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研究生:林恆
研究生(外文):Lin Heng
論文名稱:第一型環氧及前列腺環氧在缺氧性腦中風所扮演的保護角色
論文名稱(外文):CYCLOOXYGENASE-1 (COX-1) AND BICISTRONIC COX-1/PROSTACYCLIN SYNTHASE GENE TRANSFER PROTECT AGAINST ISCHEMIC CEREBRAL INFARCTION
指導教授:吳成文林天南
指導教授(外文):Wu C. C.Lin T. N.
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:106
中文關鍵詞:基因治療腦中風前列腺環氧第一型環氧
外文關鍵詞:gene therapyprostaglandinsstrokeischemia
相關次數:
  • 被引用被引用:1
  • 點閱點閱:302
  • 評分評分:
  • 下載下載:42
  • 收藏至我的研究室書目清單書目收藏:3
摘要
由結果得知,在接有外來基因環氧-1,或環氧-1和前列腺環氧病毒刺激下,皆會產生環氧-1和前列腺環氧,進而使老鼠免受腦中風傷害
Abstract
Cerebral ischemia triggers an initial rise in intracellular calcium ion leading to activation of arachidonic acid (AA). AA can be metabolized to prostanoides including prostacyclins, thromboxanes, prostaglandin and HETE via cyclooxygenase (COX) pathway. Prostanoid is important in controlling vascular tone and immune response. However, its role in ischemia reperfusion is not well defined. COX is a rate-limiting enzyme in the oxidation of AA into prostanoid. There are two isoforms of COX COX-1 and COX-2. COX-1 is constitutiveyly expressed, and is thought to be the key enzyme for the production of porstacyclin (PGI2), which is involved in vasodiatatory response of cerebral ischemia. COX-2 is present only in some organ, but its expression is upregulated by inflammation and COX-2 reaction products such as PGE2 are thought to cytotoxicity associated with inflammation. In the present study, gene transfer of COX-1 or COX-1/PGIS into brain cell was used to investigate its underling mechanism, in a well-defined three-vessel occlusion model. COX-1 mRNA and protein levels were upregulated in the ischemic cortex, beginning 24 hours after the onset of reperfusion, and reaching to a peak at 72 hour after reperfusion. We infused adenoviruses (rAd) containing COX-1 (Adv-COX-1), COX-1 and PGIS (Adv-COX-1/PGIS) or Adv-PGK control vector into lateral ventricle of a rat brain with cerebral ischemia. COX-1, PGIS protein and eicosanoid levels as well as infarct volume were then determined. COX-1 and PGIS protein levels were increased in a time- dependent manner. Pre-ischemic injection of Adv-COX-1 reduced the infarct volume by 55%±15 (p<0.01) along with the increasing prostacyclins (PGI2) levels and suppressed leukotrienes (LTC4 and LTB4) levels. Protective effect of infusion Adv-COX-1 on cerebral ischemic rat brains was abrogated by treatment with a COX-1 specific inhibitor SC-560. Adv-COX-1/PGIS infusion selectively augmented PGI2 levels with reduction of other eicosanoids like PGE2, PGD2, LTC4, and LTB4 in the ischemic cortex, and significantly reduced the infarct volume about 60%±10(p<0.01). The effect could be observed when the virus was administered 5 hours after ischemia. Ad -COX-1 or Adv-COX-1/PGIS showed protection effect on the infected C6 glioblastoma and primary cultured astrocytes against hydrogen peroxide insults. Thus, we conclude that COX-1 or/and PGIS and PGI2 upregulation is important for cell survival after ischemic insult. The detailed mechanisms remain to be further characterized.
Table of Content
Page
Acknowledgements Ⅰ
Table of Content---------------------------------------------------------------------------- Ⅱ
Abstract-------------------------------------------------------------------------------------- Ⅴ
List of Table-------------------------------------------------------------------------------- Ⅶ
List of Figure-------------------------------------------------------------------------------- Ⅷ
List of Abbreviation------------------------------------------------------------------------ Ⅸ
中文摘要----------------------------------------------------------------------------------- ⅩⅠ
Chapter
1.Overview---------------------------------------------------------------------------------- 1
2.Introduction------------------------------------------------------------------------------ 4
2.1 Cerebral ischemia-------------------------------------------------------------------- 5
2.2 Biosynthesis of leukotrienes-------------------------------------------------------- 6
2.3 Mechanisms of leukotrienes action------------------------------------------------ 7
2.4 Biosynthesis of prostaglandin------------------------------------------------------ 8
2.5 Mechanisms of prostaglandin action---------------------------------------------- 8
2.6 COX-1 gene characteristic and expression--------------------------------------- 12
2.7 Up-regulation of COX-1 expression ---------------------------------------------- 13
2.8 COX-2 gene characteristic and expression--------------------------------------- 14
2.9 Induction of COX-2 gene expression expression------------------------------- 14
2.10 Biochemistry and crystal structure difference between COX-1 and COX-2--15
2.11 Distribution difference between COX-1 and COX-2------------------------- 16
2.11.1 Microglial cell expression----------------------------------------------- 16
2.11.2 Astrocytic cell expression----------------------------------------------- 17
2.11.3 Neuron cell expression-------------------------------------------------- 17
2.12 Physiological and pathological function difference between COX-1 and COX-2-------------------------------------------------------------------------- 18
2.12.1 Stomach and intestine-------------------------------------------------- 18
2.12.2 Cerebral ischemia------------------------------------------------------- 18
2.13 Specific aim of this study------------------------------------------------------ 20
3. Materials and methods
3.1 Reverse Transcription-Polymersee Chain reaction (RT-PCR)------------------24
3.2 RNA isolation--------------------------------------------------------------------------24
3.3 Northern blot analysis-----------------------------------------------------------------24
3.4 SDS-PAGE/immunoblot analysis -------------------------------------------------- 25
3.5 Preparation of adenoviral vectors carrying gene for COX-1 or COX-1-2----- 26
3.6 Cell culturing conditions------------------------------------------------------------- 27
3.7 Indirect immunofluorescent microscopy------------------------------------------- 27
3.8 In vitro hydrogen peroxide toxicity assay----------------------------------------- 28
3.9 Assay for prostaglandins in vitro -------------------------------------------------- 28
3.10 Stroke Model----------------------------------------------------------------------- -- 29
3.11 Intraventricular infusion of adenoviral construct-------------------------------- 30
3.12 Morphometric Measurement of Infarct Volume--------------------------------- 30
3.13. Statistics------------------------------------------------------------------------------- 31
3.14. Sample preparation in vivo----------------------------------------------------------31
3.15.Quantitative determinations of Prostaglandin E2(PGE2), 6-keto-PGF1α, Thromboxane B2(TXB2)---------------------------------------------------------- 31
3.16. Quantitative determination of Leukotrience B4 (LTB4)----------------------- 32
3.17. Quantitative determination of prostaglandin D2 (PGD2)----------------------- 32
3.18. Quantitative determination of leukotriene C4 (LTC4)-------------------------- 33
3.19. Chemical----------------------------------------------------------------------------- 33
4. Result
4.1. Expression of transgene in rat brain after intraventricular infusion of adenoviral constructs--------------------------------------------------------------- 35
4.2. Expression level of COX-1 protein and mRNA after ischemia-reperfusion in rat brain------------------------------------------------------------------------------- 35
4.3. Intraventricular infusion of Adv-COX-1 and Adv-COX-1/PGIS increased COX-1 and PGIS protein--------------------------------------------------------- 36
4.4. Adv-COX-1 administration increase prostaglandin, prostacyclins and reduced leukotrienes, infarct volume------------------------------------------------------- 36
4.5. Combined COX-1/PGIS gene transfer selective augmented brain prostacyclins levels and reduced infarct volume------------------------------------------------ 38
4.6. A COX-1 specific inhibitor abrogated the protective effect of COX-1 gene transfer------------------------------------------------------------------------------- 39
4.7. Expression of COX-1 and COX-1/PGIS in C6 gliomablastoma or primary culture astrocyte cells transduced with Adv-COX-1or Adv-COX-1/PGIS-- 40
4.8. Adv-COX-1 administration against hydrogen peroxide induced cytotoxicity in vitro---------------------------------------------------------------------------------- 40
4.9. Adv-COX-1/PGIS administration against hydrogen peroxide induced cytotoxicity in vitro---------------------------------------------------------------- 41
4.10. Subcellular localization of COX-1 in C-6 and primary astrocyte cells----- 42
5. Discussion--------------------------------------------------------------------------------- 45
6. References list----------------------------------------------------------------------------- 51
7. Figures------------------------------------------------------------------------------------- 72
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