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系統識別號 U0026-0812200911330139
論文名稱(中文) 纖維母細胞生長因子-9對雄性小鼠萊氏細胞固醇類生成之影響
論文名稱(英文) The effect of fibroblast growth factor-9 on steroidogenesis in normal mouse Leydig cells
校院名稱 成功大學
系所名稱(中) 細胞生物及解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 93
學期 2
出版年 94
研究生(中文) 蔡志謙
研究生(英文) Chih-Chien Tsai
電子信箱 n_asnas@yahoo.com.tw
學號 T9692102
學位類別 碩士
語文別 英文
論文頁數 55頁
口試委員 指導教授-黃步敏
指導教授-蔡少正
口試委員-郭余民
中文關鍵字 固醇類生成  纖維母細胞生長因子-9  萊氏細胞 
英文關鍵字 FGF-9  steroidogenesis  Leydig cells 
學科別分類
中文摘要 先前的研究指出,纖維母細胞生長因子-9在生物胚胎發育時期扮演重要的角色,其中一項功能是影響睪丸的發育。研究指出,在缺乏纖維母細胞生長因子-9表現的小鼠,不但其中胚層的細胞減少,也會導致肺臟發育較為不全;而且其睪丸生成有從雄性轉變成為雌性的情況發生,由此也顯示出纖維母細胞生長因子-9的訊息調節對於睪丸功能的發展,扮演決定性的角色。然而,纖維母細胞生長因子-9對於雄性小鼠萊氏細胞固醇類生成會造成的影響,至今仍然未有定論。因此,本篇論文的目的在於探討纖維母細胞生長因子-9對於未成熟雄性小鼠萊氏細胞固醇類生成之影響及調節機制。結果顯示,隨著濃度及時間的增加,纖維母細胞生長因子-9具有刺激未成熟小鼠萊氏細胞睪固酮的生成。另外,我們也在小鼠的萊氏細胞上偵測到FGFR2IIIb,FGF3IIIb及FGF3IIIc這三種纖維母細胞生長因子受器傳訊者核醣核酸的表現。在探討纖維母細胞生長因子-9對未成熟小鼠萊氏細胞固醇類生成之訊息傳導調節部份,我們發現,FPT inhibitor III這種Ras的抑制劑能夠抑制由纖維母細胞生長因子-9所誘導的睪固酮生成。SB203580這種p38 MAPK的抑制劑,及wortmannin這種PI3K的抑制劑,皆能個別抑制由纖維母細胞生長因子-9所誘導的睪固酮生成。H89這種PKA的抑制劑也能夠抑制由纖維母細胞生長因子-9所誘導的睪固酮生成。MEK1/2的抑制劑(U0126)、ERK1/2的抑制劑(PD98059)、PLCγ的抑制劑(U73122與ET-18-OCH3)、PKC的抑制劑(staurosporine與calphostin C)、及calmodulin的拮抗劑(W7),對纖維母細胞生長因子-9所誘導的睪固酮生成則無任何影響。西方點墨法及反轉錄酶聚合酶鏈聚反應的實驗結果顯示,纖維母細胞生長因子-9能有效的刺激磷酸化p38 MAPK蛋白質的表現,及固醇類速控蛋白(StAR)在蛋白質上及傳訊者核醣核酸的表現。總結,纖維母細胞生長因子-9可能是藉由與纖維母細胞生長因子受器結合,活化Ras-p38-MAPK、PI3K以及PKA傳導路徑,進一步去調控固醇類速控蛋白的表現以刺激小鼠萊氏細胞睪固酮之生成。



英文摘要 Fibroblast growth factors-9 (FGF-9), a potent mitogen for mesenchymal cells, is necessary for fetal testicular development, and can be localized inside adult testis. It has been demonstrated that mice with FGF-9-knockout exhibit lung hypoplasia and male-to-female sex reversal, indicating a novel role for FGF signaling in testicular functions. However, the effect of FGF-9 on steroidogenesis in immature mouse Leydig cells remains elusive. Thus, the aim of this study is to investigate the effect and the regulatory mechanism of FGF-9 on steroidogenesis in immature mouse Leydig cells. The results showed that FGF-9 could stimulate testosterone in immature mouse Leydig cells with dose-dependent manner. The stimulatory effect of FGF-9 reached maximum in 24 hr. The expression of FGFR2IIIb, FGF3IIIb and FGFR3IIIc mRNA were detected in immature mouse Leydig cells. Ras inhibitor, FPT inhibitor III, could suppress the FGF-9-stimulated testosterone production. Both p38-MAPK inhibitor (SB203580) and PI3K inhibitor (wortmannin) could suppress the FGF-9-stimulated testosterone production, respectively. PKA inhibitor, H89, could also suppress the FGF-9-stimulated testosterone production. MEK1/2 inhibitor (U0126) and ERK1/2 inhibitor (PD98059) could not affect the FGF-9-stimulated testosterone production. U73122 and ET-18-OCH3 (PLCγ inhibitor), staurosporine and calphostin C (PKC inhibitor), and W7 (calmodulin antagonist) did not affect the FGF-9-stimulated testosterone production, respectively. FGF-9 did induce the expression of phospho-p38 MAPK protein, Steroidogenic acute regulatory (StAR) protein, and StAR mRNA in immature mouse Leydig cells. Taken together, FGF-9 might bind to FGFRs and then act through Ras-p38-MAPK, PI3K and PKA signaling pathways to induce the expression of StAR protein, and thus stimulate the testosterone production in immature mouse Leydig cells.


論文目次 Table of contents

Acknowledgements---------------------------------------------------------------------------
Table of Contents------------------------------------------------------------------------------I
List of Table------------------------------------------------------------------------------------III
List of Figures----------------------------------------------------------------------------------IV
Abstract in Chinese--------------------------------------------------------------------------- 1
Abstract----------------------------------------------------------------------------------------- 2
Introduction------------------------------------------------------------------------------------ 3
Materials and Methods----------------------------------------------------------------------- 9
Chemicals----------------------------------------------------------------------------------- 9
Animals------------------------------------------------------------------------------------- 10
Leydig cell isolation----------------------------------------------------------------------- 10
Cell culture--------------------------------------------------------------------------------- 11
Radioimmunoassay (RIA) --------------------------------------------------------------- 11
Immunoblot Analysis--------------------------------------------------------------------- 12
Isolation of total RNA-------------------------------------------------------------------- 13
Reverse transcription-polymerse chain reaction (RT-PCR) ------------------------- 14
Statistical analysis------------------------------------------------------------------------- 14
Results----------------------------------------------------------------------------------------- 16
FGF-9-induced steroidogenesis with dose-dependent manner
in normal mouse Leydig cells------------------------------------------------------- 16
FGF-9-induced steroidogenesis with time-dependent manner
in normal mouse Leydig cells------------------------------------------------------- 16
Expression of FGFR isoforms in normal mouse Leydig cells-----------------------16
FGF-9-induced steroidogenesis is Ras-p38 MAPK signal pathway dependent,
but Ras-MEK-ERK signal pathway independent
in normal mouse Leydig cells------------------------------------------------------- 17
FGF-9-induced steroidogenesis require the activation of PI3K signal pathway
in normal mouse Leydig cells------------------------------------------------------- 18
FGF-9-induced steroidogenesis is PLCγ signal pathway independent
in normal mouse Leydig cells------------------------------------------------------- 18
FGF-9-induced steroidogenesis require the activation of PKA signal pathway
in normal mouse Leydig cells------------------------------------------------------- 19
FGF-9-induced steroidogenesis is PKC signal pathway independent
in normal mouse Leydig cells------------------------------------------------------- 19
FGF-9-induced steroidogenesis is Ca2+ signal pathway independent
in normal mouse Leydig cells------------------------------------------------------- 20
FGF-9 induces the expression of phospho-p38 MAPK
in normal mouse Leydig cells------------------------------------------------------- 20
FGF-9 induces the expression of StAR protein
in normal mouse Leydig cells------------------------------------------------------- 21
FGF-9 induces the expression of StAR protein
in normal mouse Leydig cells------------------------------------------------------- 21
Discussion------------------------------------------------------------------------------------- 23
References------------------------------------------------------------------------------------- 47
About the author------------------------------------------------------------------------------ 58

List of Table
Table 1 Sequence of primers used for reverse transcription-polymerase chain
Reaction (RT-PCR)------------------------------------------------------------- 15

List of Figures

Fig. 1. Dose effects of FGF-9 on testosterone production in normal mouse
Leydig cell.------------------------------------------------------------------------- 28

Fig. 2. Time course effects of FGF-9 on testosterone production in normal
mouse Leydig cell.--------------------------------------------------------------- 29

Fig. 3. Expression of FGFR2IIIb mRNA stimulated by FGF-9 in normal
mouse Leydig cells.-------------------------------------------------------------- 30

Fig. 4. Expression of FGFR3IIIb mRNA on stimulated by FGF-9 in normal
mouse Leydig cells.-------------------------------------------------------------- 31

Fig. 5. Expression of FGFR3IIIc mRNA stimulated by FGF-9 in normal
mouse Leydig cells.-------------------------------------------------------------- 32

Fig. 6. Effects of FPT inhibitor III on FGF-9-stimulated testosterone
production in normal mouse Leydig cells.------------------------------------ 33

Fig. 7. Effects of U0126 on FGF-9-stimulated testosterone
production in normal mouse Leydig cells.------------------------------------ 34

Fig. 8. Effects of PD98059 on FGF-9-stimulated testosterone
production in normal mouse Leydig cells.------------------------------------ 35

Fig. 9. Effects of SB203580 on FGF-9-stimulated testosterone
production in normal mouse Leydig cells.------------------------------------ 36

Fig. 10. Effects of wortmannin on FGF-9-stimulated testosterone
production in normal mouse Leydig cells.------------------------------------ 37

Fig. 11. Effects of U73122 on FGF-9-stimulated testosterone
production in normal mouse Leydig cells.------------------------------------ 38

Fig. 12. Effects of ET-18-OCH3 on FGF-9-stimulated testosterone
production in normal mouse Leydig cells.------------------------------------ 39

Fig. 13. Effects of H89 on FGF-9-stimulated testosterone
production in normal mouse Leydig cells.------------------------------------ 40

Fig. 14. Effects of staurosporine on FGF-9-stimulated testosterone
production in normal mouse Leydig cells.------------------------------------ 41

Fig. 15. Effects of calphostin C on FGF-9-stimulated testosterone
production in normal mouse Leydig cells.------------------------------------ 42

Fig. 16. Effects of W7 on FGF-9-stimulated testosterone
production in normal mouse Leydig cells.------------------------------------ 43

Fig. 17. Effect of FGF-9 on the expression of phospho-p38 MAPK in normal
mouse Leydig cells.-------------------------------------------------------------- 44

Fig. 18. Expression of phosphor-p38 MAPK stimulated by FGF-9 in normal
mouse Leydig cells.-------------------------------------------------------------- 45

Fig. 19. Expression of StAR mRNA stimulated by FGF-9 in normal
mouse Leydig cells.-------------------------------------------------------------- 46
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