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龔思豪

          

 

學歷

南佛羅里達大學

微生物與免疫學 博士

國立陽明大學

醫事技術 學士

現職及經歷

國立陽明大學

醫學生物技術暨檢驗學系 副教授

國立陽明大學

醫學生物技術暨檢驗學系 助理教授

美國賓州大學

病理系 博士後研究

 

研究領域

 

腸病毒及登革熱病毒的致病機制及藥物開發。

人類腸病毒是小兒科的重要致病原。台灣地區在過去十餘年爆發了數波大小不一的腸病毒流行,而腸病毒71型則是造成重症的主要因子。然而,臨床上目前還沒有抗病毒藥治療腸病毒71型,而疫苗的發展尚在臨床試驗階段。因此,我們實驗室長期以來研究腸病毒的致病機制及開發抗腸病毒藥物。另外,台灣南部地區過去有數波的登革熱大流行,也是沒有臨床抗病毒藥物。因此,我們近年來也開始從事登革熱藥物開發。總之目前實驗室有以下三個研究方向:

(A) 腸病毒感染與細胞的互動-細胞自體吞噬

所謂細胞自體吞噬(autophagy),指細胞能夠藉由形成自噬體(autophagosome) 與細胞內溶酶體(lysosome) 融合,將自身的胞器(organelle)或其他物質進行分解,以進行回收再利用,是調控細胞生長、分化、體內平衡的重要機轉。近年來發現,腸病毒感染細胞後,會引導類自噬體(autophagosome- like)膜狀結構的產生,作為其病毒基因體複製的場所。病毒並會抑制自噬體與溶酶體融合的步驟,以逃避寄主細胞溶酶體的分解酶降解腸病毒的組成物,進而完成病毒的生命週期。這個現象已經見諸於許多腸病毒的感染,然而,腸病毒感染如何誘導細胞自噬體產生的分子機制至今未明。因此,闡明腸病毒誘導細胞自噬體產生的分子機制為本實驗室的研究重點。了解其作用機制,不但能更加認識寄主細胞與病毒的互動模式,也有助於發展藉由抑制細胞自噬體的抗腸病毒藥物。

  

(B) 開發抗腸病毒藥物

本實驗室已經應用螢光共振能量轉移(fluorescence resonance energy transfer; FRET)的原理發展抗腸病毒藥物篩選平台從1280個小分子組成的藥庫 (drug library) 篩選出數個具抑制腸病毒複製的化合物,其中有數個藥物是美國食品藥物管理局批准,臨床上用於治療其他疾病的藥物,目前其中一個藥物idarubicin已經闡明其作用機制是選擇性抑制腸病毒轉譯,其他幾個藥物的作用機制在研究當中。由於這些臨床用藥的在人體的藥物動力學及安全性已經了解相當清楚,如能將舊藥新用,將有助於加速抗腸病毒藥物的發展。這幾個新找到的藥物目前已經在申請美國專利中。

(C) 開發抗登革熱病毒藥物

    目前在研發抗登革熱病毒藥物的新穎篩藥平台,有助於快速篩選及鑑定抗登革熱病毒藥物。並針對幾個有潛力的化合物,研究其抑制登革熱病毒複製的作用機制。

 

抑腸病毒試劑認證

本實驗室已經發展出抑制環境中腸病毒試劑的標準測試流程在經由廠商與學校簽約委託後可鑑定待測試劑的效用並出具正式檢驗報告至今已經有數家廠商經此管道認證其產品的抑腸病毒效能得以據此向相關主管單位申請產品的功效

 

代表著作

Hou HY, Lu WW, Wu KY, Lin CW, Kung SH (2016). Idarubicin is a broad-spectrum enterovirus replication inhibitor that selectively targets the virus internal ribosomal entry site. J Gen Virol. 97(5): 1122-33.

Lu WW, Kung FY, Deng PA, Lin YC, Lin CW, Kung SH. (2016). Development of a fluorescence resonance energy transfer–based intracellular assay to identify novel enterovirus 71 antivirals. Arch. Virol. Accepted.

Lu JR, Lu WW, Lai JZ, Tsai FL, Wu SH, Lin CW, Kung SH.(2013) Calcium flux and calpain-mediated activation of the apoptosis-inducing factor contribute to enterovirus 71-induced apoptosis. J Gen Virol. 94(7):1477-85.

Lu WW, Sun JR, SS Wu, Lin WH, Kung SH (2011). A dual reporter cell assay for identifying serotype and drug susceptibility of herpes simplex virus. Analytical Biochemistry. Aug 15;415(2):97-104.

Li SW, Lai CC, Ping JF, Tsai FJ, Wan L, Lin YJ, Kung SH, Lin CW. (2011). Severe acute respiratory syndrome coronavirus papain-like protease suppressed alpha interferon-induced responses through downregulation of extracellular signal-regulated kinase 1-mediated signalling pathways. Journal of General Virology. 92:1127-40.

Hsu YY, Liu YN, Lu WW, Kung SH. (2009). Visualizing and quantifying the differential cleavages of the eukaryotic translation initiation factors eIF4GI and eIF4GII in the enterovirus-infected cell. Biotechnol Bioeng. 104(6):1142-52.

Tsai MT, Cheng YH, Liu YN, Liao NC, Lu WW, Kung SH. (2009). Real-time monitoring of human enterovirus (HEV)-infected cells and anti-HEV 3C protease potency by fluorescence resonance energy transfer. Antimicrob Agents Chemother. 53(2):748-755.

Hsu YY, Liu YN, Wang W, Kao FJ, and Kung SH. (2007). In Vivo Dynamics of Enterovirus Protease Revealed by Fluorescence Resonance Emission Transfer (FRET) based on a novel FRET pair. Biochem Biophys Res Commun. 353, 939–945.

Kung SH, Wang SF, Huang CW, Hsu CC, Liu HF, Yang JY. (2007). Genetic and antigenic analyses of enterovirus 71 isolates in Taiwan during 1998-2005. Clin Microbiol Infect. 13(8):782-7.

Ghukasyan V, Hsu YY, Kung SH, Kao FJ. (2007). Application of fluorescence resonance energy transfer resolved by fluorescence lifetime imaging microscopy for the detection of enterovirus 71 infection in cells. J Biomed Opt. 12(2):024016.

Lu WW, Hsu YY, Yang JY, Kung SH. (2004). Selective inhibition of enterovirus 71 replication by short hairpin RNAs. Biochem Biophys Res Commun. 325(2):494-9.

1998-2002

Kuo YC, Lin LC, Tsai WJ, Chou CJ, Kung SH, Ho, YH.. Samarangenin B from Limonium sinense suppresses herpes simplex virus type 1 replication in Vero cells by regulation of viral macromolecular synthesis. Antimicrobial Agents and Chemotherapy 2002;46(9):2854-2864

Y-C Wang, C-L Kao, W-T Liu, J-R Sun, Y-E Tai, and Kung SH.. A Cell Line That Secretes Inducibly a Reporter Protein for Monitoring Herpes Simplex Virus Infection and Drug Susceptibility. Journal of Medical Virology 2002;68(4):599-605.

Kuo, RL, Kung, S.H., Hsu, YY, and Liu, WT. Infection with Enterovirus 71 or expression of its 2A protease induces apoptotic cell death. Journal of General Virology 2002;83:1367-1376.

Tai, H.Y., Sun, K.H., Kung, S.H., Liu, W.T. A quantitative assay for measuring human foamy virus using an established indicator cell line. Journal of Virological Methods 2001;94:155-162.

Liu, W.T., Sun, JR, Lin, CH, Kuo RL, and Kung SH.. An indicator cell assay for detection of human cytomegalovirus based on enhanced green fluorescent protein. Journal of Virological Methods 2001;96:85-92.

Kung, S.H., Wang, Y.C., Lin, C.H., Kuo, R.L., and Liu, W.T. Rapid diagnosis and quantification of herpes simplex virus with a green fluorescent protein reporter system. Journal of Virological Methods 2000;90:205-212.

Kung, S.H., Hagstrome, J.N., Cass, D., Tai, S.J., Lin, H.F., Stafford, D. and High K.A.. Human coagulation factor IX corrects the bleeding diathesis of mice with hemophilia B. Blood 1998;91:784-790.

Nakai, H., Herzog, R.H., Hagstrome, J.H., Walter, J.H., Kung, S.H., Yang, E.Y., Tai, S.H., Iwaki, Y., Kurtzman, G.J., Fisher,K.J., Colosi,P., Couto, L.B., and High, K.A.. Adeno-associated viral vector-mediated gene transfer of human blood coagulation factor IX into mouse liver. Blood 1998;91:4600-4607.

Herzog, R.W., Hagstrome, J.N., Kung, S.H., Tai, S.J., Wilson, J.M., Fisher, K. J., and High, K.A. Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus. Proceedings of the national academy of sciences of the United States of America 1997;94:5804-5809.

Kung, S.H. and Medveczky, P. Identification of a Herpesvirus saimiri cis-acting DNA fragment that permits stable replication of episomes in transformed T cells. Journal of Virology 1996;70:1738-1744.