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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 黃德富 | |
dc.contributor.author | Pei-Lin Ho | en |
dc.contributor.author | 何佩陵 | zh_TW |
dc.date.accessioned | 2021-06-13T04:30:07Z | - |
dc.date.available | 2006-08-02 | |
dc.date.copyright | 2006-08-02 | |
dc.date.issued | 2006 | |
dc.date.submitted | 2006-07-20 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/33226 | - |
dc.description.abstract | 蛇毒成分中,有一類含 RGD 序列之低分子量強力血小板凝集抑制劑,稱作抗黏著蛇毒蛋白 (Disintegrin), Accutin、 Triflavin、 Rhodostomin 皆是屬於 Disintegrin。此類蛋白不僅可抑制 fibrinogen 結合到血小板 integrin αIIbβ3,也能阻斷其他細胞與 RGD 有相關性的黏著分子的結合反應。我們從台灣的百步蛇原毒中精製出 accutin。 Accutin 為一種血小板凝集抑制劑,可依濃度相關性的抑制 collagen 引發的凝集反應。 AP2 為醣蛋白 IIb/IIIa 即 integrin αIIbβ3 之 IgG1 單元抗體,本身也有抑制血小板凝集的作用。但若在血小板懸浮液中加入 accutin 和 AP2 這兩個抑制劑卻發現血小板凝集的現象 ; 這個現象在其他 disintegrin 和 AP2 作用也都有相同的結果,因此, disintegrin 都可以和 AP2 一起活化血小板。此外, accutin 和 AP2 會促使許多蛋白質的磷酸化,包括 PLCγ2、 FAK、 PI3K、 Syk、 Src 和 LAT 。而一些抑制劑,如 PP2、 piceatennol、 U73122、 LY294002 和 quinacrine 皆會抑制 accutin 和 AP2 造成的凝集反應, cytochalasin D 也會完全抑制 accutin/AP2 活化血小板作用,顯示 cytoskeleton 受到活化。 Accutin 和 AP2 也會引起細胞內鈣離子的移動,並產生大量的 thromboxane A2, indomethacin 可以拮抗其引發之凝集反應; 藉由流式細胞儀來探討他們和血小板間的結合程度,可發現在 disintegrin 的存在下可增加 AP2 和血小板之間的結合反應 ; 在 AP2 的存在下,也可增加 disintegrin 和血小板之間的結合反應。 accutin 和 AP2 還可促使血小板 P-selectin 的高度表現。由於血小板上有 Fc receptor, FcγRIIA (CD32),會和 IgG 分子產生免疫反應,從實驗結果得知, FcγRIIA mAb 不僅會抑制兩者所引發的凝集反應, 且完全抑制 P-selectin release。
綜合上述, accutin/AP2 的活化乃經由 FcγRIIA 和醣蛋白 GPIIb/IIIa 之交互作用而來,他們的活化是透過多種 kinases 的磷酸化並產生細胞內鈣離子之游離如大量的 thromboxane A2,來引發血小板之活化和凝集 ; accutin 和 AP2 一起存在時可促進彼此對GPIIb/IIIa 的結合,還可促使 P-selectin 的表現。目前使用在臨床上GPIIb/IIIa 拮抗劑最常發生的副作用就是thrombocytopenia,而這個活化反應或許可以當成類似 thrombocytopenia 的模式,可進一步探討它產生的機制。 | zh_TW |
dc.description.abstract | Disintegrins, a family of low molecular weight, cysteine-rich, Arg-Gly-Asp (RGD) containing peptides derived from snake venoms, inhibit platelet aggregation by antagonizing fibrinogen binding to platelet glycoprotein IIb/IIIa. Accutin, a member of disintegrin (5241 daltons) derived from venom of Agkistrodon acutus, potently inhibits platelet aggregation induced by thrombin, collagen and ADP. AP2, a monoclonal antibody (IgG1) raised against GPIIb/IIIa, also inhibits the aggregation of platelets. Both disintegrin and AP2, bind to GPIIb/IIIa, leading to blockade of fibrinogen binding to activated platelets and subsequent aggregation response. However, if accutin and AP2 are present in platelet suspension, they paradoxically induced platelet aggregation. We also found other disintegrin, triflavin and rhodostomin also induced platelet aggregation in the presence of AP2.
In platelet suspension, accutin and AP2 induced tyrosine phosphorylation of signal molecules, e.g. PLCγ2, FAK, PI3K, Syk, Src and LAT. We also detected that intracellular Ca2+ mobilization in the process. Using flow cytometric analysis, we found that disintegrin enhanced AP2 binding to platelets, and AP2 also increased disintegrin binding to platelets. The combined AP2 and accutin activated platelets and caused marked expression of P-selectin and produced high amount of thromboxane B2. Indomethacin completely inhibited thromboxane A2 formation, leading to inhibition of platelet aggregation caused by accutin/AP2. The activity of accutin/AP2-induced platelet aggregation was totally inhibited by a Syk inhibitor, PP2 (10μM) or a Src inhibitor, piceatannol (10μg/ml). Besides, quinacrine (100μM), PLA2 inhibitor completely blocked aggregation. We also found that cytochalasin D (10μM) blocked the response, indicating cytoskeletal movement is essential for aggregation. U73122 and LY294002 inhibited accutin/AP2-induced aggregation. FcγRII mAb (1μg/ml) completely suppressed shape change and aggregation cuased by accutin/AP2, so FcγRIIA may play a role in this activation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T04:30:07Z (GMT). No. of bitstreams: 1 ntu-95-R93443018-1.pdf: 2164657 bytes, checksum: 9c32d879e6de79fb14da55b089174a60 (MD5) Previous issue date: 2006 | en |
dc.description.tableofcontents | 1. 縮寫表…………………………………………….. 1
2. 中文摘要………………………………………….. 3 3. 英文摘要………………………………………….. 5 4. 緒論………………………………………………...7 5. 實驗材料…………………………………………...16 6. 實驗方法…………………………………………...18 7. 實驗結果…………………………………………...24 8. 圖表………………………………………………...33 9. 討論………………………………………………...50 10.結論與未來展望…………………………………...59 11.參考文獻……………………………………….... 61 | |
dc.language.iso | zh-TW | |
dc.title | 蛇毒蛋白disintegrin與單元抗體AP2引發血小板凝集機轉之探討 | zh_TW |
dc.title | Platelet Activation Caused by Disintegrin and a GPIIb/IIIa Monoclonal Antibody AP2 | en |
dc.type | Thesis | |
dc.date.schoolyear | 94-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 鄧哲明,王寧,顏茂雄,楊春茂 | |
dc.subject.keyword | 蛇毒蛋白,血小板活化,單元抗體, | zh_TW |
dc.subject.keyword | disintehrin,GPIIb/IIIa,platelet activation, | en |
dc.relation.page | 70 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2006-07-21 | |
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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