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系統識別號 U0026-0812200910450580
論文名稱(中文) 前列腺素E2在子宮內膜異位症基質細胞中功能之探討
論文名稱(英文) Functional Study of Prostaglandin E2 in Endometriotic Stromal Cell
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 91
學期 2
出版年 92
研究生(中文) 許智超
研究生(英文) Chih-Chao Hsu
電子信箱 cutsun@mail2000.com.tw
學號 s3690406
學位類別 碩士
語文別 英文
論文頁數 84頁
口試委員 指導教授-蔡少正
召集委員-黃步敏
口試委員-呂增宏
中文關鍵字 子宮內膜異位症  前列腺素E2  固醇類生合成急性調控蛋白  環氧化酵素-2 
英文關鍵字 PGE2  endometriosis  StAR  COX-2 
學科別分類
中文摘要 子宮內膜異位症之定義為子宮內膜組織存活於子宮腔以外的部分。許多証據顯示子宮內膜異位症是一種高度雌二醇依賴之疾病。本實驗室之前的研究顯示,固醇類生合成急性調控蛋白不正常表現於子宮內膜異位基質細胞,並且能被前列腺素E2所促進。本論文的主要目的是探討控制前列腺素生成的關鍵酵素環氧化酵素-2在子宮內膜異症病理的角色以及揭開前列腺素E2促進固醇類生合成急性調控蛋白表現的分子機制。利用前列腺素E2受體的同功物和拮抗物以及蛋白質激酶的活化物和抑制物,說明了前列腺素E2透過前列腺素E2受體第二亞型活化蛋白質激酶A進而促進固醇類生合成急性調控蛋白的表現,而此作用顯然與負轉錄因子DAX-1的功能無關。為了更進一步了解前列腺素E2促進固醇類生合成急性調控蛋白的表現的分子機轉,我建構了人類的固醇類生合成急性調控蛋白啟動子驅動的報導基因,並將之轉殖入子宮內膜異位基質細胞中。連續切除及定點突變的結果顯示,位於人類固醇類生合成急性調控蛋白啟動子-111到 -119核酸鹼基對的C/EBP反應元素在基礎及前列腺素E2所促進固醇類生合成急性調控蛋白啟動子之活性中扮演關鍵角色。此外,我也發現前列腺素E2能透過前列腺素E2受體第二亞型及蛋白質激酶A誘導環氧化酵素-2蛋白質的表現。總而言之,前列腺素E2藉由與前列腺素E2受體第二亞型結合,活化單磷酸環腺苷-蛋白質激酶A-C/EBP之訊息傳導路徑,進而促進子宮內膜異位基質細胞中固醇類生合成急性調控蛋白基因的表現。而前列腺素E2所誘導之環氧化酵素-2表現將可形成增進固醇類生合成急性調控蛋白表現的正回饋機制,並在子宮內膜異位症的發展中扮演關鍵的角色。
英文摘要 Endometriosis is defined by the presence of viable endometrial tissue outside the uterine cavity and has been suggested to be a highly estrogen-dependent disease. Previous study in our laboratory demonstrated that the steroidogenic acute regulatory protein (StAR) is aberrantly expressed in endometriotic stromal cell and is induced by prostaglandin (PG) E2. This study was designed to characterize the role of cyclooxygenase (COX) -2, the key enzyme controlling PG production, in the pathophysiology of endometriosis and to unravel the molecular mechanism responsible for PGE2-induced StAR expression. By using specific EP receptor agonist/antagonist and selective protein kinase activators/inhibitors, I was able to demonstrate that induction of StAR expression by PGE2 was mediated via EP2-coupled, protein kinase A-dependent pathway. However, the effect of PGE2 was not related with the function DAX-1 (Dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X-chromosome, gene-1), a negative regulator of StAR gene. To further unravel the molecular mechanism responsible for transcriptional regulation of StAR gene expression by PGE2, the human StAR promoter was cloned and transfected into endometriotic stromal cells. Serial deletion and site-direct mutation analyses demonstrated the CCAAT/enhancer-binding protein (C/EBP)response element located in -111 to -119 base pair of StAR promoter is critical for the basal and PGE2-induced promoter activities. Besides, I also found that PGE2 induced COX-2 expression by EP2-PKA signaling. In conclusion, PGE2 activates cAMP-PKA-C/EBP signal pathway via EP2 receptor to stimulate StAR gene expression in endometriotic stromal cell. Moreover, induction of COX-2 by PGE2 suggests a positive feedback loop in augmentation of StAR expression, which may play critical role in the development of endometriosis.
論文目次 Acknowledgments II
Table of Contents III
List of Figure VI
Abbreviation VIII
Abstract
Chinese 1
English 3
Introduction 5
Materials and Methods 18
Tissue collection 18
Isolation and culture of endometriotic stromal cell 18
Subculture 19
Cryopreservation and thawing of the cryopresserved cell 19
In vitro study 19
Isolation of mRNA 20
Quantification of mRNA concentration using standard curve quantitative, competitive RT-PCR (SC-QC-RT-PCR) 21
Isolation of nuclear protein 22
Western blotting 22
Progesterone assay 23
Plasmid construction 25
1) Cloning of human StAR promoter 25
2) Subclone of StAR promoter from PCR2 to pGL3-basic 26
3) Serial deletion 26
4) Site-directed mutagenesis 27
Midipreparation of plasmid DNA 28
Transient transfection and luciferase assay 29
Statistical analysis 30
Results 34
PGE2 induced StAR protein expression in a time dependent manner in endometriotic stromal cell 34

Activation of cAMP-PKA signal pathway induced StAR expression in endometriotic stromal cell 34

Inhibition of cAMP-PKA signal pathway abrogated PGE2-induced StAR protein expression in endometriotic stromal cell 35

The PKA inhibitors inhibited PGE2-induced StAR expression in a dose dependent manner in endometriotic stromal cell 35

The EP2 and EP2/EP4 agonists stimulated StAR protein expression in endometriotic stromal cell 36

EP agonists induced StAR expression was abolished by PKA inhibitor and EP1/EP2 antagonist in endometriotic stromal cell 36

Effect of PKA inhibitor on PGE2-induced progesterone production in endometriotic stromal cell 37

DAX-1 protein level was inversely related to StAR protein level in eutotopic endometrial and endometriotic stromal cell 46

Nuclear level of DAX-1 was unaffected after PGE2 treatment in endometriotic stromal cell 46

PGE2 and EP2 agonist induced StAR promoter activities via activation of PKA signal pathway in endometriotic stromal cell 49

C/EBP response element is required for basal and PGE2-induced StAR promoter activities in endometriotic stromal cell 49

Protein levels of C/EBP and C/EBP protein in endometriotic and endometrial stromal cell 50

PGE2 didn't induce nuclear translocation of C/EBP or C/EBP in endometriotic stromal cells 51

PGE2 induced COX-2 protein expression in a time dependent manner in endometriotic stromal cell 57

PGE2 induced COX-2 protein expression via EP2-cAMP-PKA signal pathway in endometriotic stromal cell 57
Discussion 60
References 71
Appendix (I): Reagent Preparation 80
Appendix (II): Chemical Acquisition 83
Resume 84
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