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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林淑華 | |
| dc.contributor.author | I-Shing Yu | en |
| dc.contributor.author | 游益興 | zh_TW |
| dc.date.accessioned | 2021-06-13T16:55:44Z | - |
| dc.date.available | 2005-06-15 | |
| dc.date.copyright | 2005-06-15 | |
| dc.date.issued | 2005 | |
| dc.date.submitted | 2005-06-08 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/38983 | - |
| dc.description.abstract | Thromboxane A2合成酶(TXA2 synthase)所生產的TXA2具有引發血小板凝集、血管收縮及調節腎臟等功能，且在包含心肌梗塞、中風、氣喘及許多的腎臟疾病發生的過程中均扮演重要的角色。除了參與眾所周知的凝血與血栓形成外，TXA2被認為可能參與血小板生成及淋巴球的分化。為了進一步了解其生理功能，本論文以基因轉殖的方式製作TXA2合成酶基因剔除(TXAS-/-)小鼠模式。分析結果發現TXAS-/-小鼠具有正常的骨髓巨核細胞，其胸腺及脾臟的淋巴球數量也正常。但其出血時間異常且以花生四烯酸(arachidonic acid；AA)刺激TXAS-/-小鼠的血小板，血小板無法凝集且無法釋出TXB2，但是prostaglandin-E2 (PGE2)、PGD2及PGF2α的代謝卻增加。以花生四烯酸注入正常的小鼠血管內會造成小鼠血壓急速下降、心跳停止而導致死亡，但TXAS-/-小鼠或是以TP受體拮抗劑(antagonist)處理過的野生型小鼠卻不會休克。進一步實驗發現在花生四烯酸刺激下，當TP受體存在時，TXAS-/-小鼠可維持正常的血壓，但是當TP受體以拮抗劑阻斷時，血壓即下降，此結果顯示受體參與血壓的維持。此外，本論文發現TXAS缺乏會影響花生四烯酸經lipoxygenase路徑中15-HETE及LTB4的生成，顯示TXA2可調節其他發炎介體(inflammatory mediator)的生成。由目前的實驗結果可知，血小板生成及淋巴球的分化不需TXA2合成酶的參與，缺乏TXA2合成酶會有輕微的凝血缺陷，然而對花生四烯酸的刺激較無反應，且不易產生休克及死亡。TXS-/-小鼠模式將是研究與TXA2及花生四烯酸代謝相關病理現象的良好素材。 | zh_TW |
| dc.description.abstract | Thromboxane A2 (TXA2) has potent actions on platelet aggregation, vasoconstriction, as well as regulating renal hemodynamics. It plays a role in the pathogenesis of a number of disease states including myocardial infarction, thrombotic stroke, bronchial asthma and a variety of renal diseases. Besides its well-recognized role in hemostasis and thrombosis, thromboxane A2 synthase (TXAS) is proposed to be involved in thrombopoiesis and lymphocyte differentiation. To evaluate its various physiological roles, TXAS-deleted mice was generated by gene targeting. TXAS-/- mice had normal bone marrow megakaryocytes, blood platelet counts, and normal CD4 and CD8 lymphocyte counts in thymus and spleen. Platelets from TXAS-/- mice failed to aggregate or generate thromboxane B2 in response to arachidonic acid (AA) but produced increased PGE2, PGD2 and PGF2α. AA infusion caused a progressive drop of mean arterial pressure (MAP), cardiac arrest and death in WT mice, but did not induce shock in TXAS-/- mice, nor in WT and TXAS-/- mice treated with antagonist to the TP receptor. The TXAS-/- mice were able to maintain normal MAP upon AA insult when TP was present but were unable to do so when TP was blocked by an antagonist, suggesting a role of endoperoxide accumulation in influencing MAP. We also found that TXAS deletion can influence 15-HETE and LTB4 production from lipoxygenase pathway, suggested that TXA2 may regulate inflammatory mediator formation. We conclude that TXAS is not essential for thrombopoiesis and lymphocyte differentiation. Its deficiency causes a mild hemostatic defect and protects mice against arachidonate-induced shock and death. The TXAS-deleted mice will be valuable for investigating the roles of arachidonate metabolic shunt in various pathophysiological processes. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T16:55:44Z (GMT). No. of bitstreams: 1 ntu-94-D91424002-1.pdf: 7573765 bytes, checksum: 2eb1ae56f7a19c368e56b9ce7e426871 (MD5) Previous issue date: 2005 | en |
| dc.description.tableofcontents | 摘要 ------------------------------------------------ 1
Abstract ----------------------------------------------- 2 目錄 ----------------------------------------------- 3 圖目錄 ----------------------------------------------- 6 表目錄 ----------------------------------------------- 8 附錄目錄 ---------------------------------------------- 9 縮寫表 ----------------------------------------------- 10 第一章 導論 -------------------------------------- 12 1.1 本章概要 ------------------------------------- 12 1.2 前列腺素的(prostaglandin)早期研究 -------------- 12 1.3 Thromboxane A2 (TXA2)的生成 ------------------- 14 1.4 TXA2的生理功能 ---------------------------- 14 1.5 Thromboxane A2合成酶(TXAS)的分子及生理功能 ------ 15 1.6 TXA2合成酶基因互補DNA的選殖及其重要的氨基酸位置--- 16 1.7 TXA2合成酶的基因結構及多型性對偶基因(allele) ------17 1.8 TXA2合成酶的表現 ---------------------------- 18 1.9 TXA2的受體及基因剔除鼠的相關研究 ---------- 18 1.10 尚待研究的部分及引發本論文的動機 ---------- 19 第二章 TXA2合成酶基因剔除鼠的製造 ------------------- 21 2.1 本章概要 ------------------------------------- 21 2.2 材料與方法 ------------------------------------- 21 2.2.1 小鼠TXA2合成酶genomic DNA基因庫的篩選及基因剔除 載體的構築 ------------------------------------- 21 2.2.2 胚胎幹細胞的培養，轉染及基因剔除胚胎幹細胞的選殖- 22 2.2.3 胚胎幹細胞DNA的製備及南方墨點法 --------- 23 2.2.4 囊胚期細胞注射及嵌合鼠的育種及剔除鼠的基因型鑑定-- 23 2.2.5 反轉錄聚合酶鏈反應(RT-PCR) 及北方墨點法 --------- 24 2.3 結果 ---------------------------------------------- 25 2.3.1 小鼠胚胎幹細胞TXAS基因剔除 ------------------- 25 2.3.2 TXAS-/-小鼠的製造 --- ------------------------ 25 2.4 討論 ---------------------------------------------- 26 2.5 本章結論 ------------------------------------- 27 第三章 TXAS基因剔除鼠的生理及病理分析 ---------- 28 3.1 本章概要 ---------------------------- 28 3.2 材料與方法 ------------------------------------- 28 3.2.1 全血計數，生化分析及病理切片分析 ---------- 28 3.2.2 血小板的電子顯微鏡分析 ------------------- 29 3.2.3 流式細胞儀分析 ---------------------------- 29 3.2.4 出血時間的測量 ---------------------------- 29 3.2.5 血小板凝集及釋放能力分析 ------------------- 30 3.2.6 花生四烯酸(Arachidonic acid)的代謝分析 ---------- 31 3.2.7 小鼠血壓的量測及花生四烯酸引發休克模型 ---------- 31 3.2.8 花生四烯酸代謝產物的測量 -------------------------32 3.2.9 Lipooxygenase代謝路徑相關酵素的RT –PCR分析 ---- 32 3.3結果 ---------------------------------------------- 32 3.3.1 TXAS缺乏不會影響血液中血球組成及血漿中的生化成分-- 32 3.3.2 TXAS缺乏不會影響小鼠主要器官的型態 --------- 33 3.3.3 TXAS缺乏不會影響血小板的生成 ------------------ 33 3.3.4 TXAS缺乏不會影響脾臟及胸腺免疫細胞的組成 ------ 33 3.3.5 TXAS-/-小鼠凝血時間延長且血小板凝集功能異常------ 34 3.3.6 TXAS缺乏的血小板無法代謝AA產生TXA2，且其他產物有 代償性增加的現象 ---------------------------- 35 3.3.7 TXAS缺乏對正常時血壓無影響，但對AA引發的休克反 應具有保護作用 ---------------------------- 35 3.3.8 TXAS缺乏影響AA經lipooxygenase路徑的代謝---------- 36 3.4 討論 ---------------------------------------------- 37 3.5 本章結論 ----------------------------------------- 41 第四章 總結與展望 ----------------------------------- 43 附圖 ---------------------------------------------- 44 附表 ---------------------------------------------- 71 參考文獻 ---------------------------------------------- 77 已發表或投稿之相關論文 ---------------------------- 86 附錄 ------------------------------------------------ 94 | |
| dc.language.iso | zh-TW | |
| dc.subject | Thromboxane A2合成酶 | zh_TW |
| dc.subject | 花生四烯酸 | zh_TW |
| dc.subject | 基因剔除 | zh_TW |
| dc.subject | thromboxane A2 | en |
| dc.subject | rachidonic acid | en |
| dc.subject | nockout | en |
| dc.title | Thromboxane A2合成酶剔除鼠功能研究 | zh_TW |
| dc.title | Investigation of thromboxane A2 synthase knockout mice | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 93-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 李君男,鐘邦柱,吳華林,陶秘華,蔡亭芬,江福田 | |
| dc.subject.keyword | 花生四烯酸,基因剔除,Thromboxane A2合成酶, | zh_TW |
| dc.subject.keyword | thromboxane A2,nockout,rachidonic acid, | en |
| dc.relation.page | 106 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2005-06-08 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫事技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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