Model Organisms in Drug Discovery

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REFERENCES 117 Vogel, E. W. and Nivard, M. J. (2000). Parallel monitoring of mitotic recombination, clastogenicity and teratogenic effects in eye tissue of Drosophila. Mutat. Res. 455, 141– 153. Vogel, E. W., Graf, U., Frei, H. J. and Nivard, M. M. (1999). The results of assays in Drosophila as indicators of exposure to carcinogens. IARC Sci. Publ. 146, 427–478. Worby, C. A., Simonson-Leff, N. and Dixon, J. E. (2001). RNA interference of gene expression (RNAi) in cultured Drosophila cells. Sci. STKE 95, L1. Xu, T. and Harrison, S. D. (1994). Mosaic analysis using FLP recombinase. Methods Cell. Biol. 44, 655–681. Xu, T. and Rubin, G. M. (1993). Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117, 1223–1237. Xu, T., Wang, W., Zhang, S., Stewart, R. A. and Yu, W. (1995). Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053–1063. Zhang, J. H., Chung, T. D. and Oldenburg, K. R. (1999). A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J. Biomol. Screen. 4, 67–73. Zhu, D., Ganji, S. H., Kamanna, V. S. and Kashyap, M. L. (2002). Effect of gemfibrozil on apolipoprotein B secretion and diacylglycerol acyltransferase activity in human hepatoblastoma (HepG2) cells. Atherosclerosis 164, 221–228.
5 Drosophila – a Model System for Targets and Lead Identification in Cancer and Metabolic Disorders Corina Schu¨tt, Barbara Froesch and Ernst Hafen Genetic and genomic research in model organisms has tremendously accelerated our understanding of the basic biological processes that lie at the heart of human disease. The genetic dissection of disease-relevant signaling pathways in Drosophila offers an ideal tool to identify novel drug targets for human diseases. In this chapter we outline the conservation of signaling pathways and the different tools available in Drosophila that are suitable for target identification and target validation, as well as for direct screening for biologically active low-molecular-weight compounds. 5.1 Evolutionary conservation of disease-related pathways in Drosophila Analysis of the genetic basis of the development of invertebrate model organisms such as Drosophila melanogaster and Caenorhabditis elegans has confronted us with a stunning degree of conservation of basic developmental processes in invertebrates and disease-related processes in humans. Of more than 1000 genes associated with human diseases, 77% are conserved in Model Organisms in Drug Discovery. Edited by Pamela M. Carroll and Kevin Fitzgerald Copyright © 2003 John Wiley & Sons, Ltd. ISBN: 0-470-84893-6
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Model Organisms in Drug Discovery M
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Copyright u 2003 John Wiley & Sons
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Contents List of contributors .....
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CONTENTS ix 7 Genetics and Genomics
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List of Contributors Hector Beltran
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LIST OF CONTRIBUTORS xiii Stefan Sc
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1 Introduction to Model Systems in
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Organism INTEGRATING MODEL ORGANISM
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INTEGRATING MODEL ORGANISM RESEARCH
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INTEGRATING MODEL ORGANISM RESEARCH
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10 GROWING YEAST FOR FUN AND PROFIT
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3 Caenorhabditis elegans Functional
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THE DRUG DISCOVERY PROCESS 43 thoug
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multivulva phenotype of Ras gain-of
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disease. These molecular targets ar
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FROM DISEASE TO TARGET 49 Figure 3.
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FROM DISEASE TO TARGET 51 Figure 3.
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signaling pathway. The third catego
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FROM DISEASE TO TARGET 55 resistant
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phenomenon was first observed in C.
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profiles. The C. elegans gene expre
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emerging technologies. Forward gene
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The compound library LEAD DISCOVERY
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Page 91 and 92: 82 DROSOPHILA AS A TOOL FOR DRUG DI
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Page 129 and 130: EVOLUTIONARY CONSERVATION OF DISEAS
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Page 151 and 152: CHEMICAL GENETICS 143 acid identity
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Page 159 and 160: REFERENCES 151 Rintelen, F., Stocke
Page 161 and 162: 6 Mechanism of Action in Model Orga
Page 163 and 164: INTRODUCTION TO COMPOUND DEVELOPMEN
Page 165 and 166: MODEL ORGANISMS ARRIVE ON THE SCENE
Page 167 and 168: ELUCIDATING THE MECHANISM OF COMPOU
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Page 171 and 172: A CASE STUDY FOR ALZHEIMER’S DISE
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A CASE STUDY FOR ALZHEIMER’S DISE
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NEW CHEMICAL GENETIC STRATEGIES 171
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A CASE STUDY FOR INNATE IMMUNITY 17
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GLOBAL GENE EXPRESSION STUDIES IN M
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As described above, the extensive i
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REFERENCES 179 Austin, J. and Kimbl
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REFERENCES 181 Hughes, T. R., Marto
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REFERENCES 183 Sin, N., Meng, L., W
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186 GENETICS AND GENOMICS IN THE ZE
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8 Lipid Metabolism and Signaling in
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FISH AS A MODEL ORGANISM 205 genes
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LIPID METABOLISM SCREEN 207 transpo
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LIPID METABOLISM SCREEN 209 Figure
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the embryo media containing radioac
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ZEBRAFISH AS A MODEL SYSTEM 213 Fig
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ZEBRAFISH AS A MODEL SYSTEM 215 Reg
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aspirin, which has potent inhibitor
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REFERENCES 219 Chau, I. and Cunning
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REFERENCES 221 Patrono, C., Patrign
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224 CHEMICAL MUTAGENESIS IN THE MOU
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252 SATURATION SCREENING OF DRUGGAB
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280 INDEX bupropion 92 busulfan 143
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282 INDEX Dscam 171 dual-energy X-r
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284 INDEX L-685,818 16 lead discove
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286 INDEX protein function 19-22 pr
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288 INDEX yeast (continued) functio
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