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研究生:吳煥斌
研究生(外文):Huan-pin Wu
論文名稱:在高血壓分子致病機轉中脂質第二訊息傳遞物質及其調控因子所扮演的角色
論文名稱(外文):Roles of Lipid Second Messengers and Their Modulators in the Molecular Pathogenesis of Hypertension
指導教授:蕭宏昇
學位類別:碩士
校院名稱:國立中山大學
系所名稱:生物科學系研究所
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:2004
畢業學年度:92
語文別:英文
論文頁數:161
中文關鍵詞:孤立束核一氧化氮胰島素高血壓脂質第二訊息傳遞物質
外文關鍵詞:insulinlipid second messengerNTShypertensionnitric oxide
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摘要


磷脂質PI(3,4,5)P3在PI3K細胞訊息傳遞路徑中是扮演第二傳訊者(second messenger)的角色。胰島素(insulin)刺激血管內皮細胞產生一氧化氮(nitric oxide)進而使血管舒張及增加血流量的調控機制也涉及PI3K細胞訊息傳遞路徑。然而一氧化氮也曾經被報導過產生在神經細胞裡面,在此一氧化氮的作用是神經傳導物質(neurotransmitter)。此外,一氧化氮也被報導在孤立束核(NTS)的中樞血壓調控裡扮演著重要的角色。先前在我們實驗室裡,將胰島素微注射到大鼠的孤立束核裡會造成明顯的血壓降低以及心博舒緩的現象,另外也會造成PI3K下游的蛋白激酶Akt的活化。為了研究胰島素在孤立束核裡造成一氧化氮產生更詳細的下游訊息傳遞機制,我們在神經細胞株PC12和GH3裡以及在大鼠的孤立束核裡,研究脂類第二傳信者- PI(3,4,5)P3對一氧化氮產生的影響。將PC12和GH3細胞以10 �嵱 PI(3,4,5)P3處理後,Akt的磷酸化和一氧化氮的產生都增加了。將1 mM PI(3,4,5)P3微注射到SD大鼠的孤立束核裡也會造成血壓降低以及心博舒緩的現象,而且也造成Akt磷酸化的增加。此外,為了研究高血壓的分子致病機轉,我們比較在自發性高血壓大鼠(SHR)和正常血壓的控制組WKY大鼠對PI(3,4,5)P3造成的心血管反應的不同。研究結果顯示,和SHR比較起來,PI(3,4,5)P3在WKY大鼠裡會造成時間較久的血壓下降反應以及在16周大的WKY大鼠會有較大的心博舒緩的反應。 綜合以上結果,PI(3,4,5)P3活化Akt訊息在孤立束核對中樞心血管調控裡扮演一個重要的角色。此外,在自發性高血壓大鼠裡可能是PI(3,4,5)P3的下游基因有缺陷以致於產生高血壓。

Neurogranin (Ng)和neuromodulin (Nm)是一種只在神經細胞表現的蛋白質。Ng和Nm平常是和calmodulin鍵結在一起,因此Ng和Nm可能參與了鈣離子造成的一氧化氮產生的調控。此外,由於Ng和Nm對PI(3,4,5)P3的高親合力,所以Ng和Nm也可能調控PI(3,4,5)P3引發一氧化氮產生之作用。在此研究裡,我們純化了Ng和Nm的合成蛋白及其多株抗體。將Ng (0.3 �慊/�愮)或Nm (0.3 �慊/�愮)微注射到SD大鼠的孤立束核並沒有造成任何的心血管反應。然而,若先將Ng或Nm微注射到SD大鼠的孤立束核則會減弱PI(3,4,5)P3的心血管反應。因此,Ng和Nm在孤立束核裡可能會調控PI(3,4,5)P3的心血管反應。
Abstract


The phospholipid PI(3,4,5)P3 works as a second messenger in PI3K signaling pathway. The PI3K signaling pathway is involved in insulin stimulated nitric oxide (NO) production in vascular endothelium, leading to vasodilation and increased blood flow. However, the production of NO also has been reported in neurons as a neurotransmitter and in nucleus tractus solitarii (NTS), NO plays a role in central cardiovascular regulation. Previously, microinjection of insulin into the NTS of rats produces prominent depressor and bradycardic and activates the PI3K downstream Akt. Therefore, to investigate the detail downstream signaling of insulin stimulated NO production in NTS, the effects of PI(3,4,5)P3 on NO production were determined in neuronal cell lines PC12 and GH3 and in NTS of SD rats. The GH3 and differentiated PC12 exposed to 10�嵱 PI(3,4,5)P3 showed an increase in Akt phosphorylation and in NO production. Microinjection of 1 mM PI(3,4,5)P3 into the NTS of SD rats produces blood pressure depression and bradycardic effects and induces Akt phosphorylation. Moreover, to investigate the molecular pathogenesis of hypertension, the cardiovascular effects of PI(3,4,5)P3 in NTS are compared between spontaneous hypertensive rats (SHR) and the normotensive control Wistar-kyoto rats (WKY). Microinjection of 1 mM PI(3,4,5)P3 into the NTS in WKY produces long term blood pressure depression compared to SHR. In 16 weeks old WKY, PI(3,4,5)P3 also produces the greater bradycardic effects than in 16 weeks old SHR. Taken together, these results suggested that PI(3,4,5)P3 activated Akt signaling in NTS may play a role in central cardiovascular regulation. Moreover, there may be something defect in PI(3,4,5)P3 downstream in SHR, leading to the hypertention.

Neurogranin (Ng) and neuromodulin (Nm) are neural-specific and Ca2+-sensitive calmodulin (CaM)-binding protein which may be involved in the regulation of Ca2+ dependent NO production. In addition, since the high affinity of Ng and Nm with PI(3,4,5)P3, Ng and Nm may also modulate the NO production induced by PI(3,4,5)P3. The recombinant proteins and specific antibodies of Ng and Nm are prepared for this study. Microinjections of Ng or Nm into the NTS of SD rats do not induce any cardiovascular effects. However, pretreatment of Ng (0.3 �慊/�愮) or Nm (0.3 �慊/�愮) can attenuate the cardiovascular effects of PI(3,4,5)P3. Thus, Ng and Nm may modulate cardiovascular effects of PI(3,4,5)P3 in NTS.
Contents


Contents 1
Abbreviations 2
中文摘要 4
English Abstract 6
Chapter 1
General Introduction
1.1 Backgrounds and Significance 9
1.2 Specific Aims 20
1.3 References 21
Chapter 2
Lipid Second Messenger Activated Akt/PKB Signaling in the Nucleus Tractus Solitarii Contributes to Central Cardiovascular Regulation
2.1 Summary 28
2.2 Introduction 30
2.3 Materials and Methods 34
2.4 Results 41
2.5 Discussion 47
2.6 References 54
Figures and Figure Legends 59
Chapter 3
Roles of Neurogranin and Neuromodulin in Nucleus Tractus Solitarii
3.1 Summary 84
3.2 Introduction 85
3.3 Materials and Methods 89
3.4 Results 101
3.5 Discussion 106
3.6 References 110
Figures and Figure Legends 114
Chapter 4
Future Perspectives
4.1 Future Perspectives 134
4.2 References 138
Appendix 139
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