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  • 1. Taiwan International Graduate Program Molecular Medicine Program Faculty Institute of Biomedical Sciences / National Yang Ming University
  • 2. Taiwan International Graduate Program Molecular Medicine Program Institute of Biomedical Sciences Faculty 2
  • 3. Name in Chinese:張程 Name in English:Chang, Chen Education: University of Alabama at Birmingham Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3032, 886-2-2789-9027 Fax:886-2-2788-7641 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/cchang_c.htm E-mail:bmcchen@ibms.sinica.edu.tw Fields of Specialty: Functional MRI/S , Neuroscience Research Description: My research focus primarily on the development and application of magnetic resonance imaging and spectroscopy techniques for the study of brain metabolic, functional and structural alterations in a variety of cerebral diseases. Specific goals include: 1) developing and validating diffusion and perfusion MRI to evaluate the changes in cerebral hemodynamics as a result of brain damage; 2) combining BOLD-, diffusion tensor- and manganese- MRI to study the functional connectivity in rat brains; 3) developing molecular imaging techniques in studying specific biological pathways, and cell and gene therapy; 4) developing MR microscopy at cellular resolution to follow key intercellular and intracellular events; and 5) developing in vivo localized 1H NMR spectroscopy to investigate the biochemical and physiological integrity of the brain. We have established a functional and micro-magnetic resonance imaging center (FMIC) core facility in 2002 to serve the Medical Genomics Program. The core is dedicated to: (1) provide state of 3
  • 4. the art MRI equipments and comprehensive MR technical support, including experimental design, targeted technology development and imaging data analysis; (2) promote collaborative links between the MR and basic science research, and (3) educate and train researchers, fellows, and students in the use of MR imaging technologies in biomedical research. FMIC provides cutting-edge magnetic resonance techniques, emphasizing on providing anatomical, biochemical, functional, genetic and pharmacological information in vivo for small animals. Selected Recent Publication: 1. Chang, C. and Shyu, B. C. A fMRI Study of Brain Activations During Non-noxious and Noxious Electrical Stimulatiion of the Sciatic Nerve of Rats. Brain Res., 2001; 897:71-81.. 2. Sun, S. W.; Song, S. K.; Hong, C. Y.; Chu, W. C.; and Chang, C. Improving Relative Anisotropy Measurement using Directional Correlation of Diffusion Tensors. Mag. Reson. Med., 2001; 46:1079-1087. 3. Lin, T. N.; Sun, S. W.; Cheung, W. M.; Li, Fuhai and Chang C. Dynamic Changes in Cerebral Blood Flow and Angiogenesis after Transient Focal Cerebral Ischemia in Rats: Evaluation with Serial MRI. Stroke, 2002; 33: 2985 - 2991. 4. Song, S.K.; Sun, S.W.; Ramsbottom, M.J.; Chang, C.; Russell, J. and Cross, H. Dysmyelination Revealed through MRI as Increased Radial (But Unchanged Axial) Diffusion of Water. NeuroImage, 2002; 17:1429-1436. 5. Sun, S. W.; Song, S. K.; Hong, C. Y.; Chu, W. C.; and Chang, C. Directional correlation characterization and classification of white matter tracts: Magn. Reson. Med. 2003; 49:271-275. 6. Lee, W. T. and Chang, C. Magnetic Resonance Imaging and Spectroscopy in Assessing 3- Nitropropionic Acid-Induced Brain Lesions: Animal Model of Huntington's Disease. Progress in Neurobiology 2004, 72:87-110. 7. Shyu, B.C.; Lin, C. Y.; Sun, J.J.; Chen, S. L. and Chang, C. BOLD response to direct thalamic stimulation reveals functional connection of the medial thalamus and anterior cingulate cortex in the rat. Magn. Reson. Med (in press). 8. Shyu, B.C.; Lin, C. Y.; Sun, J.J.; Chen, S. L.; Sylantyeva, S.and Chang, C. A method for direct thalamic stimulation in fMRI studies using a glass-coated carbon fiber electrode. J. Neuro. Methods (in press). 4
  • 5. Name in Chinese:常蘭陽 Name in English:Lan-Yang Ch’ang Education:Vanderbilt University Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Associate Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3940, 886-2-2789-9128 Fax:886-2-2785-8847 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/lychang_c.html E-mail:lychang@ibms.sinica.edu.tw Fields of Specialty:Genomics, Bioinformatics Research Description: Our research objective is to dissect the complexity of human biology from the perspectives of genome, transcriptome and proteome. It is thus of critical importance to establish in the laboratory appropriate technological competence that enables the study of large-scale biology. The ultimate goal of this undertaking is to understand better how the complex genetic networks operate and govern all aspects of biological processes in living organisms. The human genomic sequence, completed in 2003, provides us a genetic framework for examining the complexity of life. The functionality of each annotated gene will be described in the context of its biological role under normal physiology or in response to external factors. In the revolutionary era of new biology, this knowledge foundation will greatly assist us to identify genes involved in various disease processes for future development of diagnostic, therapeutic and preventive measures. Our ongoing research efforts cover three major areas of interest: 5
  • 6. (1.) Functional Genomics A complexity reduction technology has been developed for profiling the expressed genes in normal and diseased conditions, and during early embryogenesis. DNA microarray has also been set up for the analysis of gene expression pattern. Recently we have begun to characterize the function of novel genes in the human genome by the molecular and cellular approaches as well. (2) Bioinformatics We have developed an alternative algorithm –CRASA– for mapping the expressed sequence tags (ESTs) to the genome, which enables us to annotate the transcribed sequence in the public databases. A fully automated gene annotation pipeline has been established for large-scale EST-to- genome mapping. In addition we are in process of developing a new algorithm for the identification of evolutionarily conserved syntenic markers in the mammalian genomes. (2.) Human Genetic Diversity Sequence variation among different individuals accounts for 0.1% of our genomic content. Yet, the biological consequence, or phenotype, is often dictated by the polymorphic genotypes functioning alone or interacting with environmental factors. Currently, we are developing a haplotyping technique to address the correlation between genotype and phenotype using the human disease model. Selected Recent Publication: 1. J.-Y. Chiu, C.-S. Liu, L.-Y. Ch'ang and W.-C. Lin. Comparative Ping-pong Analysis of EST Databases. J. Genet. & Mol. Biol. 2:94-100, 2002. 2. S.-J. Wei, W.-K. Yang, L.-Y. Ch'ang, D.-M. Yang, Y.-M. Hung and W.-C. Lin. Combination Gene Therapy of Cancer: Granulocyte-Macrophage Colony Stimulating Factor Enhances Tumor Regression Induced by Herpes Simplex Virus Thymidine Kinase/ Ganciclovir "Suicidal" Treatment in a Mouse Tumor Model. J. Genet. & Mol. Biol. 3:194- 208, 2002. 3. T.-J. Chuang, W.-c. Lin, H.-C. Lee, C.-W. Wang, K.-L. Hsiao, Z.-H. Wang, D. Hsieh, S.C. Lin and L.-Y. Ch'ang. A Complexity Reduction Algorithm for Analysis and Annotation of Large Genomic Sequence. Genome Res. 13:313-322, 2003 4. Lin, T.-Y., Twu, N.-K., Ho, M.-S., Ch'ang, L.-Y., and Lee, C.-Y. Enterovirus 71 outbreak, Taiwan: occurrence and recognition. J. Emerging Inf. Dis. 9:291-293, 2003. 5. Liu, C.C. and Ch'ang, L.-Y. Down-regulation of human NDR gene in megakaryocytic 6
  • 7. differentiation of erythroleukemia K562 cells. J. Biomed. Sci. 11:104-111, 2004. 7
  • 8. Name in Chinese:趙麗洋 Name in English:Chau, Lee-Young Education:University of Kentucky Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3931, 886-2-2789-9137 Fax:886-2-2785-8847 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/ lychau_c.html E-mail:lyc@ibms.sinica.edu.tw Fields of Specialty:Cardiovascular Diseases, Inflammation, Gene therapy Research Description: Cardiovascular diseases are the leading cause of morbidity and mortality in developed countries. As the worldwide incidence of cardiac diseases continues to increase steadily, fully understanding the pathological mechanisms underlying the disease development at the molecular and genetic levels as well as developing new successful approaches for the therapeutic intervention imposes a great challenge in biomedical research nowadays. The research interests in my laboratory include the development of gene-based therapeutic treatment for the diseases, and the identification of disease- related genes using ENU-mutagenesis approach. Besides, we are very interested in the study of the cytoprotective function of heme oxygenase-1 (HO-1), which is a stress-inducible enzyme to catalyze the degradation of prooxidant heme to produce carbon monoxide (CO), bilirubin and free iron. Recent studies from our liaboratory and others have demonstrated that HO-1 plays an important role in iron homeostasis and exerts potent anti-inflammatory effect via CO, although the mode of action is not yet 8
  • 9. clear. Experiments are ongoing to elucidate the signaling network underlying the protective function of HO-1. Furthermore, the therapeutic potential of HO-1 in treating cardiovascular diseases was explored in animal models. Selected Recent Publication: 1. Lee T-S., Yen, H-C., Pan, C-C. and Chau, L-Y. The role of interleukin 12 in the development of atherosclerosis in apoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 19: 734-742, 1999. 2. Pang, J-H.S. and Chau, L-Y. Copper-induced apoptosis and immediate early gene expression in murine J774.A1 macrophages. Atherosclerosis. 146: 45-52, 1999. 3. Ai, L-S. and Chau, L-Y. Post-transcriptional regulation of H-ferritin mRNA: Identification of a pyrimidine-rich sequence in 3'-untranslated region associated with message stability in human monocytic THP-1 cells. J. Biol. Chem. 274: 30209-30214, 1999. 4. Lee, T-S. and Chau, L-Y. Fas/Fas ligand-mediated pathway is involved in oxidized LDL-induced apoptosis in vascular smooth muscle cells. Am. J. Physiol.Cell Physiol. 280: C709-C718, 2001. 5. Juan, S-H., Lee, T-S., Tseng, K-W., Liou, J-Y., Shyue, S-K., Wu, K-K. and Chau, L-Y. Adenovirus- mediated heme oxygenase-1 gene transfer inhibits the development of atherosclerosis in apoE- deficient mice. Circulation 104, 1519-1525, 2001. 6. Lee, T-S. and Chau, L-Y. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat. Med. 8, 240-246, 2002. 7. Chen, Y-H., Lin, S-J., Lin, M-W., Tsai, H-L., Kuo, S-S., Chen, J-W., Charng, M-J., Wu, T-C., Chen, L-C., Ding, P.Y-A., Pan, W-H., Jou, Y-S., and Chau, L-Y. Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients. Hum. Genet. 111:1-8; 2002 8. Lee, T-S., Tsai, H-L., and Chau, L-Y. Induction of heme oxygenase-1 expression in muirne macrophages is essential for the anti-inflammatory effect of low dose 15-deoxy-△12,14- prostaglandin J2. J. Biol. Chem. 278:19325-19330; 2003. 9. Chen, Y-H, Chau, L-Y, Lin, M-W, Chen, L-C, Yo, M-H, Chen, J-W, and Lin, S-J. Heme oxygenase-1 gene promotor microsatellite polymorphism is associated with angiographic restenosis after coronary stenting. Eur Heart J. 25:39-47; 2004. 10. Hu, C-M., Chen, Y-H., Chiang, M-T., and Chau, L-Y. Heme oxygenase-1 inhibits angiotension II- induced cardiac hypertrophy in vitro and in vivo. Circulation accepted pending revision; 2004. 9
  • 10. Name in Chinese:陳志成 Name in English:Chen, Chih-Cheng Education:University College London, UK Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Assistant Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3917, 886-2-2789-9057 Fax:886-2-2782-9224 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/ccchen_c.html E-mail:chih@ibms.sinica.edu.tw Fields of Specialty: Pain, Neurobiology, Gene Targeting, Mouse Genetics Research Description: Acid (protons) is one of the major factors in pain sensation. High concentrations of protons or tissue acidosis occur in pain associated with inflammation, ischemia, tumors, etc. Therefore, the study of genes involved in acid signaling will be beneficent to the development of new analgesic drugs. We have cloned a few acid-sensing ion channels (ASICs) from sensory neurons and generated ASIC3 knockout and transgenic mice. From the study of ASIC3 knockout mice, we have confirmed that ASIC3 is involved in pain sensation. In many nociceptive tests, we found that mice lack of the ion channels showing hyperalgesic behaviors. This result was surprising but provided us a new insight of role of protons, which may be involved in many different physiological functions. Thus, we will continue screening and cloning the receptor genes for protons, as well as studying their roles in pain sensation and other physiological functions by using transgenic and knockout mice models. Specific projects include: 1. Transgenic & knockout mouse model of human familial disautonomia. 10
  • 11. 2. Pain behavior alteration of mice lack of proton-gated ion channel ASIC3 3. The roles of acid-sensing ion channels in sensory neurons. 4. Genetic mapping and molecular cloning of genes involved in acid-signaling and nociception Selected Recent Publication: 1. Chen, C.-C., Zimmer, A.M., Sun, W.H., Hall, J.E., Brownstein, M.J., and Zimmer, A. (2002). A role for ASIC3 in the modulation of high-intensity pain stimuli. Proc. Natl. Acad. Sci. USA 99, 8992-8997. 2. Akopian, A.N., Chen, C.-C., Ding, YN., Cesare, P., and Wood, J.N. (2000). A new member of the acid-sensing ion channel family. Neuroreport 11, 2217-2222. 3. Akopian, A.N., Chen, C.-C., Souslova, V., Okuse, K., and Wood, J.N. (2000). Sensory neuron- specific ion channels and receptors. In: Molecular Basis of Pain Induction, ed Wood, J.N., Wiley- Liss Inc., pp.113-128 4. Chen, C.-C., England, S., Akopian, A.N., and Wood, J.N. (1998). A sensory neuron-specific, proton-gated ion channel. Proc. Natl. Acad. Sci. USA 95, 10240-10245. 5. Krylova, O., Chen, C.-C., Akopian, A., Souslova, V., Okuse, K., Abson, N., Ravenal, S., and Wood, J.N. (1997). Ligand-gated ion channels of sensory neurons: from purines to peppers. Biochemical Society Transactions 25, 842-844. 6. King, B., Chen, C.-C., Akopian, A.N., Burnstock, G., and Wood, J.N. (1997). A role for calcineurin in the desensitisation of P2X3. Neuroreport 8, 1009-1102. 7. Chen, C.-C., Akopian, A.N., Sivilotti, L., Colquhoun, D., Burnstock, G., and Wood, J.N. (1995). A P2X purinoceptor expressed by a subset of sensory neurons Nature 377, 428-431. 8. Hsu, Y.L., Chen, C.-C., and Wu, J.L. (1995). Molecular relationships in infectious pancreatic necrosis virus. Virus Research 37, 239-252. 11
  • 12. Name in Chinese:張久瑗 Name in English:Chen, Joanne Jeou-Yuan Education:University of Minnesota Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Associate Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3966, 886-2-2789-9046 Fax:886-2-2785-8594 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/jychen_c.html E-mail:bmchen@ibms.sinica.edu.tw Fields of Specialty:Cancer Genomics, Molecular and Tumor Biology Research Description: A major problem in the management of patients with cancer is the lack of specific tumor markers for the early detection, the accurate prediction of the biological behavior and the accurate assessment of prognosis. The identification of tumor-associated candidate genes provides an answer to this problem. Gastric cancer (GC) is highly prevalent. To systematically dissect the pathways that are involved in the initiation and progression of this disease, various approaches of representational difference analysis (RDA) have been taken to isolate gastric cancer-associated genes. By genomic RDA, chromosomal instability and microsatellite instability have been determined in GC at a genome- wide level. A subset of GC was characteristic of high microsatellite instability as the result of mutations in mismatch repair genes. In other GCs, distinct patterns of chromosomal instability and DNA copy number changes are tightly associated with specific clinicopathologic features. Candidate gene approach is underway to further explore he regions that may harbor candidate oncogenes or 12
  • 13. tumor suppressor genes dominating the pathogenic development of specific subtypes of GC. By various mRNA RDA, we have identified two thousands more genes that are differentially expressed in GC. A gastric cancer gene chip based on the cDNA of these genes was established and microarray hybridization was performed followed by cluster analyses to identify candidate genes associated with the pathogenic development of GC of specific histopathologic subtypes and stages. Genes that are involved in various pathways regulating cell proliferation or survival are focused and the potential usage of them as molecular markers for GC patients is evaluated. By proteomics, we are using humoral antibodies elicited in the sera of GC patients as reagents to isolate tumor antigens, with the hope to identify overexpressed candidate genes that may play important roles in gastric tumorigenesis. The goals of these studies are to provide a broad scope of the genetic events that are involved in the pathogenic development of gastric adenocarcinoma, with the hope to establish better choices of useful diagnostic and prognostic markers, and in the long run, to provide us the common denominator for understanding, treating, and preventing this disease. Selected Recent Publication: 1. Lo, P.-K., Chen, J.-Y., Tang, P.-P., Lin, J., Lin, C.-H., Su, L.-T., Wu, C.-H., Chen, T.-L., Yang, Y. and Wang, F.-F.* Identification of a mouse thiamine transporter gene as a direct transcriptional target for p53. J. Biol. Chem. 276: 37186-37193, 2001. 2. Wu, C.-W., Chen, G.-D., Fann, C. S.-J., Lee, A. F.-Y., Chi, C.-W., Liu, J. M., Weier, U. and Chen, J.-Y.* Clinical implications of chromosomal abnormalities in gastric adenocarcinomas. Genes, Chromosomes and Cancer. 35:219-231, 2002. 3. Huang, C.-J. and Chen, J.-Y.* Identification of Additional IE2-p86-responsive Cis-repressiive Sequences within the Human Cytomegalovirus Major Immediate Early Promoter. J. Biomed. Sci. 9:460-470, 2002. 4. Fann, C. S.-J., Chen, J.-Y.*, Wu, C.-W., and Chi, C.-W. Regarding clinical implications of chromosomal abnormalities in gastric adenocarcinomas. Genes, Chromosomes, and Cancer 38:204-206, 2003. 5. Kao, C.-F., Chen, S.-Y., Chen, J.-Y., and Lee, Y.-H. W.* Modulation of p53 Transcription Regulatory Activity and Posttranslational Modification by Hepatitis C Virus Core Protein. Oncogene (In press), 2004. 6. Liu, C.-A., Wang, M.-J., Chi, C.-W., Wu, C.-W., and Chen, J.-Y.* Overexpression of Rho Effector Rhotekin Confers Increased Survival in Gastric Adenocarcinoma. J. Biomed. Sci. (In press), 2004. 13
  • 14. Name in Chinese:陳士隆 Name in English:Chen, Steve S.-L. Education:Purdue University Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3933, 886-2-2789-9035 Fax:886-2-2785-8847 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/slchen_c.html E-mail:schen@ibms.sinica.edu.tw Fields of Specialty:Retrovirology, Virus-host Interactions, Viral Protein Functions, Viral Pathogenesis Research Description: Our current research focuses on HIV-1 viral protein functions, viral protein-protein interactions underlying viral pathogenesis, and on the development of genetic anti-HIV strategies. In the Gag project, we recently demonstrated a novel mode of trans-dominant inhibition in HIV-1 replication by a cytoplasmic domain fusion protein β-gal/706-856. We aim to further understand the molecular, viral, and cellular bases for the role of this inhibitor in modulation of Gag and Env expression. In the Env project, we intend to examine the role of palmitoylation of the Env cytoplasmic domain in viral replication and Env targeting to lipid rafts, and to understand the biological functions of the putative cholesterol-binding motif located in the ectodomain of gp41. In a new SARS coronavirus project, we intend to characterize the biological functions of the heptad repeat (HR)1, and HR2 motifs in the spike protein in virus replication. In the gene transfer and therapy program, we attempt to understand 14
  • 15. whether IL10, which was known to downregulate HIV-1 replication in vitro, can be used as a candidate for designing a genetic, immunotherapeutic approach to controlling HIV-1 replication. Moreover, we will examine whether expression of a cytoplasmic tail fragment and β-gal/706-856 in lentiviral vector- transduced human CD4+ T cells and primary cells can inhibit HIV-1 replication. Selected Recent Publication: 1. Lee, S.-F., Wang, C.-T., Liang, J. Y.-P., Hong, S.-L., Huang, C.-C. and Chen, S. S.-L. Multimerization potential of the cytoplasmic domain of the human immunodeficiency virus type 1 transmembrane glycoprotein gp41. J. Biol. Chem. 275: 15809-15819, 2000. 2. Wang, C.-T., Chen, S. S.-L., and Chiang, C.-C. Assembly and release of human immunodeficiency virus type 1 Gag proteins containing tandem repeats of the matrix protein coding sequences in the matrix domain. Virology 278: 289-298, 2000. 3. Chiou, S.-H., Liu, J.-H., Hsu, W.-M., Chen, S. S.-L., Chang, S.-Y., Juan, L.-J., Lin, J.-C., Yang, Y.- T., Wong, W.-W., Liu, C.-Y., Lin, Y.-S, Liu, W.-T., and Wu, C.-W. Upregulation of Fas ligand expression by human cytomegalovirus immediate-early gene 2: a novel mechanism in CMV- induced apoptosis in human retina. J. Immnol. 167: 4098- 4103, 2001. 4. Chen, S. S.-L., Lee, S.-F., and Wang, C.-T. Cellular membrane-binding ability of the C-terminal cytoplasmic domain of human immunodeficiency virus type 1 envelope transmembrane protein gp41. J. Virol. 75: 9925-9938, 2001. 5. Lee, S.-F., Ko, C.-Y., Wang, C.-T., and Chen, S. S.-L. Effect of point mutations in the N-terminus of the lentivirus lytic peptide-1 sequence of human immunodeficiency virus type 1 transmembrane protein gp41 on Env stability. J. Biol. Chem. 277: 15363-15375, 2002. 6. Hsu, W.-M., Chen, S. .S.-L., Peng, C.-H., Chen, C.-F., Ko, Y.-C., Tsai, D.-C., Chou, C.-K., Ho, L.- L., Chiou, S.-H., and Liu, J.-H. Elevated nitric oxide level in aqueous humor of AIDS patients with cytomegalovirus retinitis. Ophthalmologica 217: 298-301, 2003. 7. Chen, S.-W., Chiu, H.-C., Liao, W.-H., Wang, F.-D., Chen, S. S.-L., and Wang, C.-T. The virion- associated human immunodeficiency virus type 1 Gag-Pol carrying an active protease domain in the matrix region is severely defective both in autoprocessing and in trans processing of gag particles. Virology 318: 534-541, 2004. 8. Chan, W.-E., Wang, Y.-L., Lin, H.-H., and Chen, S. S.-L. Effect of extension of the cytoplasmic domain of human immunodeficiency type 1 virus transmembrane protein gp41 on virus replication. 15
  • 16. J. Virol. 78:5157-5159, 2004. 16
  • 17. Name in Chinese:陳垣崇 Name in English:Chen, Yuan-Tsong Education:Columbia University Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Distinguished Research Fellow/ Director, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3001, 886-2-2789-9104 Fax:886-2-2782-5573 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/ytchen_c.htm E-mail:chen0010@ibms.sinica.edu.tw Fields of Specialty:Human Genetics, Genomic Medicine Research Description: Our overall research interests are in translational research. We aim at translating the promise of genomic medicine into clinical reality. Specific projects at present time include: 1). Identification of novel genes/targets associated with human diseases. This includes susceptibility genes for common multi-factorial diseases and pharmacogenetic disorders and disease causing genes for single gene disorders. Genetic epidemiology, mouse ENU mutagenesis, bioinformatics and proteomics are some approaches that we use in identification of novel genes associated with the human disease. Genes for several monogenic diseases have been mapped and/or identified. Genetic markers associated with drug-induced Stevens-Johnson syndrome have been identified. A systematic, genome-wide, phenotype-driven mutagenesis program for gene function studies in the mouse have resulted in the identification of a mouse model resembling human maple syrup urine disease. We will continue our research along these lines to identify more novel disease genes/ targets and to increase our understanding of the diseases. 17
  • 18. 2). Functional characterization of a novel glucose transporter and its role in diabetes mellitus. We cloned a novel glucose transporter (Glu 10), which is highly expressed in pancreas and liver and is located on a region of a chromosome where a diabetes mellitus type II locus has been mapped. We are currently investigating its role in diabetes by generation of knock out mouse model and by direct genetic association study of human patients affected with diabetes. 3). Enzyme and gene therapy and targeting mechanisms of Pompe disease. Pompe disease is a fatal genetic muscle disorder. As enzyme replacement therapy for Pompe disease moves into clinical trials the fundamental question of how the enzyme targets the heart and skeletal muscle remains unanswered. In vitro studies have established that the uptake of the enzyme in cultured fibroblasts is due to receptor-mediated endocytosis via the mannose-6-phosphate receptor (MPR300), however, it is presently unclear if the same system is involved in vivo. We have generated tissue-specific MPR300 knockout mouse model to help us answer this question and to better define the role of the receptor in vivo. In anticipation of expanding the clinical trial to adult and juvenile patients, we are also evaluating what effects advanced age may have upon the efficacy of the enzyme and gene therapy using animal models. Selected Recent Publication: 1. Sun BD, Chen Y-T, Bird A, Amalfitano A, Koeberl DD. Long-term correction of glycogen storage disease type II with a hybrid adenovirus-adeno-associated virus vector. Mol Ther 7:193-201, 2003. 2. Wu JY, Kao HJ, Li SC, Stevens RD, Hillman S, Millington DS, and Chen YT. ENU mutagenesis identifies mice with mitochondrial branched-chain aminotransferase deficiency resembling human maple syrup urine disease. J Clin Invest, 113:434-440, 2004. 3. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JW, Chen YT. A marker for Stevens-Johnson syndrome. Nature, 428:486 2004. 4. Quan H, Athirakul K, Westle, WC, Torres, GE, Stevens R, Chen YT, Coffman TM, Caron MG. Hypertension and impaired glycine handling in mice lacking the orphan transporter XT2. Molecular & Cellular Biology, 24: 4166-4173, 2004. 5. Hwu WL, Yang CF, Fann Cathy S J, Chen CL, Tsai TF, Chien YH, Chiang SC, Chen CH, Hung SI , Wu JY, and Chen YT. Mapping of psoriasis to 17q terminus. J Medical Genetics, in press, 2004. 6. Chen, Y.T. Glycogen storage diseases. In: Harrison Principles of Internal Medicine, 14th Edition, pp 2176-2182, 1998, 15th Edition, pp 2281-2289, 2001, 16th edition, in press 2004. 18
  • 19. Name in Chinese:陳儀莊 Name in English:Chern, Yijuang Education:University of Massachusetts Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3913, 886-2-2789-9028 Fax:886-2-2782-9143 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/ychern_c.html E-mail:bmychern@ccvax.sinica.edu.tw Fields of Specialty:Signal Transduction , Gene Regulation Research Description: We previously cloned the cDNA and the gene of the rat A2A adenosine receptor (A2A-R), which contains seven transmembrane domains and belongs to the G protein-coupled receptor family. Stimulation of A2A-R results in activation of adenylyl cyclase/protein kinase A (PKA) and protein kinase C (PKC). One of A2A-R’s physiological functions is to protect cells against various assaults. Using PC12 as a neuron-like model system, we demonstrated that atypical PKCs function downstream of PKA to mediate the protective effect of the A2A-R against apoptosis evoked by serum withdrawal in PC12 cells. In addition, A2A-R stimulation rescued the blockage of NGF-induced neurite outgrowth when the NGF-evoked MAPK cascade was suppressed. In the central nervous system (CNS), the A2A- R gene is heavily expressed in GABAergic striopallidal neurons, which selectively degenerate during progression of Huntington’s disease (HD). We therefore are investigating the potential therapeutic effects of A2A-R-selective agonists on HD using a transgenic mouse model (R6/2) of HD. Moreover, 19
  • 20. we also are using cellular and transgenic approaches to study the gene regulation and function of A2A-R in vivo. The principal objective of this research group is to understand the molecular mechanisms underlying the physiological functions and the regulation of A2A-R. Selected Recent Publication: 1. Liu, F.C., Wu, G.C., Hsieh, S.T., Lai, H.L., Wang, H.F., Wang, T.W. and Chern, Y. Expression of type VI adenylyl cyclase in the central nervous system: implication for a potential regulator of multiple signals in different neurotransmitter systems. FEBS Lett. 436: 92-98, 1998. 2. Lai, H.L., Lin, T.H., Kao, Y.Y., Lin, W.J., Hwang, M.J. and Chern, Y. The N terminal domain of type VI adenylyl cyclase mediates its inhibition by protein kinase C. Mol. Pharmacology 56: 644-650, 1999. 3. Lee, Y.C., Chang, C.W., Su, C.W., Lin, T.N., Sun, S.H., Lai, H.L. and Chern, Y. The 5' untranslated regions of rat A2A adenosine receptor gene function as negative translational regulators. J. Neurochem. 73: 1790-1798, 1999. 4. Chern, Y. Regulation of adenylyl cyclase in the central nervous system. Cellular Signalling 12: 195-204, 2000. 5. Huang, N.K., Lin, Y.W., Huang, C.L., Messing, R.O. and Chern, Y. Activation of protein kinase A and atypical protein kinase C by A2A adenosine receptors antagonizes apoptosis due to serum deprivation in PC12 cells. J. Biol. Chem. 276: 13838-13846, 2001. 6. Wu, G.C., Lai, H.L., Lin, Y.W., Chu, Y.T. and Chern, Y. N-glycosylation and residues Asn805 and Asn890 are involved in the functional properties of type VI adenylyl cyclase. J. Biol. Chem. 276: 35450-35457, 2001. 7. Lin, T.H., Lai, H.L., Kao, Y.Y., Sun, C.N., Hwang, M.J. and Chern, Y. Protein kinase C inhibits type VI adenylyl cyclase (ACVI) by phosphorylating the regulatory N domain and two catalytic C1 and C2 domains. J. Biol. Chem. 277: 15721-15728, 2002. 8. Lee Y.-C., Chien C.-L., Sun C.-N., Chiang, M. C., Huang C.-L., Huang N.-K., Lai H.-L., Lin Y.-S., Chiou S.-Y., Liao W.-L., Liu F.-C., Wang L., Tai M.-H., Lin T.-N. and Chern Y. Characterization of the rat A2A adenosine receptor gene: a 4.8-kb promoter-proximal DNA fragment confers selective expression in the central nervous system. Eur. J. Neurosci. 18: 1786- 1796,2003. 9. Kao, Y.Y., Lai, H.L., Hwang, M.J. and Chern, Y. An important functional role of the N terminus domain of type VI adenylyl cyclase (ACVI) in Gia-mediated inhibition. J. Biol. Chem. (in press) 20
  • 21. Name in Chinese:何美鄉 Name in English:Ho, Mei-Shang Education: Indiana University Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Associate Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3045, 886-2-2789-9120 Fax:886-2-2782-3047 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/ msho_c.html E-mail:homs@ibms.sinica.edu.tw Fields of Specialty:Epidemiology ,Virology. Research Description:. Probing into the biological basis that renders the wide spectrum of clinical outcomes of microbial infections represents one of the most intriguing aspects in clinical practice and research in infectious diseases. It is generally contended that the interplay between hosts and micriobes contributes to the main thrust in steering an infectious process towards a certain clinical outcome, i.e., the microbial virulent or attenuated genes/factors vis-a- vis host 掇 susceptible factors derived at the genetic level or during the process of immunological response. The central themes in our laboratory are revolved around queries into precisely the above question by studying two infection models: hepatitis B virus (HBV) and enterovirus 71. For HBV investigation, our focus is on vaccine-related issues with emphasis on vaccine failure and chronic HBV infection of vaccines. The ongoing projects include study of genetic predisposition for chronic infection by the immune escape mutants and study of human susceptible genes for HBV infection by genetic epidemiological approach. Enterovirus 71 - the 21
  • 22. newly identified neurotropic enteroviruse, is epidemic prone in causing morbidity and mortality in recent years. The ongoing projects include establishing animal models to distinguish strain differences in virulence; studying the molecular basis for viral virulence by infectious clones derived from reverse genetic technology, therefore, the host-virus interaction can be further studied by series of in vivo experiments using mutant and chimera virus in conjunction with knock-out mice. Furthermore, we are identifying the mammalian cellular receptors for enterovirus 71 which would provide basis for establishment of a susceptible transgenic mice model for enterovirus 71 in vivo study. Selected Recent Publication: 1. Ho, M.S., Mau, Y.C., Lu, C.F., Huang, S.F., Hsu, L.C., Lin, S.R. and Hsu, H.M. Patterns of circulating hepatitis B surface antigen variants among vaccinated children born to hepatitis B surface antigen carrier and non-carrier mothers. Journal of Biomedical Science 5: 355-362, 1998. 2. Shih, S.R., Ho, M.S., Lin, K.H., Wu, S.L., Chen, Y.T., Wu, C.N., Lin, T.Y., Chang, L.Y., Tsao, K.C., Ning, H.C., Chang, P.Y., Jung, S.M., Hsueh, C. and Chang, K.S.Genetic analysis of enterovirus 71 isolated from fatal and non-fatal cases of hand, foot and mouth disease during an epidemic in Taiwan, 1998. Virus Research 68: 127-136, 2000. 3. Wu, C.N., Lin, Y.C., Fann, C., Liao, N.S., Shih, S.R. and Ho, M.S. Protection against lethal enterovirus 71 infection in newborn mice by passive immunization with subunit VP1 accines and inactivated virus. Vaccine 20: 895-400, 2002. 4. Lin, Y.C., Wu, C.N., Shih, S.R. and Ho, M.S. Characterization of a vero cell-adapted virulent strain of enterovirus 71 suitable for use as a vaccine candidate. Vaccine 2002. 5. Ho, M.S., Chiu, L.Y., Lin, Y.C., Hu, C.Y., Lee, T.D., Fann, C.S.J., Tsai, J.F. and Chen, D.S. Genetic predisposition to chronic hepatitis B infection in vaccinated children with emphasis on immune escape variants. J. Med. Virology 2002. 6. Lin, Y.-C., Wu, C.-N., Shih, S.-R. and Ho, M.-S. Characterization of a vero cell-adapted virulent strain of enterovirus 71 suitable for use as a vaccine candidate. Vaccine 20, 2485-2493, 2002. 7. Lin, T.-Y., Twu, S.-J., Ho, M.-S., Ch'ang, L.-Y. and Lee, C.-Y. Enterovirus 71 outbreak, Taiwan: occurrence and recognition. J. Emerging Infectious Disease 9:291-293, 2003. 8. Shih, S.-R., Chiang, C., Chen, T.-C., Wu, C.-N., Hsu, J.-T., Lee, J.-C., Hwang, M.-J.,Li, M.-L., Chen, G..-W. and Ho, M.-S. Mutations at KFRDI and VGK domains of enterovirus 71 3C protease affect its RNA binding and proteolytic activities. J. Biomed. Sci. 11(2):239-248, 2004. 22
  • 23. Name in Chinese:李旭東 Name in English:Lee, Sho Tone Education: University of Manitoba, Canada Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3935, 886-2-2789-9170 Fax:886-2-2785-8847 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/stlee_c.html E-mail:bmtom@ccvax.sinica.edu.tw Fields of Specialty: Drug Resistance ,Vaccine Development Research Description: As a member of the Division of Infectious Diseases, our laboratory focuses our effort on two topics: (1) study of the mechanism of genesis of drug resistance and gene amplification in protozoan Leishmania parasites and the mechanism(s) of infection of Leishmania parasite to host mononuclear phagocytes and (2) development of subunit and DNA vaccines against flavivirus. In drug resistance: (i) a genome wide search of the genes activated during resistance induction in order to understand the mechanisms of genesis behind drug resistance and gene amplification. Subtractive hybridization and proteomic approaches are used for a genome wide comparison between the wildtype and the drug-resistant Leishmania; (ii) an intercellular adhesive molecule (ICAM) cloned and expressed is used to investigate the mechanism involved in the interaction between the parasite and its host macrophage. In the flaviral vaccine study, we focus on the development of subunit and DNA vaccines against 23
  • 24. Japanese encephalitis virus (JEV) which is an important pathogen in Taiwan as well as in Eastern and Southeastern Asia. A C-terminal fragment of JEV envelope (E) protein was found to induce protective immunity against JEV. We are now mapping the smallest and most immunodominant fragment of this antigen for inducing protective immunity against JEV using DNA priming-protein boosting strategies. Selected Recent Publication: 1. Singh, A.K. and Lee, S.T. Status of respiration and ATP content in arsenite resistant Leishmania mexicana amazonensis. Microbiol. Pathogen. 26(3): 171-174, 1999. 2. Lye, L.F., Chiang, S.C., Hsu, J.Y. and Lee, S.T. Expression and cellular localization of ribonucleotide reductase small subunit M2 protein in hydroxyurea-resistant Leishmania mexicana amazonensis Mol. Biochem. Parasitol. 102: 263-271, 1999. 3. Chiang, S.C., Ali, V., Haung, A.L., Chu K.U., and Lee, S.T. Molecular, cellular and functional characterizations of a novel ICAM-like molecule of the Ig-superfamily from L. m. amazonensis. Mol. Biochem. Parasitol. 112: 263-275, 2001. 4. Chia, S.C., Leung, P.S.C., Liao, C.P., Huang, J.H. and Lee, S.T. Fragment of Japanese encephalitis virus envelope protein produced in Escherichia coli protects mice from virus challenge. Microbial Pathogenesis 31(1): 9-19, 2001. 5. Chang, Y.H., Lee, S.T. and Lin, W.W. Effects of cannabionoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of Eicosanoids. J. Cell. Biochem. 81: 715-723, 2001. 6. Chiang, S.C., Chang, S.C. and Lee, S.T. ICAM-L gene is conserved only in Leishmania species in the family of kinetoplastida. Mol. Biochem. Parasitol. 124: 47-50, 2002. 7. Hsu, M.J., Lee, S.S., Lee, S.T. and Lin, W.W. Signaling mechanisms of enhanced neutrophil phagocytosis and chemotaxis by the polysaccharide purified from Ganoderma lucidum. Br. J. Pharmacol. 139(2): 289-98, 2003. 8. Chen, C.W., Lee, S.T., Wu, W.T., Fu W.M., Ho, F.M. and Lin, W.W. Signal transduction for inhibition of inducible nitric oxide synthase and cyclooxygenase-2 induction by capsaicin and related analogs in macrophages. Br. J. Pharmacol. 140: 1077-1087, 2003. 9. Wu, H.W., Chen, C.T., Lin, Y.L. and Lee, S.T. Subfragments of the envelope gene are highly protective against the Japanese encephalitis virus lethal infection in DNA priming/protein boosting immunization strategies. Vaccine, 22: 793-800, 2004. 24
  • 25. Name in Chinese:林天南 Name in English:Lin, Teng-Nan Education:University of Missouri-Columbia Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Associate Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3396, 886-2-2789-9141 Fax:886-2-2785-8847 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/tnlin_c.html E-mail:bmlth@ibms.sinica.edu.tw Fields of Specialty:Cerebral Ischemia , Angiogenesis ,Neurochemistry Research Description: Brain injury as a result of cerebral vascular disease (stroke) is a major health problem in Taiwan. Unfortunately, no treatment to limit brain damage is yet available. The need for intervention is great, both because of the seriousness of the disorder and its prevalence. The ultimate goal for us is to unravel the cellular and molecular mechanism of neuronal injury and/or recovery following ischemia-reperfusion. Both in vivo “focal cerebral ischemia model (MCAO)” and in vitro “primary neuronal and glial cultures” are using in our laboratory to explore these questions. Both pharmacological and genetic approaches are using to facilitate our goal. Research Interest: 1. Mechanism of Angiogenesis 2. Gene regulation of growth factors and their receptor 3. Cellular and molecular mechanism of neuronal injury and recovery 4. Gene transfer in CNS 25
  • 26. Selected Recent Publication: 1. Lin T-N, Wang PY, Chi SI, Kuo JS (1998) Differential regulation of ciliary neurotrophic factor (CNTF) and CNTF receptor α(CNTFRα) expression following focal cerebral ischemia. Mol Brain Res 55:71-80. 2. Cheung WM, Wang CK, Kuo JS, Lin T-N (1999) Changes in the level of glial fibrillary acidic protein (GFAP) after mild and severe focal cerebral ischemia. Chinese J Physiology 42(4):227-235. 3. Lin T-N, Wang CK, Cheung WM, Hsu CY (2000) Induction of angiopoietin and tie receptor mRNA expression following cerebral ischemia-reperfusion. J. Cereb. Blood Flow Metab. 20:387-395. 4. Cheung WM, Chen SF, Nian GM, Lin T-N (2000) Induction of angiogenesis related genes in the contralateral cortex with a rat three-vessel occlusion model. Chinese J Physiology 43(3):119-124. 5. Chi SI, Wang CK, Chen JJ, Chau LY, Lin T-N (2000) Differential regulation of H- and L-ferritin mRNA subunits, ferritin protein and iron following focal cerebral ischemia-reperfusion. Neuroscience 100(3):475-484. 6. Shih CL, Chi SI, Chiu TH, Sun GY, Lin T-N (2001) Ethanol Effects on Nitric Oxide Production in Cerebral Pial Cultures. Alcoholism: Clin. Exp. Res. 25(4):612-618. 7. Lin T-N, Nian GM, Chen SF, Cheung WM, Chang C, Lin WC, Hsu CY (2001) Induction of Tie-1 and Tie-2 protein expression after cerebral ischemia-reperfusion. J. Cereb. Blood Flow Metab. 21(6):690-701. 8. Lin H, Lin T-N, Cheung WM, Nian GM, Tseng PH, Chen SF, Chen JJ, Shyue SK, Liou JY, Wu CW, Wu KK (2002) Cyclooxygenase-1 (COX-1) and Bicistronic COX-1/Prostacyclin synthase gene transfer protect against ischemic cerebral infarction. Circulation 105:1962-1969 (r67-r74). 9. Lin T-N, Sun SW, Cheung WM, Li F, Chang C (2002) Dynamic changes in cerebral blood flow and angiogenesis after transient focal cerebral ischemia in rats: evaluation with serial MRI. Stroke 33:2985-2991. 10. Lin T-N, Kim GM, Chen JJ, Cheung WM, He YY, Hsu CY (2003) Differential regulation of TSP-1 and TSP-2 following focal cerebral ischemia-reperfusion. Stroke 34:177-186. 26
  • 27. Name in Chinese:林文昌 Name in English:Lin, Wen-Chang Education:Case Western Reserve University Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Associate Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3967, 886-2-2789-9148 Fax:886-2-2785-8594 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/ wclin_c.html E-mail:wenlin@ibms.sinica.edu.tw Fields of Specialty:Bioinformatics, Tumor Biology, Cancer Metastasis Research Description: The long-term research goal of our laboratory is to utilize bioinformatic tools/databases in elucidating molecular and cellular aspects of tumor progression and host-tumor immune responses. Our research efforts are intended to improve treatment strategies of human cancer patients. Current major projects involve: 1. Examination of protein tyrosine-kinase and tyrosine-phosphatase expression profiles in human gastric cancer tissues. By using degenerated PCR primers according to the consensus catalytic domain motifs, we could amplify kinase/phosphatase molecules from cancer tissues. We have identified more than 50 different protein kinases as well as 20 different new protein kinase genes. We have demonstrated that expression of tie-1 and mkk4 kinases correlates with prognostic outcomes of gastric cancer patients. RAGE based bioinformatic tools are now in development to improve their applications in clinical studies. Bioinformatic is emerging as a new research field and becoming an important 27
  • 28. research tool. We have created a novel comparative-gene-identification (CGI) approach by applying comparative proteomics in human dbEST data-mining efforts. With the CGI tool and human dbEST, we have discovered over 500,000 cSNP and a new wobble splicing mechanism in human gene transcripts. Our present goal is to integrate protein functional motif discovery and bioinformatic databases by building bioinformatic data-mining tools. Selected Recent Publication: 1. Hsiao-Wei Kao, Huan-Chen Chen , Hsing-Jien Kung, and Wen-chang Lin. 2003. Tyrosine-Kinase Expression Profiles in Human Gastric Cancer Cell Lines and Their Modulations with Retinoic Acids. British Journal of Cancer. 88: 1058-1064. 2. Chew-Wun Wu, Anna F.-Y. Li, Chin-Wen Chi, Cheng-Jien Huang, Chen Lung Huang, Wing-Yiu Liu, and Wen-chang Lin. 2003. Arg Tyrosine Kinase Expression in Human Gastric Adenocarcinoma is Associated with Vessel Invasion. Anticancer Res. 23: 205-210. 3. Trees-Juen Chuang, Wen-Chang Lin, Hurng-Chun Lee, Chi-Wei Wang, Keh-Lin Hsiao, Zi-Hao Wang, Danny Shieh, Simon C. Lin, and Lan-Yang Ch'ang. 2003. A Complexity Reduction Algorithm for Analysis and Annotation of Large Genomic Sequences. Genome Research. 13: 313-322. 4. Wen-chang Lin. 2002. Protein Tyrosine Kinase and Phosphatase Expression Profiling in Human Cancers. In Methods in Molecular Medicine, Vol. 218: Cancer Cell Signaling: Methods and Protocols (David M. Terrian, ed.), Humana Press, Inc., Totowa, N.J. pp. 113-125. 5. Chew-Wun Wu, Anna F.-Y. Li, Chin-Wen Chi, Chun-Hung Lai, Chen Lung Huang, Su-Shun Lo, Wing-Yiu Liu, Wen-chang Lin. 2002. Clinical Significance of Axl Kinase Family in Gastric Cancer. Anticancer Res. 22: 1071-1078. 6. Chew-Wun Wu, Chin-Wen Chi, and Wen-chang Lin. 2002. Gastric Cancer: Prognostic and Diagnostic Advances. Expert Reviews in Molecular Medicine. 21 March, " http://www- ermm.cbcu.cam.ac.uk/02004337h.htm ". 7. Chun-Hung Lai, Jian-Yuan Chiu, and Wen-chang Lin. 2001. Identification of the Human crooked neck gene by Comparative Gene Identification. Biochimica et Biophysica Acta. 1517: 449-454. 8. Wen-chang Lin, Hsiao-Wei Kao, Daniel Robbinson, Hsing-Jien Kung, Chew-Wun Wu, and Hua- Chien Chen. 2000. Tyrosine Kinases and Gastric Cancer. Oncogene. 19: 5680-5689. 9. Chun-Huang Lai, Chang-Yuan Chou, Lan-Yang Ch'ang, Chung-Shyan Liu, Wen-chang Lin. 2000. Identification of Novel Human Genes Evolutionarily Conserved in C. elegans by Comparative 28
  • 29. Proteomics. Genome Res. 10: 703-713. 29
  • 30. Name in Chinese:潘文涵 Name in English:Pan, Wen-Harn Education:Cornell University Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3042, 886-2-2789-9121 Fax:886-2-2782-3047 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/whpan_c.html E-mail:pan@ibms.sinica.edu.tw Fields of Specialty: Cardiovascular, Nutrition, Genetic Epidemiology Research Description: Our research mainly focuses on mRNA processing and transport in eukaryotic cells. The splicing of precursor mRNA is a key step of gene expression. In higher eukaryotes, alternative splicing of pre-mRNAs greatly increases the complexity of the genome8. We have been interested in the molecular mechanisms by which alternative splicing is controlled. Serine/arginine- rich splicing factors (SR proteins) play important roles in both constitutive and regulated splicing. Dynamic localization of splicing regulatory factors provides a means by which splicing can be regulated. We therefore investigate the nucleocytoplasmic transport of SR proteins. We have identified an importin-beta family member, termed transportin-SR, and found that it is responsible for nuclear import of phosphorylated SR proteins3, 4. We have also examined the roles of SR proteins in post- splicing mRNA maturation events9. We are interested in how cellular signaling controls phosphorylation of SR proteins. We recently found that an SR protein becomes hyperphosphorylated 30
  • 31. upon inhibition of mRNA synthesis and that this SR protein is destabilized when hyperphosphorylated6. In addition, we identified a novel splicing regulatory protein, RBM4, that antagonizes the activity of SR proteins in splice site and exon selection5. We also explore the molecular mechanisms of how transcription factors control splicing regulation2 and orchestrate the assembly of the spliceosome10. RNA export is also a key step of gene expression. We recently found that SR-like protein Pnn/DRS becomes associated with the spliced mature mRNA during the splicing process. Our study indicates that Pnn functions as a platform for the assembly of splicing and/or export complexes in the nucleus7. At present, we continue to study whether phosphorylation of export factors has any effect on mRNA export. Selected Recent Publication: 1. Chang, H.Y., Suchindran, C.M. and Pan, W.H. Using the overdispersed exponential family to estimate the distribution of usual daily intakes of people aged between 18 and 28 in Taiwan. Statistics in Medicine 20(15): 2337-2350, 2001. 2. Chang, H.Y., Pan, W.H., Yeh, W.T. and Tsai, K.S. Hyperuricemia and gout in Taiwan: results from the Nutritional and Health Survey in Taiwan (NAHSIT: 1993-96). Journal of Rheumatology 28(7): 1640-1646, 2001. 3. Pan, W.H., Chang, H.Y., Yeh, W.T., Hsiao, S.Y. and Hung, Y.T. Prevalence, awareness, treatment and control of hypertension in Taiwan: results of nutrition and health survey in Taiwan (NAHSIT) 1993-1996. Journal Human Hypertension 15(11): 793-798, 2001. 4. Yeh, C.J., Pan, W.H., Jong, Y.S., Kuo, Y.Y. and Lo, C.H. Incidence and predictors of isolated systolic hypertension and isolated diastolic hypertension in Taiwan. Journal Formos Med Assoc. 100(10): 668-75, 2001. 5. Wu, S.Y., Fann, C.S.J., Chen, J.W., Jou, Y.S. and Pan, W.H. Association between markers in chromosomal region 17q23 and young-onset hypertension: A TDT study. Journal of Medical Genetics 39: 42-44, 2002. 6. Pan W.H., Yeh W.T., Chang H.Y., Hwu C.M., Ho L.T.. Prevalence and awareness of diabetes and mean fasting glucose by age, sex, and region: results from the Nutrition and Health Survey in Taiwan, 1993-1996. Diabet Med. 20(3):182-5, 2003. 7. Kang M.J., Lin Y.C., Yeh W.H., Pan W.H. Vitamin E status and its dietary determinants in Taiwanese: Results of the Nutrition and Health Survey in Taiwan 1993-1996. Eur J Nutr. 43(2): 31
  • 32. 86-92, 2004. 8. Pan W.H., Flegal K.M., Chang H.Y., Yeh W.T., Yeh C.J., Lee W.C. Body mass index and obesity- related metabolic disorders in Taiwanese and US whites and blacks: implications for definitions of overweight and obesity for Asians. Am. J. of Clinical Nutrition 79: 31-39, 2004. 32
  • 33. Name in Chinese:羅傅倫 Name in English:Roffler, Steve R. Education: University of California, Berkeley Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3079 886-2-2789-9152 Fax:886-2-2782-9142 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/roffler_c.html E-mail:sroff@ibms.sinica.edu.tw Fields of Specialty:Monoclonal Antibodies, Prodrugs, Surface Expression, Directed Molecular Evolution Research Description: We have synthesized glucuronide prodrugs that can be preferentially activated at tumor cells by antibody-enzyme conjugates (immunoenzymes). Current studies are focused on improving the utility of recombinant immunoenzymes by directed molecular evolution and translation of prodrug therapy to the clinic. We are also investigating the efficacy and mode of action of a new glucuronide prodrug of 9-aminocamptothecin that displays good antitumor activity without immunoenzyme pretargeting. Another area of interest is the development of novel gene-therapy strategies based on the expression of chimeric proteins on the surface of mammalian cells. We are focusing on the expression of enzymes for prodrug activation and single-chain antibodies for specific regulation of lymphocytes. We are interested in understanding how different domains of chimeric proteins affect their transport and retention on the cell surface. 33
  • 34. We have also developed monoclonal antibodies that identify proteins that are involved in the migration, adhesion and invasion of lung adenocarcinoma cells as well as in the regulation of endothelial cell angiogenesis. Current studies are focused on investigation of protein-protein interactions and signal transduction pathways involved in cancer cell metastasis and angiogenesis. Selected Recent Publication: 1. NM Tsai, TL Cheng and SR Roffler. Sensitive quantitation of poly(ethylene glycol)-modified proteins. Biotechniques 30: 396-402, 2001. 2. BM Chen, TL Cheng, SC Tzou and SR Roffler. Potentiation of antitumor immunity by antibody- directed enzyme prodrug therapy. Int. J. Cancer, 94: 850-858, 2001. 3. JW Chen, K Peck, TM Hong, SC Yang, YP Sher, JY Shih, R Wu, JL Cheng, SR Roffler, CW Wu and PC Yang. Global Analysis of Gene Expression in Invasion by a Lung Cancer Model. Cancer Res., 61: 5223-5230, 2001. 4. KW Liao, WC Chou, YC Lo and SR Roffler. Design of transgenes for efficient expression of active chimeric proteins on mammalian cells. Biotechnol Bioeng, 73:313-323, 2001. 5. ZM Prijovich, BM Chen, YL Leu, JW Chern and SR Roffler. Antitumor activity and toxicity of the new glucuronide prodrug 9-aminocamptothecin glucuronide (9ACG) in mice. Br. J. Cancer, 86: 1634-1638, 2002. 6. KM Bernt, DS Steinwaerder, S Ni, ZY Li, SR Roffler and A Lieber. Enzyme-activated prodrug therapy enhances tumor-specific replication of adenovirus vectors. Cancer Res., 62: 6089-98, 2002. 7. YR Kao, JY Shih, WC Wen, YP Ko, BM Chen, YL Chan, YW Chu, PC Yang, CW Wu and SR Roffler. Tumor-associated antigen L6 (TAL6) and the invasion of human lung cancer cells. Clin. Cancer Res., 9: 2807-2816, 2003. 8. KW Liao, BM Chen, TB Liu, SC Tzo, YM Lin, KF Lin, CI Su and SR Roffler. Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of anti-tumor immunity. Cancer Gene Therapy. 10: 779-790, 2003. 9. CH Lo, SC Lee, PY Wu, WY Pan, J Su, CW Cheng, SR Roffler, BL Chiang, CN Lee, CW Wu and MH Tao. Antitumor and antimetastatic activity of IL-23. J. Immunol. 171: 600-607, 2003. 10. ZM Prijovich, YL Leu and SR Roffler. Stability of the new prodrug 9-aminocamptothecin glucuronide (9ACG) in the presence of human serum albumin. Biochem. Pharmacol., 66: 1181-1187, 2003. 34
  • 35. Name in Chinese:謝如姬 Name in English:Shieh, Ru-Chi Education:University of Rochester Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Associate Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3914, 886-2-2789-9024 Fax:886-2-2782-9143 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/ruchi_c.html E-mail:ruchi@ibms.sinica.edu.tw Fields of Specialty:Electrophysiology, Biophysics, Fluorescence Research Description: Inward rectifier K+ channels (Kir) are important in maintaining stable resting membrane potentials and controlling excitability of many cells. These channels are also involved in other physiological processes such as vascular tone, heart rate, renal salt flow, and insulin release. The focus of our laboratory is on the ion permeating and gating processes in Kir2.1 channels. Recently, we have combined electrophysiology, site-directed mutangensis, and chemical modification to probe the conformational changes in Kir2.1 channels during membrane voltage-induced inactivation. Using this combination of techniques, we are currently studying the ion-ion interaction involved in ion permeation through the Kir2.1 channel. These experiments may shed light on the voltage-dependent gating processes of Kir2.1 channels and provide further insights into the interaction of permeant ions and blockers with the Kir2.1 channels. 35
  • 36. Selected Recent Publication: 1. R-C Shieh. Mechanisms underlying the time-dependent decay of inward currents through cloned Kir2.1 channels expressed in Xenopus oocytes. J Physiol (Lond), 526.2:241-252, 2000. 2. R-C Shieh and Y-L Lee. Ammonium ions induce inactivation of Kir2.1 channels expressed in Xenopus oocytes. J Physiol (Lond), 535.2:359-370, 2001. 3. Wang, I., Wu, S.H., Chang, H.K., Shieh, R-C, Yu, H.M. and Chen, C. Solution structure of a K+- channel blocker from the scorpion toxin of Tityus cambridgei. Protein Science 11: 390-400, 2002. 4. H-KChang and R-C Shieh. Conformational Changes in Kir2.1 Channels during NH4+-Induced Inactivation. J Biol Chem 278 (2): 908-918, 2003. 5. H-K Chang, S-H Yeh, R-C Shieh. The effects of spermine on the accessibility of residues in the M2 segment of Kir2.1 channels expressed in Xenopus oocytes.J Physiol, 553(1):101-12, 2003. 36
  • 37. Name in Chinese:謝小燕 Name in English:Shieh, Sheau-Yann Education:Baylor College of Medicine Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Assistant Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3916, 886-2-2789-9056 Fax:886-2-2782-9143 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/ssy_c.html E-mail:sy88@ibms.sinica.edu.tw Fields of Specialty:Cancer Research, Molecular Biology, Biochemistry Research Description: The tumor suppressor protein p53 play an important role in maintaining genome stability. The significance is fully illustrated by its high frequency (over 50%) of deletion or mutation in tumors. Under normal condition, the cellular p53 protein is unstable and barely detectable. However, upon genotoxic stress such as ionizing radiation, UV, hypoxia, or even nutrient depletion, p53 is stabilized and activated, which then leads to either G1/G2 growth arrest or programmed cell death (apoptosis). Our main interest is to decipher the signal transduction pathways and the molecular mechanisms underlying p53 induction. DNA damage-induced p53 phosphorylation The possibility that phosphorylation may play a role in the signaling to p53 has been a subject of intense investigation. In fact, we and others have discovered that DNA damage induces p53 phosphorylation at multiple sites in the N-terminus and the C-terminus of the protein. However, the 37
  • 38. connection between these phosphorylation events and p53 induction remains to be established. We have recently identified two cell cycle checkpoint kinases, hCHK1 and CHK2, as p53 kinases that phosphorylate DNA damage-inducible sites in vitro. The possibility that other cell cycle checkpoint players may also participate in the signal transduction process upstream of CHKs is now under investigation. We are also interested in identifying additional p53 kinases and their interacting proteins, as well as their effects on p53. Molecular mechanism underlying p53 stabilization Several proteins have been shown to regulate the half-life of p53 either directly or indirectly. One of them, the oncoprotein MDM2, binds the N-terminus of p53, and as a result, inhibits transcription activation by p53 and promotes p53 degredation through ubiquitin / proteasome pathway. Although p53 N-terminal phosphorylation can modulate MDM2-p53 interaction, some stress-related stabilization of p53 does not appear to involve phosphorylation. Other lines of evidence also suggest that different genotoxic agents may signal to p53 through different pathways. We are interested in locating the responsible p53 domain(s) that can mediate these stabilizing effects, as well as potential proteins that interact with these domains. Selected Recent Publication: 1. Tibbetts, R.S., Brumbaugh, K.M., Williams, J.M., Sarkaria, J.N., Cliby, W.A., Shieh, S.Y., Taya, Y., Prives, C. and Abraham, R.T. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes & Dev. 13: 152-157, 1999. 2. Shieh, S.Y., Taya, Y. and Prives, C. DNA damage-inducible phosphorylation of p53 at N-terminal sites including a novel site, serine 20, requires tetramerization. EMBO J. 18: 1815-1823, 1999. 3. Shieh, S.Y., Ahn, J., Tamai, K., Taya, Y. and Prives, C. The human homologues of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage inducible sites. Genes & Dev. 14: 289-300[user1], 2000. 4. Gottifredi, V., Shieh, S. -Y. and Prives, C. Regulation of p53 after different forms of stress and at different cell cycle stage. Cold Spring Harbor Symp. Quant. Biol. LXV: 483-487, 2000. 5. Gottifredi, V., Karni-Schmidt, O., Shieh, S.-Y. and Prives, C. p53 down-regulates CHK1 through p21 and the retinoblastoma protein. Mol. Cell. Biol. 21: 1066-1076, 2001. 6. Gottifredi, V., Shieh, S.Y., Taya, Y. and Prives, C. p53 accumulates but is functionally impaired when DNA synthesis is blocked. Proc. Natl. Acad. Sci. USA 98: 1036-1041, 2001. 38
  • 39. Name in Chinese:徐松錕 Name in English:Shyue, Song-Kun Education:Universityn of Texas-Houston Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Assistant Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3962, 886-2-2789-9153 Fax:886-2-2785-8847 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/skshyue_c.html E-mail:skshyue@ibms.sinica.edu.tw Fields of Specialty: Viral Vector Gene Transfer, Cardiovascular Diseases Research Description: We have been working with adenovirus (Ad) mediated gene transfer and therapy to study cardiovascular related diseases and molecular mechanism. Ad is one of the most efficient delivering vectors for in vivo and in vitro gene transfer. First and E2b deleted second generation Ad systems have been established in our laboratory. We have constructed many recombinant Ads related to antioxidants, vasoprotection and immune response. We are currently focusing on the following projects: 1. Modifying Ad delivery system by: 1) Cells and protocol modification to improve viral packaging and production efficiency to save time and cost. 2) To improve and develop 2nd and 3rd generation Ad in their construct and production for long term gene therapy. 2. Investigating the protection and therapeutic effects as well as their molecular mechanisms of vasoprotective molecules in cardiovascular diseases, including atherosclerosis and pulmonary hypertension. 39
  • 40. 3. Gene regulation and its mechanism of caveolin-1 in cancer cells. 4. Using microarray and proteomic tools to study the constitutional types in Traditional Chinese Medicine, such as hot and cold, to unveil their related genes and proteins, and to investigate the molecular mechanism of Traditional Chinese Medicine. Selected Recent Publication: 1. Li, W. H., Boissinot, S., Tan, Y., Shyue, S.K. and Hewett-Emmett, D. Evolutionary genetics of primate color vision. Evolutionary Biology 32: 151-178, 2000. 2. Shyue, S.K., Tsai, M.J., Liou, J.Y., Willerson, J.T. and Wu, K.K. Selective augmentation of prostacyclin production by combined prostacyclin synthase and cyclooxygenase-1 gene transfer. Circulation 103:2090-2095, 2001. 3. Liou, J.Y., Deng, W.G., Gilroy, D.K., Shyue, S.K. and Wu, K.K. Colocalization and interaction of cyclooxygenase-2 with caveolin-1 in human fibroblasts. J. Biol. Chem. 276: 34975-82, 2001. 4. Juan, S.H., Lee, T.S., Tseng, K.W., Liou, J.Y., Shyue, S.K., Wu, K.K. and Chau, L.Y. Adenovirus- mediated heme oxygenase-1 gene transfer inhibits the development of atherosclerosis in apoE- deficient mice. Circulation 104: 1519-25, 2001. 5. Lin H, Lin TN, Cheung WM, Nian GM, Tseng PH, Chen SF, Chen JJ, Shyue SK, Liou JY, Wu CW, Wu KK. Cyclooxygenase-1 and bicistronic cyclooxygenase-1/prostacyclin synthase gene transfer protect against ischemic cerebral infarction. Circulation Apr 23;105(16):1962-9, 2002. 6. Yu, N, Chen, FC, Ota, S, Jorde, LB, Pamilo, P, Patthy, L, Ramsay, M, Jenkins, T, Shyue, SK, Li, WH. Larger genetic differences within africans than between africans and eurasians. Genetics 161(1):269-74, 2002. 7. Huang CL, Huang NK, Shyue SK, Chern Y. Hydrogen peroxide induces loss of dopamine transporter activity: a calcium-dependent oxidative mechanism. J Neurochem. 86(5):1247-59, 2003. 8. 游恆懿、徐松錕、陳光偉 以基因晶片分析經附子乾薑培養的腎細胞基因表達。中西整合醫學雜 誌 4(1):1-6, 2003. 9. Lin SJ, Shyue SK, Liu PL, Chen YH, Ku HH, Chen JW, Tam KB and Chen YL Adenovirus- mediated overexpression of catalase attenuates oxLDL-induced apoptosis in human aortic endothelial cells via AP-1 and C-Jun N-terminal kinase/extracellular signal-regulated kinase mitogen-activated protein kinase pathways. J. Mol. Cell. Cardiol. 36(1):129-39, 2004. 40
  • 41. Name in Chinese:唐堂 Name in English:Tang, Tang k.. Education:Yale University Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3901, 886-2-2789-9156 Fax:886-2-2782-9143 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/ttang_c.html E-mail:tktang@ibms.sinica.edu.tw Fields of Specialty:Cell and Developmental Biology, Cell Mitosis and Germ Cell Development Research Description: A). Cell Cycle Control and Cancer Genetic Instability Genetic instability is a common characteristic of many human cancers. Although, little is known about the mechanisms that generate genetic abnormality, missegregation of chromosomes through the assembly of dysfunctional mitotic spindles may play essential roles. The centrosome functions as the major microtubule organizing center of the cells. During cell mitosis, the centrosome organizes the microtubule array of the mitotic spindle and thereby makes possible equal segregation of sister chromatids into two daughter cells. Many reports have shown that defects in centrosome function lead to aneuploid and genetic instability in cancer cells. We previously identified several centrosomal proteins including aurora-A, CPAP, protein 4.1 and NuMA. In this project, we propose to systematically and qualitatively analyze the protein composition of centrosome by proteomic approach, particularly focusing on the identification of novel centrosomal kinases and their substrates. 41
  • 42. Furthermore, we will examine the possible roles of these newly identified proteins involved in cell mitosis and genomic instability. B). Gene Regulation and Germ Cell Development Spermatogenesis in mammals is a complex system that leads to the formation of male gametes. During spermatogenesis, male germ cells undergo major morphological and biochemical changes, which are regulated by the stage-specific transcriptional and translational activation of numerous genes and protein kinases. We previously identified a novel serine/threonine kinase, Aie1 (aurora-C) and its gene regulator Tzfp (testis zinc finger protein). Both Aie1 and Tzfp are expressed in testis and particularly in meiotic pachytene spermatocytes, suggesting a possible role of these two proteins involved in spermatogenesis. Recently, we demonstrate that Tzfp binds to the promoter region of Aie1 gene through its carboxyl zinc finger domain, which suggests that the expression of Aie1 gene may be regulated by Tzfp. We currently produced Tzfp knockout mice. The possible roles of these two proteins are currently under investigation. The results from these studies should explore the unrevealed signaling pathways and regulation in germ cell development in the future. Selected Recent Publication: 1. Hung, L-Y., Tang, C-J. C., Tang, T.K. (2000). P4.1R (135 kDa) interacts with a novel centrosomal protein (CPAP), which is associated with the -tubulin complex. Mol. Cell. Biol. 20, 7813-7825. 2. Tang, C-J.C., Chuang, C-K., Hu, H-M., and Tang, T.K. (2001) The zinc finger domain of Tzfp binds to the tbs motif located at the upstream flanking region of the Aie1 (aurora-C) kinase gene. J. Biol. Chem. 276, 19631-19639. 3. Chen, S-H., and Tang T.K. (2002) Mutational analysis of the phosphorylation sites of the Aie1(aurora-C) kinase in vitro. DNA Cell Biol. 21, 41-46. 4. Peng, B., Sutherland, K.D., Sum, E.Y.M., Olayioye, M., Wittlin, S., Tang, T.K., Lindeman, G.J., and Visvader, J.E. (2002) CPAP is novel Stat5-interacting cofactor that augments Stat5-mediated transcriptional activity. Mol. Endocrinol. 16, 2019-2033. 5. Hung, L-Y., Chang, C-W., and Tang, T. K. (2003) Methods and compositions for destabilizing microtubules. USA Patent-pending application 6. Tang, C-J. C., Hu, H-M, and Tang, T. K. (2004) NuMA (Nuclear Mitotic Apparatus Protein) expression and function in mouse oocyte and early embryo. J. Biomed. Sci. (in press). 7. Hung, L-Y., Chen, H-L., Chang, C-W., Li, B-R., and Tang, T. K. (2004) Identification of a novel microtubule-destabilizing motif in CPAP that binds to tubulin heterodimers and inhibits 42
  • 43. microtubule assembly. Mol. Biol. Cell. (in press) 43
  • 44. Name in Chinese:陶秘華 Name in English:Tao, Mi-Hua Education: Columbia University Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3078, 886-2-2789-9151 Fax:886-2-2782-9142 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/ tao_c.html E-mail:bmtao@ibms.sinica.edu.tw Fields of Specialty:Infectious Disease, Immunology, Vaccines, Tumor immunology, Hepatitis B virus immunology Research Description: The major interest of our laboratory is to develop novel immunotherapeutic methods for treating cancers and chronic hepatitis B virus infection. We focus on applying cytokines and immune costimulatory molecules to modulate immune responses for enhancing the therapeutic effects. The state of the art technologies, such as DNA vaccines, dendritic cell vaccines, in vivo electroporation, and engineered antibodies are used in these studies. Details of our current research projects can be found at the web site www.ibms.sinica.edu.tw/%7Ebmtao/. Following are brief summaries of some of our research activities: 1. Cancer Immunotherapy and Gene Therapy We have generated immunocytokines that can target cytokines to the tumor site to enhance their tumoricidal effects. Application of immunocytokines is one of the most promising approaches 44
  • 45. developed recently for cancer immunotherapy. Cytokines and other costimulatory molecules are also applied to engineer tumor antigens to generate more potent cancer vaccines. 2.Therapeutic Vaccines for Treatment of Chronic Hepatitis B Virus Infection We have previously demonstrated that plasmid DNA encoding HBsAg induced humoral and cellular immune responses. We also demonstrated that the magnitude and nature of the immune responses induced by HBsAg DNA vaccine could be modulated by coexpression of cytokine plasmids. Based on these results, we are now developing therapeutic vaccines against chronic HBV infections using several novel approaches including DNA vaccines, dendritic-cell-based vaccines, and adenovirus producing cytokines/costimulatory molecules. A number of HBV transgenic mouse strains have been generated as animal models for HBV chronic infection. Selected Recent Publication: 1. Huang, T.H., Wu, P.Y., Lee, C.N., Huang, H.I., Hsieh, S.L., Kung, J. and Tao, M.H. Enhanced antitumor immunity by fusion of CTLA-4 to a self tumor antigen. Blood (Plenary paper) 96: 3663-3670, 2000. 2. Chen, H.W., Pan, C.H., Huang, H.W., Liau, M.Y., Chiang, J.R. and Tao, M.H.. Suppression of immune response and protective immunity to a Japanese encephalitis virus DNA vaccine by coadministration of an IL-12-expressing plasmid. J. Immunol. 166: 7419-7426, 2001. 3. Pan, C.H., Chen, H.W., Huang, H.W. and Tao, M.H.. Protective mechanisms induced by a Japanese encephalitis virus DNA vaccine: requirement for antibody but not CD8+ cytotoxic T cell responses. J. Virol. 75: 11457-11463, 2001 4. Lee, S.C., Wu, C.J., Wu, P.Y., Huang, Y.L., Wu, C.W. and Tao, M.H. Inhibition of estabhished subcutaneous and metastatic murine tumors by intramuscular electroporation of the Interleukin 12 gene. J. Biomed. Sci. 10: 73-86, 2003 5. Lo, C.H., Lee, S.C., Wu, P.Y., Pan, W.Y., Su, J., Cheng, C.W., Roffler, S.R., Chiang, B.L., Lee, C.N., Wu, C.W. and Tao, M.H. Antitumor and antimetastatic activity of Interleukin 23. J. Immunol. 171: 600-607, 2003 6. Wu, C.J., Huang, H.W. and Tao, M.H. Induction of cross-protection against two wild-type Taiwanese isolates of Japanese encephalitis virus using Beijing-1 strain DNA vaccine. Vaccine 21: 3938-3945, 2003 7. Huang, H.I., Wu, P.Y., Teo, C.Y., Chen, M.N., Chen, Y.C. and Tao, M.H. Idiotype-CD40 ligand fusion protein induces protective immunity against B-cell lymphoma. Int. J. Cancer 108: 696-703, 45
  • 46. 2004. 46
  • 47. Name in Chinese:譚婉玉 Name in English:Tarn, Woan-Yuh Education:National Tsing Hua University Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Associate Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3052, 886-2-2789-9015 Fax:886-2-2782-9142 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/wutarn_c.html E-mail:wtarn@ibms.sinica.edu.tw Fields of Specialty:mRNA processing, Nucleocytoplasmic transport Research Description: Our research mainly focuses on mRNA processing and transport in eukaryotic cells. The splicing of precursor mRNA is a key step of gene expression. In higher eukaryotes, alternative splicing of pre-mRNAs greatly increases the complexity of the genome8. We have been interested in the molecular mechanisms by which alternative splicing is controlled. Serine/arginine- rich splicing factors (SR proteins) play important roles in both constitutive and regulated splicing. Dynamic localization of splicing regulatory factors provides a means by which splicing can be regulated. We therefore investigate the nucleocytoplasmic transport of SR proteins. We have identified an importin-beta family member, termed transportin-SR, and found that it is responsible for nuclear import of phosphorylated SR proteins3, 4. We have also examined the roles of SR proteins in post- splicing mRNA maturation events9. We are interested in how cellular signaling controls phosphorylation of SR proteins. We recently found that an SR protein becomes hyperphosphorylated upon inhibition of mRNA synthesis and that this SR protein is destabilized when hyperphosphorylated6. In addition, we identified a novel splicing regulatory protein, RBM4, that 47
  • 48. antagonizes the activity of SR proteins in splice site and exon selection5. We also explore the molecular mechanisms of how transcription factors control splicing regulation2 and orchestrate the assembly of the spliceosome10. RNA export is also a key step of gene expression. We recently found that SR-like protein Pnn/DRS becomes associated with the spliced mature mRNA during the splicing process. Our study indicates that Pnn functions as a platform for the assembly of splicing and/or export complexes in the nucleus7. At present, we continue to study whether phosphorylation of export factors has any effect on mRNA export. Selected Recent Publication: 1. Tarn, W. Y. and Steitz, J. A. Pre-mRNA splicing: the discovery of a new spliceosome doubles the challenge. Trends Biochem. Sci. 22: 132-137, 1997. 2. Lai, M. C., Teh, B. H. and Tarn, W. Y. A human papillomavirus E2 transcriptional activator: the interactions with cellular splicing factors and potential function in pre-mRNA processing. J. Biol. Chem. 274: 11832-11841, 1999. 3. Lai, M. C., Lin, R. I., Huang, S. Y., Tsai, C. W. and Tarn, W. Y. A human importin-_ family protein, transportin-SR2, interacts with the phosphorylated RS domain of SR proteins. J. Biol. Chem. 275: 7950-7957, 2000. 4. Lai, M. C., Lin, R. I. and Tarn, W. Y. Transportin-SR2 mediates nuclear import of phosphorylated SR proteins. Proc. Natl. Acad. Sci. USA 98: 10154-10159, 2001. 5. Lai, M. C., Kuo, H. W., Chang, W. C. and Tarn, W. Y. A novel splicing regulator shares a nuclear import pathway with SR proteins. EMBO J. 22: 1359-1369, 2003. 6. Lai, M. C., Lin, R. I. and Tarn, W. Y. Differential Effects of Hyperphosphorylation on Splicing Factor SRp55. Biochem. J. 371: 937-945, 2003. 7. Li, C. Lin, R. I., Lai, M. C., Ouyang, P., and Tarn, W. Y. Nuclear Pnn/DRS protein binds to spliced mRNPs and participates in mRNA processing and export via the interaction with RNPS1. Mol. Cell. Biol. 23:7363-7376, 2003. 8. Lai, M. C. and Tarn, W. Y. Hypophosphorylated ASF/SF2 binds TAP and is present in mRNPs. J. Biol. Chem. (in press), 2004. 9. Li, C., and Tarn, W.-Y. Splicing. In: Encyclopedic Reference of Genomics and Proteomics in Molecular Medicine. (ed) K. Ruckpaul and D. Ganten; Springer-Verlag. (in press), 2004 10. Lin, K. T., Leu, R. M. and Tarn, W. Y. The WW domain-containing proteins interact with the early 48
  • 49. spliceosome and facilitate 3' splice site selection. (manuscript submitted), 2004. 49
  • 50. Name in Chinese:王寧 Name in English:Wang, Danny Ling Education: University of Nevada Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3907, 886-2-2789-9132 Fax:886-2-2782-9143 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/lwang_c.html E-mail:lingwang@ibms.sinica.edu.tw Fields of Specialty:Vascular Biology, Gene Regulation ,Oxidative Stress Research Description: Vascular endothelial cells play an important role in maintaining vessel integrity. Oxidative stress to endothelial cells contributes to the pathogenesis of vascular diseases. Our studies suggest that changes of intracellular redox status may be the underlying mechanism that modulates signaling pathways and result in alteration of gene expression in endothelial cells under chemical or mechanical stimuli. Endothelial cells under hemodynamic flow protect themselves from cytokine-induced responses. These protective mechanisms are not clear. Protein tyrosine phosphatases may play important roles in suppressing signaling pathways. In addition, endothelial cells constantly release nitric oxide that plays as a negative regulator for endothelial responses. How nitric oxide affects signaling pathways and gene expression is not well defined. The consequence of interplay between reactive oxygen species and nitrogen species may determine the endothelial responses to various stimuli. Our research interests have been focusing on: 50
  • 51. 1. Signaling mechanisms and gene regulation in endothelial cells under oxidative stress. 2. The molecular mechanisms of shear-induced protective effects in endothelial cells 3. The role of phosphatase(s) in endothelial cells under inflammatory condition. 4. The protective role of nitric oxide in endothelial cells 5.The interaction of endothelial cells with smooth muscle cells and leukocytes that contribute to vessel dysfunction. Selected Recent Publication: 1. Chiu, J.J., Wung, B.S., Hsieh, H.J., Lo, L.W. and Wang, D.L. Nitric oxide regulates shear stress- induced early growth response-1 expression via the extracellular signal-regulated kinase pathway in endothelial cells. Circ. Res. 85: 238-246, 1999. 2. Lo, L.W., Cheng, J.J., Chiu, J.J., Wung, B.S., Lu, Y.C. and Wang, D.L. Endothelial exposure to hypoxia induces Egr-1 expression involving PKC a-mediated Ras/Raf/ERK1/2 pathway. J. Cell. Physiol., 188: 304-312, 2001. 3. Chang, Y.L., Shen, J.J., Wung, B.S., Cheng, J.J. and Wang, D.L. Chinese herbal remedy wogonin inhibits monocyte chemotactic protein-1 gene expression in human endothelial cells. Mol. Pharmocol. 60: 507-513, 2001. 4. Cheng, J.J., Wung, B.S., Chao, Y.J. and Wang, D.L.Sequential activation of protein kinase C-a and -e is required for cyclic strain-induced ERK1/2 activity in endothelial cells. J. Biol. Chem. 276(33): 31368-31375, 2001. 5. Wung, B.S. and Wang, D. L.NO modulates monocyte chemotactic protein-1 expression in endothelial cells under cyclic strain. Arterioscler. Thromb. Vasc. Biol. 21: 1941-47, 2001. 6. Cheng Jing-Jy, Chao Y-J and Wang D.L. “Cyclic Strain Activates Redox-Sensitive Proline-Rich Tyrosine Kinase (PYK2) in Endothelial Cells” J. Biol. Chem. 277 (50): 48152-57, 2002. 7. Ni C-W., Wang D.L., Lien S-C., Cheng J-J., Chao Y-J, And Hsieh H-J. “Activation of PKC-ε and ERK1/2 participates in shear-induced endothelial MCP-1 expression that is repressed by nitric oxide” J. Cell. Physiol. 195:428-434 (2003). 8. Ni C-W., Hsieh H-J, Chao Y-J and Wang D.L. “Shear Flow Attenuates Serun-Induced STAT3 Activation in Endothelial Cells.” J. Biol. Chem. 278 (22):19702-08, 2003. 9. Chen S. H., Wang D. L. “Nitric oxide inhibiting MMP–2 Expression is mediated via the induction of activating transcription factor (ATF3) in endothelial cells.” Mol. Pharmacology 65(5) (in press). 2004. 51
  • 52. Name in Chinese:顏裕庭 Name in English:Yan, Yu-Ting Education: University of Medicine and Dentistry of New Jersey Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Assistant Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3914 886-2-2789-9061 Fax:886-2-2785-8847 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/yyt_c.html E-mail:yyan@ibms.sinica.edu.tw Fields of Specialty:Molecular Genetics, Developmental Biology Research Description: The left-right (L-R) asymmetry of visceral organs is known to depend on left- and right-side specific cascades of gene expression during gastrulation and early post-gastrulation stages of embryogenesis. Failure to establish correct pattern of L-R axis results in heterotaxy, either expressed as randomization (situs ambiguous) or complete reversal (situs inversus) of normal organ position. In mammals, the correct pattern of the L-R axis is very critical for viability, since defects in the L-R laterality in newborn children are often associated with severe complex congenital cardiovascular defects, such as atrial or ventricular septal defect (ASD or VSD) and transposition of great arteries (TAG). The major research interest of our laboratory is to elucidate the molecular and biochemical mechanism of specification of L-R axis patterning of mammals, and to understand how L-R positional information is interpreted at a tissue-specific level during organogenesis. We utilize mouse as an 52
  • 53. experimental system, taking advantage of the assets that the system has to offer, including its small size, genetics, transgenics and reverse genetics or gene targeting. Targeted disruption of mouse Cryptic results in L-R laterality defects including randomization of abdominal situs, hyposplenia, and pulmonary right isomerism, as well as randomized embryo turning and cardiac looping. Currently, the work of my laboratory is focused on the following two projects: (1) investigation of L-R axis lateral defects on the development cardiac and vascular system using Cryptic mutant mouse as a study model, (2) identification and characterization of new candidate genes involved in determination of L-R axis. Selected Recent Publication: 1. Iratni, R., Yan, Y.-T., Chen, C., Ding, J., Zhang, Y., Price, S. M., Reinberg, D., and Shen, M. M. (2002). Inhibition of excess Nodal signaling during mouse gastrulation by the transcriptional corepressor DRAP1. Science 298, 1996-1999. 2. Yan, Y.-T., Liu, J.-J., Luo, Y., E, C., Haltiwanger, R. S., Abate-Shen, C., and Shen, M. M. (2002). Dual roles of Cripto as a ligand and co-receptor in the Nodal signaling pathway. Mol. Cell. Biol. 22, 4439-4449. 3. Yan, Y.-T., Stein, S. M., Ding, J., Shen, M. M., and Abate-Shen, C. (2000). A novel PF/PN motif inhibits nuclear localization and DNA binding activity of the ESX1 homeoprotein. Mol. Cell. Biol. 20, 661-671. 4. Yan, Y.-T., Gritsman, K., Ding, J., Burdine, R. D., Corrales, J. D., Price, S. M., Talbot, W. S., Schier, A. F., and Shen, M. M. (1999). Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. Genes Dev. 13, 2527-2537. 53
  • 54. Name in Chinese:楊瑞彬 Name in English:Yang, Ruey Bing Ray Education:University of Texas Sounthwestern Medical Center at Dallas Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Associate Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3943, 886-2-2789-9063 Fax:886-2-2785-8847 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/rbyang_c.html E-mail:rbyang@ibms.sinica.edu.tw Fields of Specialty:Receptor biology, Signal Transduction , Vascular Biology, Genomics Research Description: Current research interest of our laboratory is to unravel the biological functions of several novel cell-surface proteins. We have previously utilized a combination of high throughput sequencing and genome-wide microarray profiling analyses to identify novel cell-surface proteins expressed in human umbilical vein endothelial cells. One gene family identified by this approach encodes potential secreted proteins harboring multiple copies of epidermal growth factor-like domain and one CUB domain at the carboxyl terminus. Recently, we have identified one additional member with an osteoblast-enriched expression profile that is completely distinct from the endothelial expression of two previously identified family members. Recent immunohistochemical staining and molecular genetic studies suggested that members of this gene family may play important roles in the pathogenesis of cardiovascular or bone diseases. Another gene identified by this approach encodes a novel type I transmembrane receptor 54
  • 55. expressed in a testis-specific fashion. In the near future, we will apply molecular and biochemical methodologies as well as gene targeting approach to further evaluate their functions in the cardiovascular, bone and reproductive biology. Selected Recent Publication: 1. Brightbill, H.D., Libraty, D.H., Krutzik, S.R., Yang, R.-B., Belisle, J.T., Maitlan, M., Norgard, M.V., Plevy, S.E., Smale, S.T., Brennan, P.J., Bloom, B.R., Godowski, P.J., and Modlin, R.L. Microbial lipoproteins trigger host defense mechanisms via Toll-like receptors. Science 285: 732-736, 1999. 2. Yang, R.-B., Mark, M.R., Gurney, A.L., and Godowski, P.J. Signaling events induced by lipopolysaccharide-activated Toll-like receptor-2. J. Immunol. 163: 639-643, 1999. 3. Yang, R.-B., Robinson, S.W., Birch, D.G., and Garbers, D.L. Disruption of a retinal guanylyl cyclase gene leads to cone-specific dystrophy and paradoxical rod behavior. J. Neurosci. 19: 5889-5897, 1999. 4. Aliprants, A.O., Yang, R.-B., Weiss, D.S., Godowski, P.J., and Zychlinsky, A. The apoptotic signaling pathway activated by Toll-like receptor 2. EMBO J. 19: 3325-3336, 2000. 5. Hollopeter, G., Jantzen, H.-M., Vincent, D., Li, G., England, L., Ramakrishnan, V., Yang, R.-B., Nurden, P., Nurden, A., Julius, D., and Conley, P.B. Molecular identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409: 202-207, 2001. 6. Yang, R.-B., Ng, C.K.D., Wasserman, S.M., Komuves, L.G., Tomlinson, J.E., and Topper, J.N. Identification of a family of cell-surface proteins expressed in human vascular endothelium. J. Biol. Chem. 277: 46364-46373, 2002. 7. Wasserman, S.M., Mehraban, F., Komuves, L.G., Yang, R.-B., Tomlinson, J.E., Spriggs, F. and Topper, J.N. Gene Expression profile of human endothelial cells exposed to sustained fluid shear stress. Physiol. Genomics 12: 13-23, 2002. 8. Yang, R.-B.*, Ng, C.K.D., Wasserman, S.M., Komuves, L.G., Gerritsen, M.E., and Topper, J.N. A novel IL-17 receptor-like protein identified in human umbilical vein endothelial cells antagonizes basic fibroblast growth factor-induced signaling. J. Biol. Chem. 278: 33232-33238, 2003. (* Corresponding author) 9. Kuhn, M., Ng, C.K.D., Su, Y.-H., Kilic, A., Mitko, D., Bien-Ly, N., Komuves, L.G., Yang, R.-B. Identification of a novel receptor guanylyl cyclase selectively expressed in mouse testis. Biochem. J. 379: 385-393, 2004. 55
  • 56. Name in Chinese:嚴仲陽 Name in English:Yen, Jeffrey J.Y. Education: Baylor College of Medicine Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3077 886-2-2789-9017 Fax:886-2-2782-9142 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/yen_c.html E-mail:bmjyen@ibms.sinica.edu.tw Fields of Specialty: Molecular & Cell Biology, Hematopoiesis, Apoptosis Regulation Research Description: The long term interest of my laboratory has been on the growth and death regulation of hematopoietic cell lineages due to the underlying mechanism may shed lights on many human detrimental diseases, including leukemia, immunodeficiencies, allergic disorders, asthma, and autoimmunities. In the past ten years, we have applied standard molecular and cellular biology techniques to pursue our goals in terms of involvement of specific genes in the death regulation of hematopoietic cells. We continued to work on the molecular mechanism triggering the programmed cell death when cytokine was depleted. A novel cytokine receptor associated signaling molecule as well as a novel cytokine deprivation-induced early gene are identified. They both were found to be strongly apoptogenic to hematopoietic cells, suggesting the likelihood of the involvement of these novel molecules in this process. On the other hand, we discovered the involvement of the erythroid transcriptional factor GATA-1 in transducing anti-apoptotic acitivity of interleukin 3 in cytokine 56
  • 57. dependent hematopoietic cell line. Intriguingly, there is a strong correlation between tissue expression profile of GATA family members and their target anti-apoptotic gene E4BP4, suggesting the survival effect of GATA family proteins may play an important role in multiple organ development. In the new millennium, we also included molecular genetic and functional genomic approaches to tackle the regulatory mechanism of apoptosis control. We are currently actively participating in the genome-wide phenotype-driven ENU-mutagenized mice screening program for the hematopoietic deficiency phenotype. Once the mutation is confirmed and chromosomal location is mapped, high- resolution genetic mapping and molecular cloning of the defected gene will be pursued using various genomic research tools, such as SNP discovery, bioinformatics and transgenic rescue. We are at present working on a mutant mouse line with segmental progeroid symdrome and another line with lymphocytopenia and combined immune deficiency. Our preliminary study suggested that both mutations affect the survival of either stem cell population or lymphoid cell lineages. Selected Recent Publication: 1. Huang, H.M., Li, J.C., Hsieh, Y.C., Yang-Yen, H.F. and Yen, J.J.Y. Optimal proliferation of a hematopoietic progenitor cell line requires either costimulation with stem cell factor or increase of receptor expression that can be replaced by overexpression of Bcl-2. Blood 93: 2569-2577, 1999. 2. Lee, S.F., Huang, H.M., Chao, J.R., Lin, S., Yang-Yen, H.F. and Yen, J.J.Y. Cytokine receptor common a chain as a potential activator of cytokine withdrawal-induced apoptosis. Mol. Cell. Biol. 19: 7399-7409, 1999. 3. Huang, H.M., Huang, C.J. and Yen, J.J.Y. Mcl-1 is a common target of stem cell factor and interleukin 5 for apoptosis prevention activity via MEK/MAPK and PI-3K/Akt pathways. Blood 96: 1764-1771, 2000. 4. Chen, W., Yu, Y.L., Lee, S.F., Chiang, Y.J., Chao, J.R., Huang, J.H., Chiong, J.H., Huang, C.J., Lai, M.Z., Yang-Yen, H.F. and Yen, J.J.Y. CREB is one component of the binding complex of the Ces-2/E2A-HLF binding element and is an integral part of the IL-3 survival signal. Mol. Cell. Biol. 21: 4636-4646, 2001. 5. Yu, Y.L., Chiang, Y.J., and Yen, J.J.Y. GATA factors are essential for transcription of the survival gene E4BP4 and the viability response of interleukin-3 in Ba/F3 hematopoietic cells. J. Biol. Chem.277:27144-27153, 2002. 57
  • 58. Name in Chinese:蕭百忍 Name in English:Yen, Pauline, H. Education: University of California, Berkeley Affiliation:Institute of Biomedical Sciences, Academia Sinica, Taipei Title:Research Fellow, Institute of Biomedical Sciences, Academia Sinica Tel:886-2-2652-3912 886-2-2789-9055 Fax:886-2-2782-9224 My Personal Homepage:http://www.ibms.sinica.edu.tw/html/PI/pyen_c.html E-mail:pyen@ibms.sinica.edu.tw Fields of Specialty:Human Genetics Research Description: The mammalian sex chromosomes play important roles in spermatogenesis. More than half of the genes on the human Y chromosome and numerous genes on the X chromosome are expressed exclusively in the testis. Microdeletion of the Y chromosome and the presence of an extra X chromosome in the Klinefelter syndrome patients are two major causes of male infertility. Our research focuses on the Deleted in Azoospermia (DAZ) gene family on the Y chromosome long arm that is frequently deleted in infertile men. We perform functional analyses of the DAZ protein and study polymorphisms associated with the DAZ genes in the male population. Our results indicate that sister chromatid exchange plays a significant role in Y chromosome polymorphism. We also study two X-linked genes with testis-specific expression to test the hypothesis that the spermatogenic failure in Klinefelter syndrome patients is caused by increased expression of X-linked spermatogenesis genes during male germ cell development. We study the temporal and spatial expression of Tex11 and Usp26 during testis development, determine their subcellular localization, and generate null mutants to 58
  • 59. elucidate their functions. Selected Recent Publication: 1. Yen, P.H. Advances in Y-chromosome mapping. Curr. Opin. Obstet. Gynecol. 11:275-281, 1999. 2. Tsui, S., Dai, T., Warren, S.T., Salido, E.C., and Yen, P.H. Association of the infertility factor DAZL1 with actively translating polyribosomes. Biol. Reprod. 62:1655-1660, 2000. 3. Tsui, S., Dai, T., Roettger, S., Schempp, W., Salido, E.C., and Yen, P.H. Identification of two novel proteins that interact with germ-cell specific RNA-binding proteins DAZ and DAZL1. Genomics, 65:266-273, 2000. 4. Moro, E., Ferlin, A, Yen, P.H., Franchi, P.G., Palka, G., and Foresta C. Male infertility caused by a de novo partial deletion of the DAZ cluster on the Y chromosome. J. Clin. Endocrinol. Metab. 85:4069-4073, 2000 5. Roettger, S., Pasantes, J.J., Baldermann, C., Reichl, E., Yen, P.H., Hansmann, I., Schempp, W. Familial mosaicism of del(Y) and inv del(Y). Cytogenet. Cell Genet. 91:208-211, 2000. 6. Lue, Y., Rao, P.N., Sinha Hikim, A.P., Im, M., Salameh, W, Yen, P.H., Wang, C., and Swerdloff, R.S. Progressive loss of germ cells by apoptosis in XXY male mice: An experimental model for Klinefelter Syndrome. Endocrinology 142:1461-1470, 2001. 7. Yen, P. The fragility of fertility. NatureGenet. 29:243-244, 2001. 8. Vera, Y., Dai, T., Lue, Y., Sinha-Hikim, A.P., Salido, E.C., Swerdloff, R.S., and Yen, P.H. DAZAP1, a DAZ associated protein, shuttles between nucleus and cytoplasm during normal germ cell maturation. J. Andrology 23:622-628, 2002. 9. Roettger, S., Yen, P.H., and Schempp, W. A fiber-FISH contig spanning the non-recombining region of the human Y chromosome. Chrom. Res. 10:621-635, 2002. 10. Yen PH (2004) Putative biological functions of the DAZ family. Int. J. Androl. 27: 125-129. 59
  • 60. Taiwan International Graduate Program Molecular Medicine Program National Yang Ming University Faculty 60
  • 61. Name in Chinese: 張國威 Name in English: Kuo-Wei Chang Education: 1983, DDS, National Yang-Ming University 1995, PhD, Department of Pathology, Northwestern University Affiliation: Department of Dentistry, National Yang-Ming University Title: Professor Tel: 886-2-2826-7223 Fax: 886-2-2826-4053 My Personal Homepage: http://www.ym.edu.tw/iob E-mail: ckcw@ym.edu.tw Fields of Specialty: Oral Pathology/Molecular Pathology Research Description: My investigation targets on oral carcinogenesis. Identification of tumor markers and karyotypic dissection of oral cancers have been my major research topics. Selected Recent Publication: 1. Liu SY, Yang SC, Yen CY, Chang KW* (2004, In press) Overexpression of Rac-1 small GTPase 61
  • 62. binding protein in areca quid-associated oral squamous cell carcinoma. J Oral Maxillofac Surg. 2. Wong YK, Lin SC, Liu CJ, Tzeng YS, Lin HC, Wong CY, Chang KW* (2003) Cyclin D1 genotype in areca-associated oral squamous cell carcinoma. J Oral Pathol Med 32: 265-70. 3. Chang, KW, Kao, SY, Tzeng RJ, Liu, CJ, Cheng AJ, Wong, YK, Yang SC and Lin SC* (2002) Multiple molecular alterations of FHIT in betel-associated oral squamous cell carcinoma. J Pathol 2002 196:300-6. 4. Lin SC, Chen YJ, Hsu MD, Chang CS, Liu TY, Lin CH and Chang KW* (2002) The chromosomal changes of oral squamous cell carcinoma associated with betel quid use. Oral Oncol 38: 266-73. 5. Chang KW, Lin SC, Chao SY, Kwan PC and Wong YK* (2001) Establishment and characterization of a new oral melanoma cell line (ME). Oral Oncol 37: 301-7. 6. Chang KW, Lin SC, Kwan PS and Wong YK* (2000) Association of p53/p21waf1 expression with outcomes of veruccous leukoplakia in Taiwan. J Oral Pathol Med 29: 56-62. 7. Chang, KW, Sarraj S, Lin SC, Tsai, PI and Solt DB* (2000) p53 expression, p53 and Ha-ras mutation, and telomerase activation during nitrosamine-mediated hamster pouch carcinogenesis. Carcinogenesis 21: 1441-51. 8. Chang KW*, Lin SC, Wong YK, Liu TY and Chang CS (2000) Alterations of APC in oral squamous cell carcinoma in Taiwan. Int J Oral-Maxillofac Surg 29: 223-6. 9. Chang LY, Lin SC, Chang CS, Wong YK, Hu YC and Chang KW* (1999) Telomerase activity and in situ telomerase RNA expression in oral carcinogenesis. J Oral Pathol Med 28: 389-396. 10. Chen YJ, Lin SC, Kao T, Chang CS, Hong PS, Shieh TM and Chang KW* (In Revision) Genome profiling of oral squamous cell carcinoma and identification of Serpine1 (Plasminogen Activator Inhibitor-1, PAI-1) expression as an important event for oral carcinogenesis. J Pathol. 62
  • 63. Name in Chinese: 張泰階 Name in English: Tai-Jay Chang Education: PhD, Molecular Cellular Pathology, Mt. Sinai Medical School, USA Affiliation: Veterans General Hospital-Taipei, Genome research Laboratory Institute of Biomedical Technology, National Yang-Ming University Title: Associated Principal Investigator Tel: 886-2-2871-2121 ext 2681 Fax: 886-2-2876-3260 My Personal Homepage: http://www.mre.vghtpe.gov.tw/laboratory/genome_research/index.htm E-mail: tjchang@vghtpe.gov.tw Fields of Specialty: Molecular Biology, Human Genome Research,Steroid Hormone Receptors Transcription Regulation Research Description: Functional Genomic approaches in cancer genome research Selected Recent Publication: 1. Chen, Y.M., Chen, W.C., Lee, J.Y., Chang, T.J. and Yang-Feng, T. Genomic structeure, expression and chromosomal localization of the human glycine N-methyltransferase. Genomics, 66:43-47, 2000. 63
  • 64. 2. Chen, Y.M., Chen, W.C., Lee, J.Y., Chang, T.J. and Yang-Feng, T. Genomic structeure, expression and chromosomal localization of the human glycine N-methyltransferase. Genomics, 66:43-47, 2000. 3. Chan, J.Y.H., Chen, W.C., Lee, J.Y., Chang, T.J.and Chan, S.H.H.Phosphorylation of transcription factor CREB mediates c-fos Induction elicited by sustained hypertension in rat nucleus tractus Solitarii. Neuroscience 88:1199-1212,1999 4. Tu,T.Y., Chiu, J.H., Chang, T.J., Yang, A.H. and Lien C.F. Expression of Isk protein mRNA in cultured rat strial marginal Cells. Acta Otolaryngol 119:544-549,1999 5. Chang TJ, Tsai TC, Yang HM, Wu YL, Chi CW, Chou MD and Lee LS. 1999 Abnormal transcripts of FHIT gene in Chinese brain tumors. Oncology Report 6:345-348,1999 6. Chan, J.Y.H., Chen, W.C., Lee, J.Y., Chang, T.J.and Chan, S.H.H.Phosphorylation of transcription factor CREB mediates c-fos Induction elicited by sustained hypertension in rat nucleus tractus Solitarii. Neuroscience 88:1199-1212,1999 7. Tu,T.Y., Chiu, J.H., Chang, T.J., Yang, A.H. and Lien C.F. Expression of Isk protein mRNA in cultured rat strial marginal Cells. Acta Otolaryngol 119:544-549,1999 64
  • 65. Name in Chinese: 陳正成 Name in English: Cheng-Chen Chen Education: London School of Hygiene and Tropical Medicine. Ph. D. 1982 National Defense Medical Center, M. Sc. 1975 National Chung-Hsing University, B. Sc. 1973 Affiliation: Institute of Tropical Medicine, National Yang-Ming University Title: Professor Tel: 886-2-2826-7074 Fax: 886-2-2821-4670 E-mail: mosquito@ym.edu.tw Fields of Specialty: Medical Entomology, Vector Biology, Mosquito innate immunity, Mosquito genome. Research Description: My work involves using genomic mass-screens, EST sequencing, microarray analysis, and proteomics, etc., to identify important mosquito defense factors. The potential candidate molecules are characterized and elucidated their biological functions by mosquito gene silencing technologies. Selected Recent Publication: 1. Huang, L.H., Christensen, B.M. and Chen, C.C. 2001, Molecular cloning of a second 65
  • 66. prophenoloxidase cDNA from the mosquito Armigeres subalbarus: prophenoloxidase expression in blood-fed and microfilariae-inoculated mosquitoes. Insect Molecular Biology 10: 87-95 2. Taft, A. S., Chen, C. C., Li, J. and Christensen, B.M 2001 Molecular cloning of two prophenoloxidase genes from mosquito Aedes aegypti. Insect Molecular Biology 10: 97-103 3. Shiao, H. S., Higgs, S., Adelman, Z., Christensen, B. M., Liu, S. H. and Chen, C. C. 2001 Effect of prophenoloxidase expression knockout on the melanization of filarial worms in the mosquito, Armigeres subalbatus. Insect Molecular Biology 10: 315-321 4. Lai, S. C., Chen, C. C. and Hou, R. F. 2001. Electron microscopic observation on wound healing in larvae of the mosquito Armigeres subalbatus (Diptera:Culicidae). Journal of Medical Entomology 38: 836-843 5. Chang, T.T., Chang T.Y., Chen, C.C., Young, K.C., Roan, J. N., Lee., Y.C., Cheng, P.N. and Wu, H.L. 2001 Existence of hepatitis C virus in Culex quinquefasciatus after ingestion of infected blood: experimental approach to evaluating transmission by mosquitoes. Journal of Clinical Microbiology 39: 3353-3355 6. Lai, S.C., Chen, C.C. and Hou, R.F. 2002. Immunolocalization of prophenoloxidase in the process of wound healing in larvae of the mosquito Armigeres subalbatus (Diptera: Culicidae). Journal of Medical Entomology 39:266-274 7.Johnson, J.K., Rocheleau, T. A., Hillier, J.F., Chen, C.C., Li, J., Christensen,B.M. 2003. A potential role for phenylalanine hydroxylase in mosquito immune responses. Insect Biochemistry and Molecular Biology 33:345-354 8. Bartholomay, L. C., Cho, W. L., Rocheleau, T. A. Boyle, J. P., Beck, E. T., Fuchs, J. F., Liss, P., Rusch, M., Butler, K. M., Wu, R. C. C., Lin, S. P., Kou, H. Y., Tsao, I. Y., Huang, C. Y., Wu, T. T, . Hsiao, K. J., Tsai, S. F., Yang, U. C., Nappi, A. J., Perna, N. T., Chen, C. C., and Christensen, B. M. 2004. Toward a description and transcriptomes of immune-activated hemocytes from the mosquito vectors, Aedes aegypti and Armigeres subalbatus. Infection and Immunity (in press). 9. Wang, X., Roucheleau, T. A., Fuchs, J. F., Hillyer, J. F., Chen, C. C. and Christensen, B. M. 2004. A novel lectin with a fibrinogen-like domain is involved in innate immune response of Armigeres subalbatus against bacteria. Insect Molecular Biology (in press). 66
  • 67. Name in Chinese: 陳紀如 Name in English:Chi-Ju Chen Education: Ph.D.Genetics Program , Michigan State University, USA Affiliation: National Yang-Ming University, Taiwan Title: Assistant Professor Tel/Fax: 886-2-2826-7180 E-mail: cjchen@ym.edu.tw Field of specialty: Virology, virus-host interaction Research Interests: Epstein-Barr virus (EBV) is a human gamma herpesvirus associated with a number of malignancies, including nasopharyngeal carcinoma (NPC), Burkitt’s lymphoma, T-cell lymphoma, gastric carcinoma, and Hodgkin’s disease. EBV is transmitted orally, infects both mucosal epithelium and B-lymphocytes where it establishes a latent infection in B-lymphocytes. The EBV genome is maintained as a chromatin-like episome at latency. High levels of reactivation are thought to be a risk factor for several EBV-related malignant lymphoid cancers. However the role of EBV in human malignancy is complex and how the virus is reactivated is not well understood. The expression of immediate early gene, Zta, is a key step in the switch from latency to the lytic cycle of EBV. Zta binds to specific sequences, ZREs, found in viral lytic-cycle origin (OriLyt), as well as viral promoters of genes required for lytic DNA replication. Zta binding to its own promoter is thought to be a key step in the autostimulation of Zta transcription. It was shown that Zta binds to a cellular factor, CREB-binding protein (CBP), which processes acetyltransferase activity, and reactivation of latent EBV by Zta can be strongly stimulated by co-expression of CBP. Zta stimulates CBP acetyltransferase activity on nucleosomes. 67
  • 68. A switch to expression of viral replication-associated genes can be achieved by treatment with histone deacetylase inhibitors, Tricostatin A (TSA) and sodium butyrate, suggesting the involvements of acetyltransferase activity in EBV reactivation. Zta interacts with CBP and stimulates its acetyltransferase activity. Our goal is to investigate the biological role of Zta-depend CBP acetyltransferase activity on Epstein-Barr virus (EBV) reactivation. Three specific aims are the recent interests: 1. Determine the effect of CBP on BZLF1 promoter and other Zta responsive viral genes upon reactivation. 2. Identify the HAT activity of CBP on oriLyt and how it affects EBV replication. 3. Determine the significance of acetylation modification of Zta by CBP. Publications: 1. Deng. Z., C-J Chen, M. Chamberlin, F. Lu,1 G. A. Blobel, D. Speicher, L. A. Cirillo, K. S. Zaret, and P. M. Lieberman1. 2003. The CBP bromodomain and nucleosome targeting are required for Zta-directed nucleosome acetylation and transcription activation. Molecular and Cellular Biology 23:2633-2644. 2. Deng. Z., L. Lezina, C-J Chen, S. Shtivelband, W. So, and P. M. Lieberman. 2002. Telomeric proteins regulate episomal maintenance of Epstein-Barr virus origin of plasmid replication. Molecular Cell 9: 493-503. 3. Deng, Z.*, C-J Chen*, D. Zerby, H. Delecluse, P. M. Lieberman. 2001. Identification of acidic and aromatic residues in the Zta activation domain essential for Epstein-Barr virus reactivation. Journal of Virology 75: 10334-10347. (co-first authors). 4. Chen, Chi-Ju, Z. Deng,, A. Kim, G. Blobel, and P. M. Lieberman. 2000. Stimulation of nucleosome-directed histone acetylase activity of CBP by transcriptional activators. Molecular and Cellular Biology 21:476-487. 5. Zerby, D, C-J Chen, E. Poon, D. Lee, R. Shiekhattar, and P. M. Lieberman. 1999. The amino- terminal C/H1 domain of CREB binding protein mediates Zta transcriptional activation of latent Epstein-Barr virus. Molecular and Cellular Biology 19: 1617-1626. 6. Chen, Chi-Ju, M. E. Quentin, L. A. Brennan, C. Kukel, and S. M. Thiem. 1998. Lymantria dispar Nucleopolyhedrovirus hrf-1 expands the larval host range of Autographa californica nucleopolyhedrovirus. Journal of Virology 72: 2526-2531. 68
  • 69. Name in Chinese: 陳志成 Name in English: Jyh-Cheng Chen Education:1992-1995 PhD, Optical Sciences, University of Arizona, Tucson, Arizona, USA Affiliation:1998-date Institute of radiological Sciences and Department of Medical Radiation Technology. Title: Associate Professor Tel: 886-2-2826-7282 Fax: 886-2-2820-1095 My Personal Homepage: E-mail: jcchen@ym.edu.tw Fields of Specialty: Nuclear molecular imaging physics and instrumentation, medical image processing and analysis Research Description: Dr. Chen is using clinical PET and microPET to do image reconstruction, processing and analysis for clinical and animal studies. Currently he is promoting the NYMU Small- animal Gamma-ray Imaging Laboratory under the collaboration from UST. Selected Recent Publication: 1. C.H.Wang, JC Chen*, and RS Liu, (2003): Development and evaluation of MRI based Bayesian image reconstruction methods for PET. Comput. Med. Imag. Grap. (2003) (in press). (SCI) 2. Wang HE, Liao AH, Deng WP, Chang PF, Chen JC, Chen FD, Liu RS, Lee JS, Hwang JJ. 69
  • 70. Evaluation of 4-Borono-2-[18F]Fluoro-L-Phenylalanine-Fructose as a Probe for BNCT in a Glioma-Bearing Rat Model. J Nucl. Med. 2004; 45:302-308. (SCI) 3. S.P.Mok, C.H.Wang, JC Chen*, and RS Liu, (2003): Performance evaluation of a high resolution small animal PET scanner. Biomed. Eng. Appl. Basis Comm. 15: 143-149. (EI) (NSC 91-3112-P-075-003-Y) 4. Tracy Chen, KS Chuang*, JC Chen, Jay Wu, ML Jan, RS Liu, and CH Hsu, (2003): Simplification of the Probability Matrix in Statistical Reconstruction for PET image. Ann. of Nucl. Med. Sci. 2003:16;137-142. 5. C.H.Wang, JC Chen*, CM Kao, and RS Liu, (2003): Evaluation of MR Images Guided Bayesian Image Reconstructions for PET. Proc. IEEE Nuclear Science Symposium and Medical Imaging Conference (in press). (EI) 6. X.X.Ye, J.J.Hwang, J.F.Hsieh, J.C.Chen*, Y.T.Chou, K.Y.Tu, S.P.Wey, and G.Ting, (2003): In Vivo Quantification of bound [123I]ADAM in Serotonin Transporters in the Brains of Rabbits by SPECT (submitted to Nuclear Medicine and Biology and in revision). 7. Ye XX, Chen JC, Hwang JJ, Wey SP, Lin KJ, Lee JS, Tzen KY, Ting G., (2003): Microautoradiography of [123I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitor. Nuclear Medicine and Biology (in press). (SCI) 70
  • 71. Name in Chinese: 陳美瑜 Name in English: Mei-Yu Chen Education: M.D., National Yang-Ming Medical College Ph.D., BCMB program, Johns Hopkins University School of Medicine Affiliation: Department of Biochemistry, School of Medicine, Nationatl Yang-Ming University Title: Associate professor Tel: 886-2-2826-7269 Fax: 886-2-2826-4843 My Personal Homepage: http://biochem.ym.edu.tw/mychen/ E-mail: meychen@ym.edu.tw Fields of Specialty: Biochemistry, Molecular Biology Research Description: Mechanism and regulation of amoeboid chemotaxis Amoeboid chemotaxis is of fundamental importance in cell-mediated immunity as well as tumor invasion and metastasis. Dictyostelium provides an excellent model system for studying chemotaxis since this organism spends most of its life cycle as chemotactic amoeboid cells and chemotaxis plays a pivotal role during its starvation-induced developmental program. We perform mutagenesis in Dictyostelium, screen for mutants with aberrant chemotactic behaviors, and from the collected mutants, identify and clone the genes responsible for the phenotype. Further analyses of the identified novel 71
  • 72. genes and their homologs in mammals should provide more insights into the molecular mechanism and regulation of eukaryotic chemotaxis. Cellular functions of Pianissimo homologs Pianissimo (piaA) was first identified in Dictyostelium as a novel cytosolic protein involved in cAMP signaling pathway. Genes homologous to piaA exist in Saccharomyces cerevisiae and Schizosaccharomyces pombe. Using a combination of molecular and genetic methods, we have found that the S. cerevisiae homolog (PIA1) is involved in modulating cell integrity and interacts functionally with the target of rapamycin (Tor2p) signaling pathway. In yeast, Tor2p controls cell growth and regulates the cell cycle-dependent organization of actin cytoskeleton. Further studies are underway to elucidate the role of PIA1 in these signaling pathways. Selected Recent Publication: 1. Pang, T.L., Wang, C.Y., Hsu, C.L., Chen, M.Y., and Lin, J.J. (2003) Exposure of single-stranded telomeric DNA causes G2/M cell cycle arrest in Saccharomyces cerevisiae. J. Biol. Chem. 278, 9318-9321. 72
  • 73. Name in Chinese: 陳宜民 Name in English: Yi-Ming Arthur Chen M.D., M.S., Sc.D. Education: D.Sc. degree at the Department of Cancer biology of Harvard School of Public Health Affiliation: Director, AIDS Prevention and Res. Center, National Yang-Ming Uni. Member, AIDS Advisory Committee, D.O.H., R.O.C President, Taiwan Society of Preventive Medicine Council of Representative, APCASO Title: Professor and Chair, Institute of Public Health National Yang-Ming University Tel: 886-2-2826-7193 Fax: 886-2-2827-0576 E-mail: Arthur@ym.edu.tw Fields of Specialty: The Institute of Public Health of NYMU in Taiwan. Prof. Chen has authored/co-authored more than 50 publications on HIV-1, HTLV-I and liver cancer genomics. He also translated Dr. Jonathan Mann’s “AIDS in the World, 2nd edition” into Chinese. At present, he is the president of the Preventive Medicine Society of Taiwan and board member of several advisory committees which including the APCASO (Asia Pacific AIDS Services Organization), amfAR (American Foundation for AIDS Research)- TREAT Asia program, Praa (PWA’s Rights Advocacy Association of Taiwan), the Department of Health and the Ministry of Education of ROC. 73
  • 74. Research Description: Cancer Selected Recent Publication: 1. Chen Y-J, Shih L-S and Chen YM. Quantitative analysis of CDKN2, p53 and retinoblastoma mRNA in human gastric carcinoma. Int J Oncol 13: 249-254, 1998. 2. Chen YM*, Ting S-T, Lee C-M, W-T Liu, Pan W-H, TA Chang, Chou P. Community-based molecular epidemiology of human T-cell leukemia virus type I infection in Taiwan and Kinmen: Implication of the origin of the cosmopolitan subtype in North East Asia. AIDS Res Human Retroviruses 15: 229-237, 1999. 3. Liao Y-P and Chen YM. The legal prostitute's space in Taipei city: stories of secret path, wood- sandals and seven dollars. The Con-temporary Magazine, 137: 44-65, 1999. 4. Chen YM*, Chen LY, Wong FH, Lee CM, Chang TJ, Yang-Feng TL. Genomic structure, expression and chromosomal localization of the human glycine N-methyltransferase gene. Genomics 66: 43-47, 2000. 5. Liou YM, Chou P, Chen YM*. Genotypic Analysis of HCV infection in Kinmen. J Microbiol Immunol Infect 33: 63-68, 2000. 6. Chen YM*, Huang KL, Jen I, Chen SC, Liu YC, Chuang YC, Wong JC, Tsai JJ. Temporal trends and molecular epidemiology of HIV-1 Subtypes in Taiwan from 1988 to 1998. J Acquir Immun Defic Syndr Hum Retrovirol 26: 274-282, 2001. 7. Yang MH, Wang KY, Kuo B IT, Chen YM. Quality of life and its related factors for people living with HIV/AIDS in the northern region of Taiwan. J Nursing Res submitted 2002. 8. Chen YM*, Rey WY, Lan YC, Lai SF, Huang YC, Wu SI, Liu TT, Hsiao KJ. Antibody reactivity to HIV-1 Vpu in HIV-1/AIDS patients on highly active antiretroviral therapy. J Biomed Sci 10: 266-275, 2003. 9. Liu HH, Chen KH, Shih YP, Lui WY, Wong FH, Chen YM*. Characterization of reduced expression of glycine N-methyltransferase in the cancerous hepatic tissues using two newly developed monoclonal antibodies. J Biomed Sci 10: 87-97, 2003. 10. Tseng TL, Shih YP, Huang YC, Wang CK, Chen PH, Chang JG, Yeh KT, Chen YM*, Buetow K. Genotypic and phenotypic characterization of a putative tumor susceptibility gene, GNMT, in liver cancer. Cancer Res, 63: 647-654, 2003. 74
  • 75. Name in Chinese: 鄭宏志 Name in English: Henrich Cheng Education: Karolinska Institute / Dept. of Neuroscience / Ph.D. / 1993 / 03 to1996 / 12 Affiliation : Taipei Veterans General Hospital, Center for Neural Regeneration, Department of Neurosurgery, Neurological Institute Title: Chief and Associate Professor Tel: 886-2-2875-7718 Fax: 886-2-2875-7702 E-mail: hc_cheng@vghtpe.gov.tw Fields of Specialty: Neurosurgery, Neurochemistry, Cell biology Research Description: Dr. Cheng has devoted his life to research in the field of neural regeneration for more than one decade. Recent breakthroughs in molecular neurobiology have ushered in a new and exciting era of central nervous system repair, lending hope to the possibility of functional recovery. Through the use of peripheral nerve grafts supported by growth factor containing fibrin glue, animal studies have demonstrated partial restoration of hind limb function in adult paraplegic rats. (Science, 1996) Using similar methods, substantial recovery of forelimb function was achieved in adult rats with avulsed cervical roots. (Experimental Neurology, 2003) Since 2000, neural repair clinical trials of the spinal cord, brachial plexus, and peripheral nerves have been performed. The results of these experiments are encouraging. 75
  • 76. At present, Dr. Cheng supervises the Neural Regeneration Laboratory at Taipei Veterans General Hospital, Taipei, Taiwan. There are over twenty researchers in the lab conducting proteomic studies and gene research, integral facets of neural regeneration. In addition, advanced cell therapy research in stem cells and olfactory ensheathing cells is also being conducted, along with microglia and related molecule studies including metalaproteinase and metalaprotein. Another team at Dr. Cheng’s laboratory is working on multi-channel brain and spinal cord recording in order to monitor central nervous system electrophysiology before and after operative repair. Animal model trials including stroke, spinal cord injury, spinal cord contusion and spinal root injury are also being investigated. A further development includes the novel rehabilitation program, which includes magnetic stimulation and virtual reality based computer feedback models. Neural prosthetic work utilizing bio-material and nano-technology are also underway. These research developments look to the future and aim for functional recovery and regeneration in central nervous system injuries and diseases. Selected Recent Publication: 1. Cao Y, Veitonmaki N, Keough K, Cheng H, Lee LS, Cao Y, and Zurakowski D. Elivated Levels of Urine Angiostatin and Plasminogen/ Plasmin in Cancer Patients. International Journal of Molecular Medicine 2000; 5: 547-551. 2. Tzeng SF, Tai MH, Cheng H, Wu JP, Liu YL, Kuo JS, Lin PR. Use of Adenoviral Gene Transfer of Glial Cell Line Derived Neurotrophic Factor for Spinal Cord Repair Following a Contusive Injury. J Neurochem 2000; 74: S77B. 3. Chuang TY, Huang MC, Chen KC, Chang YC, Yen YS, Lee LS, and Cheng H. Forelimb Muscle Activity Following Nerve Graft Repair of Ventral Roots in the Rat Cervical Spinal Cord. Life Sciences. 2002; 71, 487-496. 4. Cheng H and Lee YS. Spinal Cord Repair Strategies in Spinal Cord Medicine: Principles and Practice. Demos Medical Publishing, New York; 2002; Chapter 59, P. 801-816. 5. Cheng H, Wu JP, and Tzeng SF. Neuroprotection of Glial Cell Line-Derived Neurotrophic Factor in Damaged Spinal Cords Following Contusive Injury. Journal of Neuroscience Research 2002; 69: 397-405. 6. Cheng H, Fu YS, Kuo JW. The Ability of GDNF to Diminish Free Radical Production Leads to Protection Against Kainate-Induced Excitotoxicity in Hippocampus. Hippocampus 2003 (accepted). 76
  • 77. Name in Chinese: 鄭子豪 Name in English: Tzu-Hao Cheng Education: PhD, Rutgers University/UMDNJ  Postdoctoral fellow, Stanford University School of Medicine Affiliation: Biochemistry Institute of Yang-Ming University Title: Assistant Professor Tel: 886-2-2826-7331 Fax: 886-2-2826-4843 My Personal Homepage: under development E-mail: thcheng@ym.edu.tw Field of Specialty: Molecular Biology, Molecular Genetics Research Description: 1. The functions of human MDM2 isoforms which are generated by alternative translation initiation 2. Polyglutamine mediated protein aggregation Selected Recent Publication: 1. Cheng, T.H., Li, Y.C., and Gartenberg, M.R. (1998). Persistence of an alternate chromatin structure at silenced loci in the absence of silencers. Proc. Natl. Acad. Sci. USA 95, 5521-5526. 77
  • 78. 2. Ansari A., Cheng, T.H., and Gartenberg, M.R. (1999). Isolation of chromatin rings from yeast employing site-specific recombination in vivo. Method: A Companion to Methods in Enzymology 17, 104-111. 3. Cheng, T.H. and Gartenberg M.R. (2000). Yeast silent chromatin is a dynamic structure that requires silencers continuously. Genes & Dev. 14, 452-463. 4. Cheng, T.H., Chang, C.R., Joy, P., Yablok, S., and Gartenberg, M.R. (2000). Controlling gene expression in yeast by inducible site-specific recombination. Nucleic Acids Res. 28, e108. 5. Li, Y.C., Cheng, T.H., and Gartenberg, M.R. (2001). Establishment of transcriptional silencing in the absence of DNA replication. Science 291, 650-653. 78
  • 79. Name in Chinese: 戚謹文 Name in English: Chi, Chin-Wen Education: Ph.D., State University of New York at Buffalo, NY, USA, (1986) Affiliation: Institute of Pharmacology, School of Medicine, National Yang Ming University Title: Professor and Chairman Tel: 886-2-2826-7313 Fax: 886-2-2821-3874 E-mail: cwchi@ym.edu.tw Field of Specialty: Tumor biology, steroid hormone and receptors, experimental therapeutics Research Description: 1. The function of steroid hormones and their receptors in cancer tissues Steroid hormone receptors are cellular signal transducers. Steroid hormones regulate gene expression via specific steroid hormone receptors. It has been found that the levels of steroid hormone receptors in tumors were significantly from those of the adjacent normal tissues including hepatoma, breast cancer, gastric cancer and brain tumors. Steroids and their receptors have multiple functions in tumors, including regulation of oncogene expression, secretion of tumor markers, synthesis of proteases, cell growth and angiogenesis. Therefore, the function of steroid hormones and their receptors is worthy of further investigation. 2. Using rodent hepatoma and gastric tumor model for analysis of Chinese herbal drugs and other 79
  • 80. agents. In vivo tumor models can be generated by tumor cell transplant or by chemical carcinogen induction. In our laboratory, we have successfully established rodent hepatoma models using intrasplenic transplant of hepatoma cells. In addition, in situ injection of gastric tumor cells into stomach of SCID mice generated gastric tumor. These in vivo tumor models will be used for future analysis of Chinese herbal drugs and other therapeutic agents. 3. Analysis of oxidative stress and changes in free radicals in cancer tissues In normal cells, the intracellular oxidation and reduction status as well as the electron transport process are maintained in a balanced state. Recently, it has been found that the levels of oxidative stress and the levels of free radicals were higher in cancer tissues than in normal tissues. Drugs may modulate the intracellular oxidative stress, calcium signaling and induce apoptosis. The function of mitochondria, oxidative stress and free radicals in the regulation of tumor growth will be explored. Selected Recent publication: 1. Chau G.-Y., Wu C.-W., Lui W.-Y., Chang T.-J., Kao H.-L., Wu L.-H., King K.-L., Loong C.-C., Hsai C.-Y., and Chi C.-W. (2000) Serum interleukin 10 but not interleukin 6 related with clinical outcome in patients with resectable hepatocellular carcinoma. Ann Surg 231:552-558. 2. Lin H.-L., Liu T.-Y., Chau G.-Y., Lui W.-Y., and Chi C.-W. (2000) Comparison of 2- methoxyestradiol, docetaxel and paclitaxel induced apoptosis in hepatoma cells and its relation to reactive oxygen species. Cancer 89: 983-994. 3. Chen J.-H., Liu T.-Y., Wu C.-W., and Chi C.-W. (2001) Nonsteroidal anti-inflammatory drugs for treatment of advanced gastric cancer: cyclooxygenase-2 is involved in hepatocyte growth factor mediated tumor development and progression. Medical Hypothesis 57: 503-505. 4. Lin H.-L., Liu T-Y, Wu C.-W., Chi C.-W. (2001) 2-Methoxyestradiol-induced caspase-3 activation and apoptosis occurs via G2/M arrest-dependent and -independent pathways in human gastric cancer cells. Cancer 92: 500-509. 5. Lui W.-Y., Chi C.-W., Chang Y.-F., Chu H.-W., Hsieh C.-C., Yin P.-H., Liu T.-Y., Ou Y.-R., and P’eng F.-K. (2002) In vivo and in vitro growth stimulation of murine hepatoma cells by glucocorticoid. Anticancer Research 22: 1413-1422. 6. Wang J.-J., Chern Y.-T., Chang Y.-F., Liu T.-Y., and Chi C.-W. (2002) Dimethyladmantyl- maleimide induced in vitro and in vivo growth inhibition of human colon cancer Colo205 cells. Anticancer Drugs 13: 533-543. 7. Lin H.-L, WY Lui W.-Y., TY Liu T.-Y., Chi C.-W. (2003) Reversal of Taxol-resistance in hepatoma by cyclosporin A : involvement of the PI-3 kinase-AKT 1 pathway. British J Cancer 88:973-980. 80
  • 81. Name in Chinese: 姜安娜 Name in English: An-Na Chiang Education: Ph.D. National Taiwan Univ. (College of Medicine) Affiliation: Institute of Biochemistry, National Yang-Ming University Title: Professor Tel: 886-2-2826-7122 Fax: 886-2-2826-4843 My Personal Homepage: http://www.ym.edu.tw/bio/intro.htm E-mail: anchia@ym.edu.tw Fields of Specialty: Cardiovascular Biology/Nutritional Biochemistry/ Lipidology Research Description: The major interest of our laboratory is the study of endogenous (physiological) and exogenous (dietary) factors that may protect human from developing atherosclerosis. The basic underlying cause of atherosclerosis is LDL peroxidation within intravascular cells. We previously found that apolipoprotein H (apoH, also known as β2-glycoprotein I, β2-GPI) may inhibit LDL oxidation and lipid accumulation in macrophages. Our recent study has also implicated that β2-GPI protects macrophages and human coronary artery smooth muscle cells against apoptosis. Due to the interindividual variability of β2-GPI expression in subjects with various metabolic syndrome and disease states, we gain more insight into the control of β2-GPI gene regulation by cloning and characterization of β2-GPI gene promoter in the human hepatocytes. Moreover, the regulation of β2-GPI expression under oxidative stress is under investigation both at transcription and translation levels. 81
  • 82. We are also working on a series of studies to identify the dietary components effective in inhibiting LDL oxidation. A recent line of our study delineated the relationships among n-3 polyunsaturated fatty acids (n-3 PUFAs), peroxisome proliferators-activated receptors (PPARs), and atherogenesis. The cardioprotective effects of n-3 PUFAs come from their hypolipidemic, anti-thrombotic, anti- inflammatory, and anti-arrhythmic functions. Recent literature indicates that PUFAs may play as the activators of PPARs. PPARs are known as nuclear transcriptional factors, which may exert overall inhibitory actions on the processes in atherosclerotic lesion development. We have recently elucidated how PUFA-regulated PPARs contribute to their target gene expression and lipid homeostasis. Moreover, we have investigated the effect of herbal medicines on the clearance of cellular lipids via the regulation of PPARα or PPARγ expression. We have established vascular cell model (macrophages and smooth muscle cells) and atherosclerotic animal model (apoE-knock out mice) for exploring the control of progression and regression of atherosclerosis. Understanding how PUFAs and herbal medicines regulate the activity and abundance of PPARs will likely provide insight into the development of novel therapeutic strategies for better management of atherosclerosis. Selected Recent Publication: 1. Wang HH, Hung TM, Wei J, and Chiang AN. (2004) Fish oil increases antioxidant enzyme activities in macrophages and reduces atherosclerotic lesions in apoE-knockout mice. Cardiovas. Res. 61:169-176. 2. Chiang AN, Kou TC, and Wang HH. (2003) Influence of polyunsaturated fatty acids on the expression of PPARr in vascular cells and their effect on gene transcription. Atherosclerosis 4:216. 3. Lin, K.Y., Chen, Y. L., Shih, C.C., Pan, J.P., Chen, W.E., and Chiang, A.N.(2002)The contribution of HDL-apolipoproteins to the inhibtion of low density lipoprotein oxidation and lipid accumulation in macrophages. J. Cell. Biochem. 86: 258-267. 4. Ju-Pin Pan, Shiau-Ting Lai, Shu-Chiung Chiang, Shiu-Chin Chou, and Chiang, A.N.(2002)The risk of coronary artery disease in population of Taiwan is associated with cys-ser 311 polymorphism of human paraoxonase (PON)-2 gene. Chin. Med. J. 65: 415-421. 82
  • 83. Name in Chinese: 賈愛華 Name in English: Eileen Jea Chien Education: Albert Einstein College of Medicine, New York, USA. Ph.D. Affiliation: Department of Physiology, School of Medicine, National Yang-Ming University Title: Associate Professor Tel: 886-2-2826-7088 Fax: 886-2-2826-4049 E-mail: eileen@ym.edu.tw Fields of Specialty: Cell Physiology Research Description: 1. Effect of lipopolysaccharide (LPS) on human peripheral T cells. 2. Nongenomic effect of progesterone on human peripheral T cells. Selected Recent Publication: 1. Chen JJ, Chien EJ , and Wang PS. Progesterone attenuates the inhibitory effects of cardiotonic digitalis on pregnenolone production in rat luteal cells. J. Cell Biochem. 86:107-117, 2002 2. Chien EJ , Hsieh DJ, and Wang J. The response of alkalinization or acidification by phytohemagglutinin is dependent on the activity of protein kinase C in human peripheral T cell. J. Cell Biochem. 81:604-612, 2001. 3. Chien EJ , Chien CH, Chen JJ, Wang SW and Hsieh DJ. Bacterial lipopolysaccharide activates 83
  • 84. protein kinase C, but not intracellular calcium elevation, in human peripherial T cells. J. Cell Biochem. 76:404-410, 2000 84
  • 85. Name in Chinese: 周德盈 Name in English: Teh-Ying Chou Education: M.D., Yang-Ming University School of Medicine, 1984 Ph.D., Biochemistry, Johns Hopkins University School of Medicine, 1995 Affiliation: Yang-Ming University/Veterans General Hospital-Taipei Title: Associate Professor of Pathology and Biochemistry Tel: 886-2-2875-7449 ext 212 Fax: 886-2-2875-7056 My Personal Homepage: http://my.so-net.net.tw/tehying/index.html E-mail: tehying@yahoo.com Fields of Specialty: Thoracic Pathology / Tumor Metastasis Research Description: Our long-term research goal is to develop methodology for prevention, early detection and suppression of cancer metastasis. We intend to achieve this goal through the identification and characterization of metastasis-associated genes using pulmonary adenocarcinoma as a model system. Selected Recent Publication: 1. Small GW, Chou TY, Dang CV, and Orlowski RZ. Evidence for involvement of calpain in c-Myc proteolysis in vivo. Archives of Biochemistry and Biophysics 400:151-161, 2002 85
  • 86. 2. Chou TY and Hart GW. O-linked N-acetylglucosamine and cancer. The Molecular Immunology of Complex Carbohydrates-II, edited by Albert M. Wu. Plenum Press-New York, 2001 86
  • 87. Name in Chinese: 范明基 Name in English: Ming-Ji Fann Education: California Institute of Technology, Ph. D. Affiliation: Department of Life Sciences Title: Associate Professor Tel: 886-2-2826-7184 Fax: 886-2-2820-0259 My Personal Homepage: http://www.dls.ym.edu.tw/t9.htm E-mail: mjfann@ym.edu.tw Fields of Specialty: Molecular and cellular neuroscience Research Description: Three intertwined research directions in the laboratory The first direction is to find novel protein kinases whose expression is differentially in the developing nervous system and to analyze their roles during the development of the nervous system. As protein kinases are known to participate in forming many neural characteristics, including neural connection, transmitter and channel expression, and cognition, I believe this research could have potentials to unravel puzzles in the development of the nervous system. By using degenerate primer- based reverse transcription-polymerase chain reaction, we had demonstrated the expression profile of protein kinases in cultured neurons. From an extension of this study, we identified a novel nuclear CDC2-like, and arginine/serine (RS)-rich protein kinase from embryonic day 14 (E14) rat cortex. Northern and western analyses indicated that it is present mainly in brain. The immunofluorescent staining of postnatal day 14 (P14) hippocampus showed its expression is likely in postmitotic neurons. As this kinase contains RS domain, we suspected that it could phosphorylate SR proteins that are a family of nuclear phosphoproteins involved in constitutive and alternative splicing. Evidence shows that activities of SR proteins, including their subcellular localization, interaction among various SR proteins, and assembly of functional spliceosome, are controlled by phosphorylation. Thus, we named this kinase as protein kinase for spliceosome components (PKSC). In cellular level, PKSC is colocalized with SC35 in nuclear speckles. We also demonstrated that PKSC is a SR protein kinase by its ability to phosphorylate SR proteins in an in vitro assay. Analyses from sequence profiles, subcellular localization, and functional assay suggested that PKSC is a novel type of SR protein 87
  • 88. kinases. The highly specialized and developmentally regulated expression pattern of PKSC implicates that it may be involved in the generation of diversity of neuronal genes by regulating alternative splicing patterns, which in turn forms the basis of a variety of neuronal phenotype. We are currently using transgenic mouse approach to test this possibility. The second research direction is to search for surface molecules that may function in early neural development and could use as stem cell markers. By subtractive hybridization, we had found a novel member of immunoglobulin family whose expression is very abundant in the E10.5 neural tube but gradually disappears after E12. We named this gene as Shian-Dan (SD). Using P19 cell line as a neural differentiation model we demonstrated that the expression of this gene was quickly suppressed when cell differentiate into neurons under influence of retinoic acid. We suspect that this gene is expressed in neural progenitor cells, and was down-regulated when cells entered into differentiated status. More over, we used yeast two hybrid assay and have identified several molecules that bind to the extracellular domain of SD and function as ligands of SD. We intend to pursue further by setting up a tissue culture system to test whether these ligands activate SD and what effects of activation of SD are in term of proliferation and differentiation of neural cells. The third research direction is to search ways that may help neural regeneration in retinal ganglion cells. This is a collaborative project with Dr. An-Guor Wang, an ophthalmologist in General Veteran Hospital (Taipei). As a first step, we used subtractive hybridization to find molecules whose levels of expression change after optic nerve injury. An expression profile database was thus established. Using RT-PCR and histochemical staining, we demonstrated that cytochrome oxidase is upregulated in the early phase after injury. We had published two papers to report these findings. Selected Recent Publication: 1. Wang, A.-G., Lee, C.-M., Wang, Y.-C., Lin, C.-H., and Fann, M.-J. (2002). Upregulation of cytochrome oxidase in the retina following optic nerve injury. Exp. Eye Res. 74, 651-659. 88
  • 89. Name in Chinese: 謝世良 Name in English: Shie-Liang Hsieh Education: Ph.D. University of Oxford, UK (1989-1992) Affiliation: Institute of Microbiology and Immunology National Yang-Ming University Taipei, Taiwan Title: Professor Tel: 886-2-2826-7161 Fax: 886-2-2827-7933 My Personal Homepage: http://www.ym.edu.tw/imi/SLHsieh.html E-mail: slhsieh@ym.edu.tw Fields of Specialty: Immunology Cancer Biology Research Description: 1. Signaling of human lymphotoxin-beta and HVEM receptors 2. Reverse Signaling of TNF-like molecules triggered by decoy receptor 3 (DcR3) and osteoprotegrin (OPG) 3. Dendritic-cells based gene therapy for cancers 4. Interaction between TNF superfamily and stem cells 5. Functional genomics approaches for the identification of novel tyrosine kinases in cancer patients and death-domain containing genes Selected Recent Publication: 89
  • 90. 1. Hsu, P.N., Lin, H.H., Chen, N.J., Wu, K.M., Tu, C.F., Tsai, H.F. and Hsieh, SL (2001) * Human FasL gene does not induce inflammation in pancreas but is unable to protect islet graft from transplantation rejection in pancreas-specific hFasL transgeneic mice. J. Bio. Sci, 8, 262-269 2. Chou, A, Lin, LL, Tsai, HF, Hsieh, SL, Hsu, PI and Hsu, PN (2001) Enhanced proliferation and increased interferon-g production in T cells by signal transduced through TRAIL. J. Immunology, 167, p1347-1352 3. Chow KP, Lu HC, Chou HF, Liu HP, Hsieh SL, Chang YS, Choo KB. (2002) Induction of chemosensitivity in nasopharyngeal carcinoma cells using a human papillomavirus regulatory sequence and the thymidine kinase gene. J Biomed Sci.;9:41-6. 4. Hung, S. C., Chen, N. J., Hsieh, S. L., Li, H., Ma, H. Li., Lo., WH (2002).Isolation and characterization of size-sieved stem cells from human bone marrow. Stem Cells, 20, p249-258 5. Hsu, T.L., Chang, Y.C., Chen, S.R., Chen, S.R.. Liu Y.C., Chiu, A.W., Chio, C.C., Chen, L. Hsieh, S.L.* (2002) Modulation of Dendritic Cell Differentiation and Maturation by Decoy Receptor 3 (DcR3). J. Immunology 168, 4846-4853 6. Chang, Y.H., Hsieh, S.L., Chen, M.C., Lin, W.W. (2002) Lymphotoxin-beta Receptor Induces Interleukin 8 Gene Expression via NF-kB and AP-1 Activation. Exp. Cell Res. 278, 166-174 7. Chen MC, Hwang MJ, Chou YC, Chen WH, Cheng G, Nakano H, Luh TY, Mai SC, Hsieh, S.L.* (2003) The Role of ASK1 in Lymphotoxin-beta Receptor-Mediated Cell Death J. Biol. Chem., 278, 16073-16081 8. Hsu, MJ, Lin, W.W., Tsao, W.C., Hsu, T.L., Chang, Y.C., Chiu, A.W., Chio, C.C., and Hsieh, S.L.* (2004) Enhanced Adhesion of Monocytes via Reverse Signaling Triggered by Decoy Receptor 3 (DcR3), Exp. Cell Res. (in press) 9. Yung-Chi Chang,Tsui-Ling Hsu, Hsi-Hsien Lin, Chung-Ching Chio, Allen W. Chiu, Nien-Jung Chen, Chi-Hung Lin, and Hsieh, S.L.* (2004) Modulation of Macrophage Differentiation and Activation by Decoy Receptor 3. J. Leuk.Biol., (in press) 10. Shu-Fen Wu, Tan-Mei Liu, Yu-Chun Lin, Huey-Kang Sytwu*, Hsueh-Fen Juan, Shui-Tein Chen, Kuo-Liang Shen, Sheng-Chuan Hsi, and Hsieh,S.L.* (2004) Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory: From regulatory mechanism to clinical implicationJ. Leuk.Biol. (in press) 11. Yang, C.R., Hsieh, S.L., Su, W.L., Teng, C.M., Lin, W.W (2004) Soluble decoy receptor 3 (DcR3) induces angiogenesis by neutralization of TL1A, a cytokine belonging to TNF superfamily and exhibiting angiostatic action. Cancer Research (in press) 90
  • 91. Name in Chinese: 徐明達 Name in English: Ming-Ta Hsu Education: P h .D. California Institute of Technology Affiliation: National Yang Ming University Title: professor Tel: 886-2-2826-7230 Fax: 886-2-2826-4843 E-mail: mth@ym.edu.tw Fields of Specialty: epigenomic analysis、DNA replication、cancer biology Research Description: Comprehensive analysis of cis-regulator sequences in specific tissues and in breast cancer Selected Recent Publication: 1. Jong Yj, Li LH, Tsou MH, Chen YJ, Cheng SH, Wang-Wuu S, Tsai SF, Chen CM, Huang AT, Hsu MT, and Lin CH.(2003) Chromosomal CGH abnormalities in early and late onset human breast cancers: correlations with disease progression and p53 mutations. Cancer Genetics and Cytogenetics (in press) 2. Chen YJ., Chen, PJ,Lee MC,Yeh SH,Hsu MT,Lin CH.(2002) Chromosomal analysis of hepatic adenoma and focal nodular hyperplasia by comparative 91
  • 92. genomic hybridization Genes Chromosome Cancer35:138-43 3. Lin SC, ChenYJ,kaoSY,HsuMT,LinCH,YangSC,LiuTY.(2002). Chromosomal changes in betal-associated oral squamous cell carcinomas and their relationship to clinical parameters.Oral Oncol.266-73 4. YangYC,ShyongWY,ChangMS,ChenYJ,LinCH,HuangZD,Wang, HsuMT,ChenML.(2002)Frequent gain of copy number on the long arm of chromosome 3in human cervical adenocarcinoma.Cancer Genet.Cytogent.131:48-53 5. ShannYJ,HsuMT.Cloning and characterization of liver-specific isoform of Chkl gene from rat. (2001)J.Biol.Chem.276;48863-70 6. ChenYJ,YehSH,ChenJT,WuCC,HsuMT,TsaiSF,ChenPJ,LinCH.(2000) Chromosomal Changes and clonality relationship between primary and recurrent hepatocellular carcinoma.Gasteroenterology119:431-40 7. Chen PH, Tseng WB, ChuY, Hsu MT(2000)Interference of the simian virus40 origin of replication by the cytomegalovirus immediate early gene enhancer: evidence for competition of active regulatory chromatin conformation in single domain. Mol. Cell. Biol 20:4062-4074 92
  • 93. Name in Chinese: 洪善鈴 Name in English: Shan-Ling Hung Education: Ph. D. Molecular Biology Graduate Group, Program in Microbiology, University of Pennsylvania, PA, U. S. A. Affiliation: Institute of Oral Biology, National Yang-Ming University Title: Professor Tel: 886-2-2826-7224 Fax: 886-2-2826-4053 My Personal Homepage: none E-mail: slhung@ym.edu.tw Fields of Specialty: molecular biology, microbiology and immunology Research Description: The overall goal of Dr. Hung’s research is to understand the functions of viral proteins, viral entry and pathogenesis, and the relationship between microbiology and immunology and oral diseases. Two main areas of current research are as followed: (A) The pathogenesis of herpes simplex virus: Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), producing primary and reactivation infections, are the causative agents of human diseases, including gingivostomatitis, pharyngitis, herpes labialis, encephalitis, eye and genital infection. The understanding of viral pathogenesis will help eliminate the viruses and may reduce the diseases caused by viral infection. The research topics include: (1) the mechanisms involved in complement evasion of 93
  • 94. herpes simplex viruses; (2) the interaction of viral glycoproteins and cellular receptors and the possible signal transduction pathway involved during viral infection into cells of oral origin; and (3) the possible correlation of herpesvirus infection and periodontal diseases. (B) The effects of areca quid chewing on microbiology and immunology: Areca chewing is associated with an increased risk of oral squamous cell carcinoma and oral submucous fibrosis. Studies have also shown a higher prevalence of periodontal disease among areca chewers than non-areca chewers. Effects on the functions of immune cells may be one possible mechanism by which areca quid chewing compromises the oral health. The research topics include: (1) the effects of components of areca quid on oral microbiology and periodontal tissues, and (2) the molecular and functional relationship between immune system and areca-quid associated oral carcinogenesis. Selected Recent Publication: 1. Ling L-J, Hung S-L, Tseng S-C, Chen Y-T, Chi L-Y, Wu K-M, Lai Y-L. Association between betel quid chewing, periodontal status and periodontal pathogens. Oral Microbiology and Immunology 2001; 16: 364-369 2. Hung S-L (corresponding author), Wang Y-H, Chen H-W, Lee P-L, Chen Y-T. Analysis of herpes simplex virus entering into cells of oral origin. Virus Research 2002; 86: 59-69 (SCI). 3. Hung S-L (corresponding author), Cheng Y-Y, Wang Y-H, Chang K-W, Chen Y-T. Expression and roles of herpesvirus entry mediators A and C in cells of oral origin. Oral Microbiology and Immunology 2002; 17: 215-223 4. Hung S-L, Lin Y-W, Wang Y-H, Chen Y-T, Su C-Y, Ling L-J. Permeability of Streptococcus mutans and Actinobacillus actinomycetemcomitans through guided tissue regeneration membranes and their effects on attachment of periodontal ligament cells. Journal of Periodontology 2002; 73(8): 843-851 5. Hung S-L (corresponding author), Chen Y-L, Chen Y-T. Effects of safrole on the defensive functions of human neutrophils. Journal of Periodontal Research 2003; 38(2): 130-134 6. Chen Y-T, Wang Y-H, Cheng Y-Y, Hung S-L (corresponding author). Direct binding of herpes simplex virus type 1 virions to complement C3. Viral Immunology 2003; 16(3): 347-355 7. Chen Y-T, Hung S-L, Lin L-W, Chi L-Y, Ling L-J. Attachment of periodontal ligament cells on chlorhexidine-loaded guided tissue regeneration membranes. Journal of Periodontology 2003; 94
  • 95. 74(11): 1652-1659 8. Ling L-J, Ho C-C, Wu C-Y, Chen Y-T, Hung S-L (corresponding author). Association between human herpesviruses and the severity of periodontitis. Journal of Periodontology 2004 (accepted) 95
  • 96. Name in Chinese: 黃正仲 Name in English: Jeng-Jong Hwang Education: 1990 Ph.D. Radiological Health Sciences, Colorado State University, Fort Collins, Colorado, U.S.A. Affiliation: Institute of Radiological Sciences Title: Professor Tel: 886-2-2826-7064 Fax: 886-2-2820-1095 My personal homepage: www.ym.edu.tw/rad/taecher/jj.htm E-mail: jjhwang@ym.edu.tw Fields of specialty: radiobiology, tumor biology, cell biology, gene/molecular imaging Research description: 1. Molecular characterization of HPRT gene mutation lesion spectrum in human nasopharygeal carcinoma cells. 2. Molecular characterization of HPRT gene mutation lesion spectrum in patients with nasopharygeal carcinoma before and after radiotherapy. 3. Dose-rate effect of ionizing radiation effect on HPRT gene mutation frequency and lesion spectrum. 4. Study on pharmacokinetics and therapeutic effects of boron-containing lipiodol with boron neutron 96
  • 97. capture irradiation in rat hepatoma and normal tissues. I 5. Study on pharmacokinetics and therapeutic effects of boron-containing lipiodol with boron neutron capture irradiation in rat hepatoma and normal tissues. II 6. The study of in vivo biodistribution and autoradiography of [I-123]-ADAM and its derivatives: a serotonin transporter binding agent 7. PET gene probe core: sub-project 3- Cell and tissue gene probe imaging core. 8. The study of the relationship between TGF-n 1 and radiation hepatitis. 9. Study of the change of plasma TGF-beta1 levels in NPC patients before and after concurrent chemoradiotherapy. 10. The study of quantification and fusion of autoradiography and microPET. Selected recent publication (Hwang JJ*-corresponding author): 1. Wang HE, Liao AH, Deng WP, Chang PF, Chen FD, Liu RS, Chen JC, Lee JS, Hwang JJ (2004): Evaluation of 4-borono-2-[18F]fluoro-L-phenylalanine-fructose as a probe for BNCT in glioma- bearing rat model. J Nucl Med, 45, 302-308. 2. Ye XX, Chen JC, Liu RS, Wey SP, Lee JS, Ting G, Hwang JJ* (2004): Microautoraduography of [123I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors. Nucl Med Biol, (in press) 3. Ye XX, Hwang JJ, Shieh JF, Chen JC (2004). In Vivo Quantification of bound [123I]ADAM to serotonin transporters in the brains of rabbits by SPECT. Nucl Med Biol, (in press). 4. Deng WP, Yang WK, Lai WF, Liu RS, Hwang JJ, Yang DM, Fu YK, Wang HE (2004): A new simplified method of preparation and radiolabeling of FIAU for in vivo imaging of herpes simplex virus type 1 thymidine kinase gene expression. Eu J Nucl Med, 31, 99-109. 5. Lin KJ, Yen TC, Wey SP, Hwang JJ, Ye XX, Tzen KY, Chen JC (2004): Characterization of the binding sites for 123I-ADAM and the relationship to the serotonin transporter in rat and mouse brains using quantitative autoradiography. J Nucl Med, (in press). 97
  • 98. Name in Chinese:高 閬 仙 Name in English: Lung-Sen Kao Education: Ph.D. , University of Massachusetts, Amherst Affiliation: Faculty of Life Sciences , National Yang-Ming University Title: Professor Tel: 886-2-2826-7268 Fax: 886-2-2823-4898 E-mail: lskao@ym.edu.tw Fields of Specialty: Neurochemistry, Cell Biology Research Description: 1. Regulation of intracellular calcium and neurotransmitter release 2. Molecular mechanism of dopaminergic neuron degeneration Selected Recent Publication: 1. Pan, C.-Y., Chu, Y.-S. and Kao, L.-S. (1998) Molecular study of the Na+/Ca2+ exchanger in bovine adrenal chromaffin cells. Biochem. J. 336, 305-310. 98
  • 99. 2. Yang, D.-M. and Kao, L.-S. (2001) Relative contribution of Na+/Ca2+ exchanger, mitochondria, and endoplasmic reticulum in the regulation of cytosolic Ca2+ and catecholamine secretion of bovine adrenal chromaffin cells. J. Neurochem. 76, 210-216. 3. Liu, P.-S., Liaw, C.-T., Lin, M.-K., Shin, S.-H., Lin, L.-F., and Kao, L.-S. (2003) Amphetamine enhances Ca2+ entry and catecholamine release via nicotinic receptors activation in bovine adrenal chromaffin cells Eur. J. Pharmacol. 460, 9-17. 4. Lo, H.-S., Chiang, H.-C., Lin, Anya , M. Y., Chiang, H.-Y., Chu, Y.-C. and Kao, L.-S. (2004) Synergistic effects of dopamine and Zn2+ on the induction of PC12 cell death and dopamine depletion in the striatum: possible implication in the pathogenesis of Parkinson's disease. Neurobiol. Dis. In press 99
  • 100. Name in Chinese: 李德章 Name in English: Te-Chang Lee Education: Ph. D. in Biochemistry, National Taiwan University Affiliation: Institute of Biopharmaceutical Science, National Yang-Ming University Title: Vice president / professor Tel: 886-2-2826-7200 Fax: 886-2-2820-1886 My Personal Homepage: E-mail: tclee@ym.edu.tw Fields of Specialty: Biochemistry, Toxicogenomics, Cancer Biology Research Description: Chronic exposure to arsenic continues to be a severe toxicological and pathological problem in 100
  • 101. humans. Epidemiological evidence strongly supports that chronic arsenic exposure is accompanied by increased risks for cancers and vascular disorders. We are currently focusing on the following two projects: 1. Arsenic-induced alteration of gene expression profiling: Recently developed colorimetric cDNA micrarray technique is adopted to investigate the effects of arsenic exposure on gene expression profile. We have collected several hundreds of plasmids with gene fragments involved in signaling pathways, transcription factors, protein kinases and phosphatases, oncogenes, tumor suppressor genes, DNA repair, and cellular defense, etc. Microarray membranes will then be prepared for elucidating the genetic or epigenetic alterations involved in arsenic-induced stress response and neoplastic transformation. 2. Molecular mechanisms underlying which arsenic triggers the initiative of atherosclerotic lesion progression: Since phenotypic modulation of VSMC resulting intimal migration and accelerated proliferation is critical in the onset of atherosclerotic lesions, knowing how arsenic modulates VSMC proliferation is of fundamental importance to understand early events in the formation of these critical lesions. Therefore, we would like to ask whether exposure of quiescent VSMC to arsenite at a low dose range modulates the profiling of gene expression and whether the modulated gene expression profiling influences the responsiveness of VSMC to endogenously and exogenously growth promoting factors. Selected Recent Publication: 1. Yih LH and Lee TC (2003) Induction of c-anaphase and diplochromosome through dysregulation of spindle assembly checkpoint by sodium arsenite in human fibroblasts. Cancer Res., 63: 6680-6688. 2. Yih LH, Peck K, Lee TC (2002) Changes in gene expression profiles of human fibroblasts in response to sodium arsenite treatment. Carcinogenesis, 23: 867-876. 3. Yih LH and Lee TC (2000) Arsenite induces p53 accumulation through an ATM-dependent pathway in human fibroblasts. Cancer Res., 60: 6346-6352 4. Huang SC, Huang CY and Lee TC (2000) Induction of mitosis-mediated apoptosis by sodium arsenite in HeLa S3 cells. Biochem. Pharmacol., 60:771-780. 5. Ho IC, Yih LH, Kao CY and Lee TC (2000) Tin-protoprophyrin potentiates arsenite-induced DNA strand breaks, chromatid breaks and kinetochore-negative micronuclei in human fibroblasts. Mutat. Res., 452: 41-50. 6. Yih LH and Lee TC (1999) Effects of exposure protocols on induction of kinetochore-plus and -minus micronuclei by arsenite in diploid human fibroblasts. Mutat. Res., 440: 75-82. 7. Huang SC and Lee TC (1998) Arsenite inhibits mitotic division and perturbs spindle dynamics in HeLa S3 cells. Carcinogenesis, 19: 889-896. 101
  • 102. Name in Chinese:吳妍華 Name in English:Yan-Hwa Wu Lee Education:B.S. Department of Agronomy (1966-1967) Department of Agricultural Chemistry (1967-1970) National Taiwan University M.S. Institute of Biochemistry, School of Medicine National Taiwan University (1970-1972) Ph.D. Department of Biochemistry University of Tennessee, U.S.A. (1972-1976) Affiliation:Institute of Biochemistry, National Yang-Ming University Title:President/Professor, National Yang-Ming University Tel:886-2-2826-7124, 886-2-2826-7001 Fax:886-2-2826-4843, 886-2-2825-0936 My Personal Homepage:http://www.ym.edu.tw/bio/teacher/wyh.htm E-mail:yhwulee@ym.edu.tw Fields of Specialty:Biochemistry, Molecular Biology, Molecular Virology Research Description: Virus often targets critical regulatory events in host cells. The effects of viruses on the host cells can be mediated by addition of virus-specific macromolecules to a cellular complex. Alternatively, the virus may cause a disassembly of a host-cell complex, or lead to the assembly of a new infected cell- specific complex. Thus, knowledge of the processes subverted by viruses has often highlighted the mechanisms of viral pathogenesis. The main goal of our study is to elaborate the types of interactions between hepatitis virus-encoded macromolecules and the host cells, which may define the ultimate outcome of a virus infection. 102
  • 103. Selected Recent Publication: 1. Yeh, T.S., and Lee, Y.H.W. (1998). Assembly of hepatitis delta virus particles: package of multimeric HDV genomic RNA and role of phosphorylation. Virology 249, 12-20. 2. You, L.R., Chen, C.M., and Lee, Y.H.W. (1999). The hepatitis C virus core protein modulates the NF-kB signal pathway triggering by lymphotoxin-b receptor ligands and tumor necrosis factor-a. J. Virology 73, 1672-1681. 3. You, L.R., Chen, C.M., Yeh, T.S., Tsai, T.Y., Mai, R.T., Lin, C.H., and Lee, Y.H.W. (1999). Hepatitis C virus core protein interacts with cellular putative RNA helicase. J. Virology 73, 2841-2853. 4. Chung, Y.L., Lee, Y.H.W., Yen, S.H., and Chi, K.W. (2000). A novel approach for nasopharyngeal carcinoma treatment uses phenylbutyrate as a protein kinase c modulator: implications for radiosensitization and EBV-targeted theraphy. Clin. Cancer Res. 6, 1452-1458. 5. Huang, W.H. Yung, B.Y.M., Syu, W.J., and Lee, Y.H.W. (2001). The nucleolar phosphoprotein B23 interacts with hepatitis delta antigen and modulates the hepatitis delta virus RNA replication. J. Biol. Chem. 276, 25166-25175. 6. Chen, S.Y., Kao, C.F., Chen, C.M., Shih, C.M., Hsu, M.J., Chao, C.H. C., Wang, S.H., You, L.R., and Lee, Y.H.W. (2003). Mechanisms for inhibition of hepatitis B virus gene expression and replication by hepatitis C virus core protein. J. Biol. Chem. 78, 591-607. 7. Kao, C.F., Chen, S.Y., Chen, J.Y., Lee, Y.H.W. (2004) Modulation of p53 transcription regulatory activity and posttranslational modification by hepatitis C virus core protein. Oncogene 23, 2472-2483. 8. Kao, C.F., Chen, S.Y., Lee, Y.H.W. (2004) Activation of RNA polymerase I transcription by hepatitis C virus core protein. J. Biomed. Sci.11, 72-94. 103
  • 104. Name in Chinese: 林姝君 Name in English: Shu-Chun Lin Education: 1987, B.S. in Zoology, National Taiwan University. 1989, M.S. in Microbiology and Immunology, National Yang-Ming University. 1995, Ph.D. in Biochemistry, University of Illinois at Chicago, USA Affiliation: Institute of Oral Biology, National Yang-Ming University Title: Associate Professor Tel: 886-2-2826-7272 Fax: 886-2-2826-4053 My Personal Homepage: http://www.ym.edu.tw/iob E-mail: sclin@ym.edu.tw Fields of Specialty: Tumor Biology/Molecular Biology/Molecular Pathology Research Description: Studying the molecular mechanisms of areca (betel)-associated oral pathogenesis is my major research interest. My recent studies also focus on insighting the cellular and molecular impacts of IGFBP-5 on oral keratinocytes. Selected Recent Publication: 104
  • 105. 1. Lin SC*, Liu CJ, Chiu CP, Chang SM, Lu SY and Chen YJ (2004) Establishment of OC3 oral carcinoma cell Line and identification of NF-κB activation responses to areca nut extract. J Oral Pathol Med 33: 79-86. 2. Lin SC, Chung MY, Huang JW, Shieh TM, Liu CJ and Chang KW* (2004, In press) Correlation between genotype in matrix metalloproteinase-1 (MMP-1) gene promoter and the risk of oral squamous cell carcinomas. J Oral Pathol Med. 3. Lin SC, Lo SS, Chung MY, Liu CJ and Chang KW* (2004) Functional matrix metalloproteinase-2 (MMP-2) genotype and the risk of oral squamous cell carcinomas. J Oral Pathol Med. (In press) 4. Lew TS, Chang CS, Fang KP, Chen CY, Cheng CH and Lin SC* (2004) The involvement of Kv3.4 voltage-gated potassium channel in the growth of an oral squamous cell carcinoma cell line. J Oral Pathol Med. (In press) 5. Chang KW, Yuan TC, Fang KP, Yang FS, Chang CS, and Lin SC* (2003) Over expression of voltage-gated potassium channel Kv3.4 in oral squamous carcinoma. J Oral Pathol Med 32: 606-11. 6. Lin SC, Wang CP, Chen YM, Lu SY, Fann MJ, Liu CJ, Kao SY, Chang KW* (2002) Regulation of IGFBP-5 expression during tumourigenesis and differentiation of oral keratinocytes. J Pathol 198: 317-25. 7. Chang, KW, Kao, SY, Tzeng RJ, Liu, CJ, Cheng AJ, Wong, YK, Yang SC and Lin SC* (2002) Multiple molecular alterations of FHIT in betel-associated oral squamous cell carcinoma. J Pathol 196: 300-6. 8. Lin SC, Chen YJ, Hsu MD, Chang CS, Liu TY, Lin CH and Chang KW* (2002) The chromosomal changes of oral squamous cell carcinoma associated with betel quid use. Oral Oncol 38: 266-73. 9. Lin SC, Chang KW, Chang CS, Tzeng YS, Yang FS, Liu TY and Wong YK* (2000) p16/MTS1 alterations in oral squamous cell carcinomas from Taiwanese - correlated with tumor progression. J Oral Pathol Med 29: 159-66. 105
  • 106. Name in Chinese: 許萬枝 Name in Engligh: Wan-Jr Syu Education: Ph.D. University of Wisconsin-Madison, USA Affiliation: Institute of Microbiology and Immunology Title: Professor Tel: 02-2826-7112; 2826-7003 Fax: 02-2821-2880 My Personal Homepage: http://www.ym.edu.tw/imi/WJSyu.html E-mail: wjsyu@ym.edu.tw Field of Specialty: Host-pathogen interaction; pathogenicity of microbes; immunochemistry Research Description: Characterization of viral or bacterial pathogenicity using molecular, immunochemical and genomic approaches; natural products that have antimicrobial or cytotoxic activities and their functional mechanism Selected Recent Publications: 1. Hsu SC, Wu JC, Sheen IJ, Syu WJ (2004) Interaction and replication activation of genotype I and II hepatitis delta antigens. J Virol. 78, 2693-2700. 2. Huang YH, Wu JC, Hsu SC, Syu WJ (2003) Varied immunity generated in mice by DNA vaccines with large and small hepatitis delta antigens. J Virol. 77, 12980-12985. 3. Chiu HJ, Lin WS, Syu WJ (2003) Type III secretion of EspB in enterohemorrhagic Escherichia coli O157:H7. Arch Microbiol. 180, 218-26. 4. Wu CF, Wang SH, Sun CM, Hu ST, Syu WJ (2003) Activation of Dengue Protease Autocleavage at the NS2B-NS3 Junction by Recombinant NS3 and GST-NS2B Fusion Proteins. Journal of Virological Methods 114, 45-54. 5. Hsu SC, Syu WJ, Sheen IJ, Liu HT, Jen KS, Wu JC. (2002) Different effiencies of viral assembly and RNA editing of genotypes I and II hepatitis D viruses. Hepatology 35, 665-674. 106
  • 107. 6. Wang SH, Syu WJ, Huang KJ, Lei HY, Yao CW, King CC, Hu ST. (2002) Intracellular localization and determination of a nuclear localization signal of the core protein of dengue virus. J Gen Virol. 83, 3093-102. 7. Syu WJ, Don MJ, Ou JC, Lee GH, and Sun CM. (2001) Cytotoxic and novel compounds from Solanum indicum. J. Natural Products 64, 1232-1233. 8. Liao CP and Syu WJ. (2002) Analysis of the baseplate region of phage AR1 that specifically infects Escherichia coli O157:H7. J Micobiol Immunol Infect 35, 269-271. 9. Yu SL, Ko KL, Chen CS, Chang YC, and Syu WJ. (2000) Characterization of the distal tail fiber locus and determination of the receptor for phage AR1 that specifically infects E. coli O157:H7. J. Bacteriol. 182, 5962-5968. 10. Lin HP, Hsu SC, Wu JC, Sheen IJ, Yan BS, and Syu WJ. (1999) Localization of isoprenylated antigen of hepatitis delta virus by anti-farnesyl antibodies. J. Gen. Virol. 80, 91-96. 107
  • 108. Name in Chinese: 蔡世峰 Name in English: Shih-Feng Tsai Education: M.D., Taipei Medical College, 1981. Ph.D., Mt. Sinai School of Medicine, CUNY, 1987 Affiliation: National Health Research Institutesm, National Yang-Ming University Title: Director, Professor Tel: 886-2-2652-4120 Fax: 886-2-2789-0484 My Personal Homepage: http://www.nhri.org.tw/nhri_org/mm/main1_1.htm E-mail: petsai@nhri.org.tw Fields of Specialty: Genomics, Human Genetics, Molecular Medicine Research Description: 1. Human Genetics. Modern genetic technology has been used to identify the molecular mechanism underlying Mendelian traits and complex traits. Recently we succeeded in isolating disease gene for an autosomal dominant form of osteonecrosis (avascular necrosis of femoral head). 2. Cancer Genomics. Re-sequencing strategy was applied to identify genomic features that distinguish cancer tissues from normal controls. A major focus is on identifying mechanism of loss of tumor suppressor gene function in the chromosome 4q region in liver cancer. 3. Microbial Genomics. Large-scale sequencing was conducted at the genome level of five 108
  • 109. bacteria. We are particularly interested in studying two human pathogens: V. vulnificus and K. pneumoniae. 4. Comparative Genomics. We have taken a comparative approach to analyze the genomic organization and regulation of alcohol dehydrogenase gene complex. Genomic sequences have been colleted for human, mouse, and chimpanzee, and help identify unique features for the evolution and regulation of this important enzyme. Selected Recent Publication: 1. Fan FF, Shen HH, Tseng WP, Chen PM, & Tsai SF. Molecular cloning and characterization of a human brain-specific gene implicated in neuronal differentiation. (1998) Molecular Brain Research 54: 113-123. 2. Tsou AP, Wu KM, Tseng TI, Chi CW, Chiu JW, Lui WY, Hu CP, Chang C, Chou,CK, & Tsai SF. Parallel hybridization analysis of multiple protein kinase genes: identification of gene expression patterns characteristic of human hepatocellular carcinoma. (1998) Genomics 50: 331-340. 3. Shen HH, Huang AM, Hoheisel J, & Tsai SF. Identification and characterization of a SET/NAP protein encoded by the brain-specific gene, MB20. (2001) Genomics 71(1): 21-33. 4. Fujiyama A, Watanabe H, Toyoda A, Taylor TD, Itoh T, Tsai SF, Park HS, Yaspo ML, Lehrach H, Chen Z, Fu G, Saitou N, Osoegawa K, de Jong PJ, Suto Y, Hattori M, & Sakaki Y. Construction and analysis of the first human-chimpanzee comparative clone map. (2002) Science 295:131-134. 5. Chen CY, Wu KM, Chang YC, Chang C-H, Tsai HC, Liao TL, Liu YM, Chen HJ, Shen Arthur BT, Li JC, Su TL, Shao CP, Lee CT, Hor LI, & Tsai SF. Comparative genome analysis of Vibrio vulnificus, a marine pathogen. Genome Research 13(12):2577-2578 6. Liu MT *, Su JS *, Huang CY, Tsai SF. Novel Mutations Involving the NF1 Gene Coding Sequence in Neurofibromatosis Type 1 Patients from Taiwan. J. Hu Genet.2003;48(10) :545-549 7. Ling-Hui Li, Jian-Chiuan Li, Yung-Feng Lin, Chung-Yen Lin, Chung-Yung Chen and Shih-Feng Tsai.Genoomic shotun array: a procedure linking large-scale DNA sequencing witg regional transcript mapping. Nucleic Acids Research, 2004, Vol. 32, No. 3 e27 8. Chang YT, Shiao YM, Chin PJ, Liu YL, Chou FC, Wu S, Lin YF, Li LH, Lin MW, Liu HN, and TSAU SF. Genetic polymorphisms of the HCR gene and a genomic segment in close proximity to HLA-C are associated with psoriasis patients in Taiwan (2003)Br. J. Dermatol.(in press) 109
  • 110. Name in Chinese 陳芬芳 Name in English: Fung-Fang Wang Education: Ph. D, Dept. of Chemistry, Indiana University, USA Affiliation: Institute of Biochemistry, National Yang-Ming University. Title: Professor Tel: 886-2-2826-7126 Fax: 886-2-2826-4843 E-mail: ffwang@ym.edu.tw Fields of Specialty: Tumor biology, signal transduction, gene regulation Research description: Our laboratory is working on the molecular mechanisms of p53 action. p53 tumor suppressor functions as a guardian of the genome that plays an important role in suppressing cancer development, and mutation on the p53 gene ranks as the most common genetic events in human cancers. A large body of evidence indicates that p53 is required for maintaining the integrity of the genome under environmental stresses. p53 is a transcription factor, central to the action of this tumor suppressor is its ability to activate specific genes carrying distinct p53 binding motif. We have isolated two novel p53 target genes, THTR-1 and DDA3, and are currently studying the function and regulation of their encoded proteins using cell culture systems as well as mouse model. Publications: 1. Chuang, C.C., Tan, S.K., Tai, L.K., Hsin, J.P. and Wang, F.F. (1998) Evidence for the involvement of protein kinase C in the inhibition of prolactin gene expression by transforming growth factor- o 2. Mol. Pharmacol. 53, 1054-1061. 2. Jang, Y.C., Kao, L.S. and Wang, F.F. (1998) Involvement of Ca2+ signaling in the vasoactive intestinal peptide and 8-Br-cAMP induction of c-fos mRNA expression. Cell. Signal. 10, 27-34. 3. Lo, P.K., Chen, J.Y., Lo, W.C., Chen, B.F., Hsin, J.P., Tang, P.P. and Wang, F.F. (1999) Identification of a novel mouse p53 target gene DDA3. Oncogene 18, 7765-7774 4. Tang, P.P. and Wang, F.F. (2000) Induction of IW32 erythroleukemia cell differentiation by p53 is dependent on protein tyrosine phosphatase. Leukemia 14, 1292-1300. 110
  • 111. 5. Lo. P.K., Chen, J.Y., Tang, P.P., Lin, J., Lin, C.H., Su, L.T., Wu, C.H., Chen, T.L., Yang, Y. and Wang, F.F. (2001) Identification of a mouse thiamine transporter gene as a direct transcriptional target for p53. J. Biol. Chem. 276, 37186-37193. 6. Lo, P.K. and Wang, F.F. (2002) Identification of transcriptional start sites and splicing of mouse thiamine transporter gene, THTR-1. Biochem. Biophys. Acta.1576, 209-213. 7. Hsieh, S.C., Lo, P.K. and Wang, F.F. (2002) DDA3 is a direct transcriptional target gene of p53 and p73. Oncogene 21, 3050-3057. 8. Tang, P.P., Hsieh, S.C. and Wang F. F. (2002) Modulation of caspase activation and p27Kip1 degradation in the p53 induced apoptosis in IW32 erythroleukemia cells. Cell. Signal. 14, 961-968. 9. Lo, P. K. and Wang F. F. (2004) 5’–heterogeneity of mouse Dda3 transcripts is attributed to differential initiation of transcription and alternative splicing. Arch. Biochem. Biophys. (in press) 111
  • 112. Name in Chinese: 魏耀揮 Name in English: Yau-Huei Wei Education: Ph.D. in Biochemistry, Department of Chemistry, State University of New York at Albany, New York, USA Affiliation: Institute of Biochemistry, National Yang-Ming University Title: Professor Tel: 886-2-2826-7118 Fax: 886-2-2826-4843 E-mail: joeman@ym.edu.tw or yhwei@nsc.gov.tw Fields of Specialty: Bioenergetics and Biomembranes, Free Radical Biology and Medicine, Mitochondrial Genetics and Diseases, Molecular Medicine Research Description: Mitochondria and sperm have been playing major roles in my research work in the past two decades. In the last 15 years, my laboratory has been involved in the studies on aging-associated mitochondrial DNA (mtDNA) mutations and their effect on mitochondrial respiratory function and production of reactive oxygen species (ROS). We are one of the few laboratories that have systematically studied mtDNAs with large-scale deletions in different tissues of the aged individuals. By developing a cybrid system based on cytoplasmic transfer, we have succeeded in delivering mtDNA with a specific mutation into host cells without mtDNA (called ρo cells) and examine the effect of certain mtDNA mutation on the phenotype of the cells. On the other hand, we have identified a number of disease-associated mutations in mtDNA of patients with various mitochondrial diseases. 112
  • 113. We have characterized the mutations associated with Leber's hereditary optic neuropathy (LHON), myoclonic epilepsy and ragged-red fiber disease (MERRF), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Kearns-Sayre syndrome (KSS), and Leigh syndrome. We are currently involved in the construction of more cybrids by re-populating the ρo cells with mtDNA from each of the patients with a distinct mitochondrial disease. These cybrids have been used as a model system to investigate the quantitative relationship between mutated mtDNA and mitochondrial dysfunction and production of ROS in human cells. We wish to gain a better understanding of the molecular mechanism underlying the pathogenesis of each of the mitochondrial diseases. The other line of research that we have been engaged is the study on mutations and depletion of mtDNA in the spermatozoa of males with infertility or subfertility. We have characterized several novel mtDNA deletions in sperm of infertile males. Recently, we found that mtDNA depletion and a CAG triplet repeat polymorphism in the gene coding for mitochondrial DNA polymerase gamma are important etiological factors for asthenospermia. The expression of mitochondrial genes in spermatozoa will be examined with an aim to understand the coordination between mitochondria and the nucleus in the regulation of sperm function. Selected Recent Publication: 1. Wei, Y. H., and H. C. Lee (2002) Oxidative stress, mitochondrial DNA mutation and impairment of antioxidant enzymes in aging. Exp. Biol. Med. 227:671-682. 2. Liu, C. S., H. W. Chen, C. K. Lii, C. S. Tsai, C. L. Kuo, and Y. H. Wei (2002) Alterations of plasma antioxidants and mitochondrial DNA mutation in hair follicles of smokers. Environ. Mol. Mutagen. 40:168-174. 3. Wei, Y. H., and H. C. Lee (2003) Mitochondrial DNA mutations and oxidative stress in mitochondrial diseases. Adv. Clin. Chem. 37:83-128. 4. Lin, P. H., S. H. Lee, C. P. Su, and Y. H. Wei (2003) Oxidative damage to mitochondrial DNA in atrial muscle of patients with atrial fibrillation. Free Radic. Biol. Med.35:1310-1318. 5. Lu, C. Y., E. K. Wang, H. C. Lee, H. J. Tsay, and Y. H. Wei (2003) Increased expression of manganese-superoxide dismutase in fibroblasts from patients with CPEO syndrome. Mol. Genet. Metabol. 80:321-329. 6. Liu, C. S., C. S. Tsai, C. L. Kuo, H. W. Chen, C. K. Lii, Y. S. Ma, and Y. H. Wei (2003) Oxidative stress-related alteration of the copy number of mitochondrial DNA in human leukocytes. Free Radic. Res. 37:1307-1317. 7. Kao, S. H., H. T. Chao, H. W. Liu, T. L. Liao, and Y. H. Wei (2004) Sperm mitochondrial DNA depletion in men with asthenospermia. Fertil. Steril., in press. 113