W., Zablocki, J.A., Keller, B.T., Broschat, K., et al. (1995). SC-54684A: an orally active inhibitor of platelet aggregation. Circulation 91, 403-410. Ozaki, Y., Asazuma, N., Suzuki-Inoue, K., and Berndt, M.C. (2005). Platelet GPIb-IX-V-dependent signaling. J Thromb Haemost 3, 1745-1751. Peng, M., Lu, W., and Kirby, E.P. (1991). Alboaggregin-B: a new platelet agonist that binds to platelet membrane glycoprotein Ib. Biochemistry 30, 11529-11536. Rinder, H.M., Snyder, E.L., Bonan, J.L., Napychank, P.A., Malkus, H., and Smith, B.R. (1993). Activation in stored platelet concentrates: correlation between membrane expression of P-selectin, glycoprotein IIb/IIIa, and beta-thromboglobulin release. Transfusion 33, 25-29. Ruan, C.G., Du, X.P., Xi, X.D., Castaldi, P.A., and Berndt, M.C. (1987). A murine antiglycoprotein Ib complex monoclonal antibody, SZ 2, inhibits platelet aggregation induced by both ristocetin and collagen. Blood 69, 570-577. Ruggeri, Z.M. (1994). Glycoprotein Ib and von Willebrand factor in the process of thrombus formation. Ann N Y Acad Sci 714, 200-210. Ruggeri, Z.M. (1997). von Willebrand factor. J Clin Invest 99, 559-564. Sakurai, Y., Fujimura, Y., Kokubo, T., Imamura, K., Kawasaki, T., Handa, M., Suzuki, M., Matsui, T., Titani, K., and Yoshioka, A. (1998). The cDNA cloning and molecular characterization of a snake venom platelet glycoprotein Ib-binding protein, mamushigin, from Agkistrodon halys blomhoffii venom. Thromb Haemost 79, 1199-1207. Savage, B., Almus-Jacobs, F., and Ruggeri, Z.M. (1998). Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 94, 657-666. Savasan, S., Lee, S.K., Ginsburg, D., and Tsai, H.M. (2003). ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity. Blood 101, 4449-4451. Schade, A.J., Arya, M., Gao, S., Diz-Kucukkaya, R., Anvari, B., McIntire, L.V., Lopez, J.A., and Dong, J.F. (2003). Cytoplasmic truncation of glycoprotein Ib alpha weakens its interaction with von Willebrand factor and impairs cell adhesion. Biochemistry 42, 2245-2251. Sekiya, F., Yamashita, T., and Morita, T. (1995). Role of calcium(II) ions in the recognition of coagulation factors IX and X by IX/X-bp, an anticoagulant from snake venom. Biochemistry 34, 10043-10047. Shen, Y., Dong Jf, J.F., Romo, G.M., Arceneaux, W., Aprico, A., Gardiner, E.E., Lopez, J.A., Berndt, M.C., and Andrews, R.K. (2002). Functional analysis of the C-terminal flanking sequence of platelet glycoprotein Ib alpha using canine-human chimeras. Blood 99, 145-150. Shock, D.D., Naik, U.P., Brittain, J.E., Alahari, S.K., Sondek, J., and Parise, L.V. (1999). Calcium-dependent properties of CIB binding to the integrin alphaIIb cytoplasmic domain and translocation to the platelet cytoskeleton. Biochem J 342 Pt 3, 729-735. Soto, J.G., White, S.A., Reyes, S.R., Regalado, R., Sanchez, E.E., and Perez, J.C. (2007). Molecular evolution of PIII-SVMP and RGD disintegrin genes from the genus Crotalus. Gene 389, 66-72. Tabrizi, P., Wang, L., Seeds, N., McComb, J.G., Yamada, S., Griffin, J.H., Carmeliet, P., Weiss, M.H., and Zlokovic, B.V. (1999). Tissue plasminogen activator (tPA) deficiency exacerbates cerebrovascular fibrin deposition and brain injury in a murine stroke model: studies in tPA-deficient mice and wild-type mice on a matched genetic background. Arterioscler Thromb Vasc Biol 19, 2801-2806. Thomas, K.B., Tune, E.P., and Choong, S.C. (1994). Parallel determination of von Willebrand factor--Ristocetin and Botrocetin cofactors. Thromb Res 75, 401-408. Turitto, V.T., Weiss, H.J., Zimmerman, T.S., and Sussman, II (1985). Factor VIII/von Willebrand factor in subendothelium mediates platelet adhesion. Blood 65, 823-831. Turrentine, M.A., Dover, S.R., and Johnson, G.S. (1987). Prepartion of botrocetin, a reagent used to evaluate canine von Willebrand factor activity. Vet Clin Pathol 16, 64-66. Wang, W.J., and Huang, T.F. (2001). A novel tetrameric venom protein, agglucetin from Agkistrodon acutus, acts as a glycoprotein Ib agonist. Thromb Haemost 86, 1077-1086. Whisstock, J.C., Shen, Y., Lopez, J.A., Andrews, R.K., and Berndt, M.C. (2002). Molecular modeling of the seven tandem leucine-rich repeats within the ligand-binding region of platelet glycoprotein Ib alpha. Thromb Haemost 87, 329-333. Wijeyewickrema, L.C., Berndt, M.C., and Andrews, R.K. (2005). Snake venom probes of platelet adhesion receptors and their ligands. Toxicon 45, 1051-1061. Yap, C.L., Hughan, S.C., Cranmer, S.L., Nesbitt, W.S., Rooney, M.M., Giuliano, S., Kulkarni, S., Dopheide, S.M., Yuan, Y., Salem, H.H., et al. (2000). Synergistic adhesive interactions and signaling mechanisms operating between platelet glycoprotein Ib/IX and integrin alpha IIbbeta 3. Studies in human platelets ans transfected Chinese hamster ovary cells. J Biol Chem 275, 41377-41388. Yeh, C.H., Wang, W.C., Hsieh, T.T., and Huang, T.F. (2000). Agkistin, a snake venom-derived glycoprotein Ib antagonist, disrupts von Willebrand factor-endothelial cell interaction and inhibits angiogenesis. J Biol Chem 275, 18615-18618. Yip, J., Shen, Y., Berndt, M.C., and Andrews, R.K. (2005). Primary platelet adhesion receptors. Iubmb Life 57, 103-108. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45238 | - |
| dc.description.abstract | 出血性蛇毒蛋白具有影響血液凝固和血小板凝集的活性。在本實驗中，將Deinagkistrodon acutus 原毒經由Sephadex G-75、FPLC Superdex75 10/30 GL、FPLC Mono-S 5/50進行純化分析得到P2F4。在15% SDS-PAGE，得知P2F4在非還原狀態下，其分子量為22kDa；若以β-mercaptoethanol還原後，則發現由兩個次單元組成，分子量在10kDa與11kDa。在定序方面，P2F4的序列和目前已知C-type lectin蛇毒蛋白 N端部分有部分相似，N端序列和Botrocetin (α50%；β35%)與Bitiscetin (α50%；β50%)這類vWF刺激劑相似度非常高，然而對於C-type lectin N端保留序列（conserve sequence）CXXXWXXXXXXC並不相符合。
P2F4在血小板懸浮液和富含血小板血漿中，都會有濃度相關性抑制由Ristocetin引發之血小板凝集。在血小板懸浮液，大約45nM即可完全抑制，而在富含血小板血漿中約2.3nM即可達完全抑制，而P2F4在富含血小板血漿有較高抑制活性，但其機轉目前仍不明瞭。但P2F4在高濃度（920nM）下對於collagen（10μg/ml）下會有些微抑制現象產生。但對Thrombin（0.03U/ml）與 ADP（10μM）引發之凝集反應不具抑制作用。利用流式細胞儀分析觀察P2F4和血小板上受體間的關係，發現P2F4可以明顯減少GPⅠb專一性抗體SZ2與AP1對血小板的結合作用，但對α2β1專一性抗體6F1，GPⅥ專一性抗體204.11及6B12， αⅡbβ3專一性抗體7E3對血小板之結合作用卻皆不會有影響。P2F4（4.6nM）可抑制ristocetin所引發之TXA2合成（約50%），且抑制agglucetin引發之P-Selectin表現，因此可以推知P2F4藉由和GPⅠb結合來降低血小板活化。當以靜脈注射時，會延長出血時間，但不引起血小板下降之現象。 由於P2F4是一個在人類富含血小板血漿中具有相當高活性類似C-type lectin的蛇毒蛋白，因此將可進一步在動物模式中評估抗血栓活性，且定出全部序列並和目前已知作用於GPⅠb蛇毒蛋白序列比較，找出活性相關序列，以供學術研究與藥物開發參考。 | zh_TW |
| dc.description.abstract | By using column chromatography of Sephadex G-75, FPLC Superdex75 10/30 GL, and FPLC Mono-S 5/50 GL in sequence, a novel snake venom protein ,P2F4 was purified form Deinagkistrodon acutus venom. It can inhibit ristocetin-induced aggregation in human platelet suspension and human platelet- rich plasma in a concentration dependent manner. P2F4 contains two subunits with molecular weight 10kDa and 11kDa,respectively. Its native molecular was estimated to be 21kDa by gel filtration. The reduced and alkylated α and β subunits were obtained and sequenced, showing the N-terminal sequence of P2F4 was partially similar to those of C-type lectin. However, the N-terminal sequence of P2F4 differed from the conserved sequence (CXXXWXXXXXXC ) of known C-type lectins. The N-terminal sequence of P2F4 was similar to Botrocetin (α50%；β35%)and Bitiscetin (α50%；β50%) two vWF-mediating agonist.
P2F4 exhibits high potency in blocking ristoction-induced aggregation. Its IC50 was estimated to be 2.3nM and 23nM in human platelet-rich plasma and in platelet suspension, respectively. P2F4 inhibited agglucetin-induced aggregation with higher concentration required in blocking ristocetin-induced aggregation. P2F4 can not reverse agglucetin-induced aggregation but can prevent further progression of platelet aggregation. On the other hand, P2F4 can reverse ristocetin- induced aggregation. P2F4 did not inhibit platelet aggregation induced by ADP, or thrombin, P2F4 at higher concentration (920nM) had slight inhibition on collagen-induced aggregation . In flow cytometric assay, P2F4 specifically interrupted GPⅠb mab ( AP1 and SZ2) binding to GPⅠb, while P2F4 did not interfere with the binding of other receptor specific antibody such as 11A12(GPⅥ), 204.11(GPⅥ), 6F1(α2β1), or 7E3(αⅡbβ3). P2F4(4.6nM) reduced TxA2 formation caused by ristocetin about 50% and reduced agglucetin-induced P-selectin expression. As P2F4 was administered intravenously it prolonged the tail bleeding time, and did not cause thrombocytopenia syndrome within 30 min. Taken together, P2F4 is a highly specific GPⅠb antagonist. It is very unique that it exhibits a higher activity in platelet-rich plasma than in platelet suspension. Whether it is a potent antithrombotic agent in vivo needs further investigation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T04:10:14Z (GMT). No. of bitstreams: 1 ntu-99-R96443011-1.pdf: 3652612 bytes, checksum: 75c104c82b7aa86ebee8a3892c60e53f (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 1. 目錄. 1
2. 縮寫表 2 3. 中文摘要4 4. 英文摘要6 5. 緒論 8 6. 實驗材料19 7. 實驗方法20 8. 實驗結果28 9. 結果圖表34 10. 討論 51 11. 參考資料57 | |
| dc.language.iso | zh-TW | |
| dc.title | 一種拮抗Glycoprotein Ⅰb的百步蛇毒蛋白之抗血栓作用之探討 | zh_TW |
| dc.title | The antithrombotic effect of a platelet glycoprotein Ⅰb antagonist derived from Deinagkistrodon acutus venom | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄧哲明,顏茂雄,吳文彬 | |
| dc.subject.keyword | 百步蛇蛇毒蛋白,抗血栓, | zh_TW |
| dc.subject.keyword | glycoprotein Ⅰb,antithrombotic,Deinagkistrodon acutus venom, | en |
| dc.relation.page | 65 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-02-01 | |
| 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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