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洪錦堂

洪錦堂 (Jim-Tong Horng)

職稱:教授

研究室名稱:細胞生物學實驗室

最高學歷Ph.D.

學校/國家:劍橋大學/英國

分機號碼5156

電子郵件帳號 jimtong@mail.cgu.edu.tw

個人網頁網址:http://memo.cgu.edu.tw/jim-tong/index.htm

研究室現有: 博士後研究員2

博士班研究生6

碩士班研究生7

專任研究助理3

大學部專題生2

 

研究方向研究室特色(10/13/2012更新)

1. Studies of EV71-induced unfolded protein response:

當折疊不完全或折疊錯誤的蛋白質留置在內質網,影響到內質網的功能,即會導致「內質網壓力」 (ER stress)。細胞為因應內質網壓力會啟動細胞存活的機制unfolded protein response (UPR)。此機制可藉由磷酸化eIF2轉譯因子的a次單元以抑制蛋白質的轉譯。另外,也可透過活化ATF6IRE1的下游路徑提高ER-resident chaperones,如GRP78/BiPGRP94等基因在轉錄層次上的活性,增加此類蛋白質在細胞內的含量,以協助蛋白質折疊,進而舒緩內質網壓力。我們發現,宿主細胞感染腸病毒後宿主及病毒蛋白質的轉譯皆受到抑制;ATF6IRE1的下游路徑也被活化。但是,與內質網壓力誘發劑dithiothreitol (DTT)thapsigargin不同的是,腸病毒感染後chaperones量的增加主要在蛋白質層次而非mRNA量的增加所致。我們使細胞大量表達GRP78/BiP以抑制UPR,發現病毒感染此細胞後,病毒mRNA的量相較於感染野生型細胞為多。因此,我們認為腸病毒71型所誘發的unfolded protein response (UPR)在宿主細胞內扮演著防禦性的角色。我會進一步探討UPR是否與腸病毒所造成重症有關。

2. Development and mechanistic study of anti-influenza virus inhibitors:

流行性感冒是一具有高度傳染性與導致急性呼吸道疾病的傳染病,此外還能感染各種不同物種族群的動物以及導致重複性的感染,主因是因為流行感冒病毒具備高突變性,高度傳染力及跨物種特性,因此流行性感冒病毒已被認為會對全球公共衛生安全造成嚴重的威脅。我們從臨床中藥複方或單味中藥,來開發與篩選具抗流行性感冒病毒活性的中藥,作為另一種選擇,以及因應可能爆發之流行性感冒大流行疫情。另外 我們參與國家製藥型計畫,開發新穎小分子抗流感藥物,在作用機轉的研究方面,於病毒感染細胞株的不同時間點的研究(time-course assay),了解藥物抑制病毒感染的時間點在病毒與接受器結合之前或之後。再以分子生物學的研究模式,包括對於核醣核酸合成的抑制作用(mRNA synthesis)、對病毒蛋白質合成的抑制作用(Viral protein synthesis)、對viral polymerase cap-bindingendonuclease的抑制作用(cap-binding and endonuclease inhibition assay)、對hemagglutinationneuraminidase的抑制作用(Hemagglutination and neuraminidase inhibition test)等,來研究有效中藥或小分子抗流感藥物抑制病毒感染的作用機轉。(長庚校訊第88)

3. Identification and functional study of genes targeted by virus-induced microRNAs:

miRNA是一段約22nt的非編碼RNA,可以結合到標的基因的3’端非轉譯區,其功能為調控基因表現,miRNA已証實在病毒複製及抗病毒免疫扮演重要的角色。我們探討病毒感染所誘發miRNA的改變,再利用定量PCR確認。我們將鑑定這些miRNA標的宿主蛋白及功能研究,利用轉錄體學(基因微陣列晶片)及蛋白質體學(SILAC)的方法,或利用生物資訊學分析(如下圖),以鑑定miRNA之標的基因,並進一步探討這些基因與病毒複製病毒毒性之關係。

最近五年所發表論文*corresponding author

1. Tang, W.F., Yang, S.Y., Wu, B.W., Jheng, J.R., Chen, Y.L., Shih, C.H., Lin, K.H., Lai, H.C., Tang, P., Horng*, J.T., 2007. Reticulon 3 binds the 2C protein of enterovirus 71 and is required for viral replication. The Journal of biological chemistry 282, 5888-5898.

2. Wu, B.W., Pan, T.L., Leu, Y.L., Chang, Y.K., Tai, P.J., Lin, K.H., Horng*, J.T., 2007. Antiviral effects of Salvia miltiorrhiza (Danshen) against enterovirus 71. The American journal of Chinese medicine 35, 153-168.

3. Lin, T.Y., Liu, Y.C., Jheng, J.R., Tsai, H.P., Jan, J.T., Wong, W.R., Horng*, J.T., 2009. Anti-enterovirus 71 activity screening of chinese herbs with anti-infection and inflammation activities. The American journal of Chinese medicine 37, 143-158.

4. Jheng, J.R., Lau, K.S., Tang, W.F., Wu, M.S., Horng*, J.T., 2010. Endoplasmic reticulum stress is induced and modulated by enterovirus 71. Cellular microbiology 12, 796-813.

5. Shih#, S.R., Horng#, J.T., Poon, L.L., Chen, T.C., Yeh, J.Y., Hsieh, H.P., Tseng, S.N., Chiang, C., Li, W.L., Chao, Y.S., Hsu, J.T., 2010. BPR2-D2 targeting viral ribonucleoprotein complex-associated function inhibits oseltamivir-resistant influenza viruses. The Journal of antimicrobial chemotherapy 65, 63-71.

6. Yeh#, J.Y., Coumar#, M.S., Horng#, J.T., Shiao, H.Y., Kuo, F.M., Lee, H.L., Chen, I.C., Chang, C.W., Tang, W.F., Tseng, S.N., Chen, C.J., Shih, S.R., Hsu, J.T., Liao, C.C., Chao, Y.S., Hsieh, H.P., 2010. Anti-influenza drug discovery: structure-activity relationship and mechanistic insight into novel angelicin derivatives. Journal of medicinal chemistry 53, 1519-1533.

7. Shih, S.R., Chu, T.Y., Reddy, G.R., Tseng, S.N., Chen, H.L., Tang, W.F., Wu, M.S., Yeh, J.Y., Chao, Y.S., Hsu, J.T., Hsieh, H.P., Horng*, J.T., 2010. Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity. Journal of biomedical science 17, 13.

8. Wu, M.S., Yen, H.R., Chang, C.W., Peng, T.Y., Hsieh, C.F., Chen, C.J., Lin, T.Y., Horng*, J.T., 2011. Mechanism of action of the suppression of influenza virus replication by Ko-Ken Tang through inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway and viral RNP nuclear export. Journal of ethnopharmacology 134, 614-623.

9. Hsu, J.T., Yeh, J.Y., Lin, T.J., Li, M.L., Wu, M.S., Hsieh, C.F., Chou, Y.C., Tang, W.F., Lau, K.S., Hung, H.C., Fang, M.Y., Ko, S., Hsieh, H.P., Horng*, J.T., 2012. Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus. Antimicrob Agents Chemother 56, 647-657.

10. Chang, C.W., Leu, Y.L., Horng*, J.T., 2012. Daphne Genkwa sieb. Et zucc. Water-soluble extracts act on enterovirus 71 by inhibiting viral entry. Viruses 4, 539-556.

11. Hsieh, C.F., Lo, C.W., Liu, C.H., Lin, S., Yen, H.R., Lin, T.Y., Horng*, J.T., 2012. Mechanism by which ma-xing-shi-gan-tang inhibits the entry of influenza virus. Journal of ethnopharmacology 143, 57-67.

12. Jheng, J.R., Lin, C.Y., Horng*, J.T., Lau, K.S., 2012. Inhibition of enterovirus 71 entry by transcription factor XBP1. Biochemical and biophysical research communications 420, 882-887.

13. Yeh, J.Y., Coumar, M.S., Shiao, H.Y., Lin, T.J., Lee, Y.C., Hung, H.C., Ko, S., Kuo, F.M., Fang, M.Y., Huang, Y.L., Hsu, J.T., Yeh, T.K., Shih, S.R., Chao, Y.S., Horng*, J.T., Hsieh, H.P., 2012. Anti-influenza Drug Discovery: Identification of an Orally Bioavailable Quinoline Derivative through Activity- and Property-Guided Lead Optimization. ChemMedChem 7, 1546-1550.

14. Hsieh, C.F., Yen, H.R., Liu, C.H., Lin, S., Horng*, J.T., 2012. Ching-fang-pai-tu-san inhibits the release of influenza virus. Journal of ethnopharmacology. In press

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