醫學研究科

[醫研科行政業務] [動物研究實驗室]

[心臟血管研究室] [神經結構與功能研究室] [流行病學研究室]

[細胞藥理學研究室] [基因工程研究室] [感染疾病與免疫學研究室] [癌症基因體研究室]

Principal Investigator: 曾清俊 (Ching-Jiunn Tseng, M.D., Ph.D.)

Assistant Investigator: 王怜藺(Ling-Lin Wang)

Research Assistant: 吳依珊,陳信宏, 陳柏榮 研究生:何文譽,葉同成,孫國清,鄭文翰,陳湘茹,蕭君輝

Room：3651 TEL：(07) 3422121-1504 & 1505

cjtseng@vghks.gov.tw      FAX：(07) 3468056    

Research Interest:

Central control of the cardiovascular system is complex and still not well understood. The central nervous system receives sensory information from many sources and sends out appropriate regulatory signals to several effecter organs. It has been suggested that disturbances of these regulatory mechanisms may be involved in chronic elevation in systemic arterial pressure. For instance, abnormalities in central autonomic control may occur early in the course of borderline hypertension, and then over a period of years, through a sequence of secondary changes, lead to essential hypertension. Indeed, the neuronal circuitry in the brain is so complex that we still do not known the precise mechanisms of the depressor effect of some of the most commonly employed antihypertensive drugs. But the more we understand about central cardiovascular regulatory mechanisms, the more we can assess its role in cardiovascular disease, and the more rationally we can approach new drug development.

Based on this background, our laboratory focused on:

1.   Investigation of central cardiovascular regulation, various neurotransmitters and neuropeptides (such as adrenaline, noradrenaline, nitric oxide, adenosine, nicotine, angiotensin II, III, neuropeptide Y, etc) were applied in the studies. 2.   Investigation of the pathogenesis of essential hypertension. 3.   Research and development of new antihypertensive agents.

 

1. 生理紀錄器 2 套
2. 立體定位儀
3. 一氧化氮分析儀
4. 生命源氨分析儀
5. 蛋白質電泳分析儀
6. 聚合?鏈鎖反應器
7. 酵素免疫分析儀
8. 螢光顯微鏡
9. 無菌操作台
10. 二氧化碳培養排煙櫃

　Education:

• 1974-1981 M.D. National Defense Medical Center. 1984-1988 Ph.D. Vanderbilt University, U.S.A.

Honors and Awards       

• 1987 年獲得 ASPET (American Society of Pharmacology and Experimental Therapeutics)之“
• Travel Award”，參與該會在夏威夷的第38界國際年會。
• 1988年獲得 Vanderbilt University 之“ Graduate Student Travel Award”獎助,參與American
• Federation for Clinical Research之國際年會。
• 1993 年獲得國科會八十二年度優等研究獎。
• 1994 年獲得國科會八十三年度優等研究獎。
• 1995 年獲得中華藥理學會該年度傑出研究獎。
• 1996 年獲得行政院年度優等研究獎。
• 1997 年獲得嚴慶齡基礎醫學傑出獎。
• 1999 年獲得中華民國基礎神經科學會王世濬院士傑出研究講座。
• 2003 年獲得行政院退除役官兵輔導委員會模範公務員。
• 2006 Outstanding Research Award行政院退輔會
• 2008 Outstanding Research Award 2008.8.27 (高雄榮民總醫院)
• 2008 Outstanding Research Award 2008.9.1 (行政院退輔會)

最近十年之研究成果:

本實驗室在過去十年期間，有極大的研究專注在氣體性分子(含一氧化氮(NO)及一氧化碳(CO))在中樞心臟血管調控所扮演的角色。我們和其它實驗室利用免疫組織化學方法，NADPH-diaphorase staining, 或autoradiography等方法已証實在腦幹內，尤其在孤立束核(NTS)及頭腹外側腦幹區(RVLM)均存在有高濃度之nNOS 。在我們最早期之研究報告指出NO確實參與在中樞心臟血管調控，而且此作用與交感神經活性之抑制有關。本研究成果在1996年發表於Hypertension後，曾獲得該領域國內外同好的熱烈迴響，迄今共有169次被文獻引用。在此論文發表後，我們陸續深入的探討NO，麩胺酸(Glutamate)及(adenosine)在NTS內的交互用及其作用機轉，成果分別發表在十多篇1996~2002年之學術期刊。

從2003年迄今，研究主軸仍是NTS，但實驗室內成功建立了一些分子生物學相關之技術，幫助我們解釋了一些從前感覺困惑之問題，同時亦可以較深入的探討一些NTS內重要神經傳遞物質的分子機轉。有了此些技術之幫忙，讓本實驗室在往後的論文發表品質方面有極大的提昇效果。此期間，在一氧化碳之研究，我們發現在NTS內，一氧化碳，腺?及麩胺酸三者之間的交互作用與NO是類似的，彼此之間會促進另一物質之釋放。另外，我們亦發現在NTS內，Heme oxygenase/CO之徑路可能couple到NOS之活化更進而促進NO釋放而參與到心臟血管功能的調節作用。在最近的一個研究成果中，我們利用免疫組織化學染色方法進一步証實了在NTS內，HO-1 (inducible Heme oxygenase)乃是負責CO之產生，而非HO-2(constitutive Heme oxygenase)，更進而影響到中樞心臟血管之調控作用。

基因治療是最近這十幾年來醫界認真在推動及執行之一治療方法。在最近幾年我們實驗室亦引進了此一觀念，期望能在不明原因性高血壓的治療上有些突破。我們選用自發性高血壓大鼠(SHR)為essential hypertension之動物模式，以腺病毒encoded eNOS 做gene transfer之研究，結果有很不錯的發現gene transfer後，這些原本高血壓之動物之血壓會降低到正常血壓且維持約二個星期之久。可惜，兩個星期後血壓又慢慢回復高血壓狀態。我們目前仍持續在做此方面之研究，希望藉由使用Adeno-associated virus(AAV)來做為vector，一方面可以減少gene transfer過程中感染之情形，另一方面可以延長transfer到NTS後作用之時間，目前我們可以monitor到半年以上的作用時間，此方面將是一個未來可以持續發展之方向。

代謝症候群(Metabolic syndrome)之產生包含有幾個重要的risk factor，其中高血壓及insulin resistance是相當重要之兩個因素，我們從2003年開始由中樞神統系統探討insulin resistance及高血壓對該症候群之影響，並尋求臨床的治療方法。首先，我們以微量注射、免疫組織化學染色及西方墨點方法率先報導insulin-PI3K-AKT-NOS之訊息傳遞徑路存在孤立束核內並對心臟血管之調控扮演著極重要之角色。該論文被接受刊登於2004年Circulation, 受到國內外學術界極大之重視。

腺?一直是我們實驗室內有興趣探討之一神經調節物質，20年前，本人曾在Hypertension發表過腺?在NTS的心臟血管作用，最近我們利用建立完成之分子生物學技術深入探對其分機轉，首先在文獻報導了腺?在孤立束核內之心臟血管作用乃透過活化adenosine-ERK-eNOS signaling pathway而達成。該論文在2008年元月刊登於Criculation，讓本實驗室研究成員士氣大振。後續我們亦探討了幾個NTS內與心臟血管有關之重要的神經傳遞物或神經胜?(如Neuropeptide Y, IGF-1等)，其成果已陸續投稿中。

Representative publications:

1.Tseng, C.J., Mosqueda-Garcia, R., Appalsamy, M., Robertson, D.: Cardioveffeascular cts of microinjection of neuropeptide Y in rat brainstem nuclei. Circ Res. 1989; 64: 55-61.

2.Tseng, C.J., Lin, H.C., Wang, S.D. and Tung, C.S. Immunohistochemical study of catecholamine and neuropeptide Y (NPY) in the rostral ventrolateral medulla and bulbospinal projection. J Comp Neurol. 1993; 334: 294-303.

3.Tseng, C.J., Chou, L.L., Ger, L.P. and Tung, C.S. Cardiovascular effects of angiotensin III in brainstem nuclei of normotensive and hypertensive rats. J Pharmacol Exp Ther. 1994; 268: 558-564.

4.Tseng, C.J., Ho, W.Y., Lin, H.C., Tung, C.S. and Kuan, C.J. Modulatory effects of endogenous adenosine on epinephrine secretion from the adrenal medulla of the rat. Hypertension. 1994; 24: 714-718.

5.Tseng, C.J., Liu, H.Y., Lin, H.C., Ger, L.P., Tung, C.S. and Yen M.H. Cardiovascular effects of nitric oxide in the brainstem nuclei of rats. Hypertension. 1996; 27:36-41.

6.Lo, W.C., Lin, H.C., Ger, L.P., Tung, C.S., Tseng, C.J. The cardiovascular effects of nitric oxide and NMDA receptors in the nucleus tractus solitarii of rats. Hypertension. 1997; 30: 1499-1503.

7.Lo, W.C., Jan, C.R., Wu, S.N., Tseng, C.J. The cardiovascular effects of nitric oxide and adenosine in the nucleus tractus solitarii of rats. Hypertension. 1998; 32: 1034-1038.

8.Lin, H.C., Wan, F.J., Kang, B.H., Wu, C.C., Tseng, C.J. Systemic administration of lipopolysaccharide induces release of nitric oxide and glutamate and c-fos expression in the nucleus tractus solitarii of rats. Hypertension. 1999; 33: 1218-1224.

9.Lin, H.C., Wan, F.J., Tseng, C.J. Modulation of cardiovascular effects produced by nitric oxide and ionotropic glutamate receptor interaction in the nucleus tractus solitarii of rats. Neuropharmacology. 1999; 38:935-941.

10.Lo, W.C., Jan, C.R., Chiang, H.T., Tseng, C.J. Modulatory effects of carbon monoxide on baroreflex activation in the nucleus tractus solitarii of rats. Hypertension. 2000.35:1253-1257.

11.Lin, C.H., Hsiao, M., Lo, W.C., Tseng, C.J. The Interaction of carbon monoxide and adenosine in the nucleus tractus solitarii of rats. Hypertension. 2003;42:380-385.

12.Tai, M.H., Hsiao, M., Lo, W.C., Wang, F.S., Liu, G.S., Chan, J.Y.H., Howng, S.L., Tseng, C.J. Gene delivery of eNOS into nucleus tractus solitarii modulates cardiovascular functions in spontaneously hypertension rats. Am. J. Hypertension. 2004; 17:63-70.

13.Lin, C.H., Lo, W.C., Hsiao, M., Tung, C.S., Tseng, C.J.. Interactions of carbon monoxide and metabotropic glutamate receptor groups in the nucleus tractus solitarii of rats. J Pharmacol Exp Ther. 2004; 308:1213-8.

14.Lo, W.C., Hsiao, M., Tung, C.S., Tseng, C.J. The cardiovascular effects of nitric oxide and carbon monoxide in the nucleus tractus solitarii of rats. J. Hypertension. 2004; 22: 1183-1190.

15.Huang, H.N., Lo, W.C., Lin, C.H., Lu, P.J., Hsiao, M., Tseng, C.J. In-situ AKT phosphorylation in the nucleus tractus solitarii is involved in the central cantrol of blood pressure and heart rate. Circulation. 2004; 110:2476-2483.

16.Lo, W.C., Lu, P.J., Ho, W.Y., Hsiao, M., Tseng, C.J. Induction of heme oxygenase-1 is involved in CO mediated central cardiovascular regulation. J Pharmacol Exp Ther.2006, 318: 8-16.

17.Tai MH, Weng WT, Lo WC, Chan JY, Lin CJ, Lam HC, Tseng CJ. Role of nitric oxide in alpha-melanocyte-stimulating hormone-induced hypotension in the nucleus tractus solitarii of the spontaneously hypertensive rats. J Pharmacol Exp Ther. 2007 321:455-61.

18.Ho W.Y., Lu P.J., Hsiao M., Hwang H.R., Tseng Y.C., Yen M.H., Tseng C.J. Adenosine modulates cardiovascular functions through activation of extracellular signal-regulated kinases 1 and 2 and endothelial nitric oxide synthase in the nucleus tractus solitarii of rats. Circulation. 2008, 117:773-780.

19.Hsiao M., Lu P.J., Huang H.N., Lo W.C., Ho W.Y., Lai T.C., Chiang H.T., Tseng C.J. Defective phosphatidylinositol 3-kinase signaling in central control of cardiovascular effects in the nucleus tractus solitarii of spontaneously hypertensive rats. Hypertensive Res. 2008, 31:1209-1218.

20.Chiang H.T.,Cheng W.H., Lu P.J.,Huang H.N., Lo W.C., Tseng Y.C., Hsiao M., Tseng C.J. nNOS activation is involved in insulin mediated Cardiovascular effects in the NTS of rats. Neuroscience 2009, in press.