Model Organisms in Drug Discovery

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more direct modeling of human diseases, demonstrating more extensively the utility of Drosophila for MOA studies, genetic screens against phenotypes generated by drug treatment and compound screens. Further technological development is also necessary, especially in the areas of high-throughput biology. However, the utility of Drosophila in drug discovery is now firmly established and what remains to be determined is how much more this remarkably robust model system can provide for the drug discovery process. 4.4 Acknowledgments We would like to thank R. Fernandez and M. Konsolaki for critical review of the manuscript and Q. Wang and X. Shi for technical help in establishing automated fly sorting and dispensing methods. 4.5 References REFERENCES 111 Abarca, C., Albrecht, U. and Spanagel, R. (2002). Cocaine sensitization and reward are under the influence of circadian genes and rhythm. Proc. Natl. Acad. Sci. USA 99, 9026–9030. Affolter, M., Schier, A. and Gehring, W. J. (1990). Homeodomain proteins and the regulation of gene expression. Curr. Opin. Cell. Biol. 2, 485–495. Andretic, R., Chaney, S. and Hirsh, J. (1999). Requirement of circadian genes for cocaine sensitization in Drosophila. Science 285, 1066–1068. Ashburner, M. (1989). Drosophila: A Laboratory Handbook and Manual (2 Vols). Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press. Ashburner, M. and Novitski, E. (1976). The Genetics and Biology of Drosophila. London: Academic Press. Bate, M. and Martinez Arias, A. (1993). The Development of Drosophila melanogaster. Plainview, New York: Cold Spring Harbor Laboratory Press. Beerli, R. R. and Barbas, C. F., III (2002). Engineering polydactyl zinc-finger transcription factors. Nat. Biotechnol. 20, 135–141. Bibikova, M., Carroll, D., Segal, D. J., Trautman, J. K., Smith, J., Kim, Y. G. and Chandrasegaran, S. (2001). Stimulation of homologous recombination through targeted cleavage by chimeric nucleases. Mol. Cell. Biol. 21, 289–297. Bibikova, M., Golic, M., Golic, K. G. and Carroll, D. (2002). Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases. Genetics 161, 1169– 1175. Brand, A. H. and Perrimon, N. (1993). Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415. Breinbauer, R., Vetter, I. R. and Waldmann, H. (2002). From protein domains to drug candidates – natural products as guiding principles in the design and synthesis of compound libraries. Angew Chem. Int. Ed. Engl. 41, 2879–2890. Brltton, J. S. and Edgar, B. A. (1998). Environmental control of the cell cycle in Drosophila: nutrition activates mitotic and endoreplicative cells by distinct mechanisms. Development 125, 2149–2158.
112 DROSOPHILA AS A TOOL FOR DRUG DISCOVERY Buszczak, M. H., Morin, X., Quinones, A. T., Chia, U. and Cooley, L. (2002). High throughput protein trapping in Drosophila. Dros. Res. Conf. Proc. 43, 982A. Calleja, M., Moreno, E., Pelaz, S. and Morata, G. (1996). Visualization of gene expression in living adult Drosophila. Science 274, 252–255. Cherbas, L. and Cherbas, P. (1998). Cell culture. In Drosophila. A Practical Approach, D.D.Roberts (ed.), pp. xx, 398. Oxford: IRL Press. Chien, S., Reiter, L. T., Bier, E. and Gribskov, M. (2002). Homophila: human disease gene cognates in Drosophila. Nucleic Acids Res. 30, 149–151. Clemens, J. C., Worby, C. A., Simonson-Leff, N., Muda, M., Maehama, T., Hemmings, B. A. and Dixon, J. E. (2000). Use of double-stranded RNA interference in Drosophila cell lines to dissect signal transduction pathways. Proc. Natl. Acad. Sci. USA 97, 6499–6503. Crews, C. M. and Splittgerber, U. (1999). Chemical genetics: exploring and controlling cellular processes with chemical probes. Trends Biochem. Sci. 24, 317–320. Demerec, M. (1994). Biology of Drosophila (Facsimile edition). Cold Spring Harbor, New York: Cold Spring Harbor Press. Dobrosotskaya, I. Y., Seegmiller, A. C., Brown, M. S., Goldstein, J. L. and Rawson, R. B. (2002). Regulation of SREBP processing and membrane lipid production by phospholipids in Drosophila. Science 296, 879–883. Drews, J. B. (2000). Drug discovery: a historical perspective. Science 287, 1960–1964. Duffy, J. B. (2002). GAL4 system in Drosophila: a fly geneticist’s Swiss army knife. Genesis 34, 1–15. Duffy, J. B., Harrison, D. A. and Perrimon, N. (1998). Identifying loci required for follicular patterning using directed mosaics. Development 125, 2263–2271. Echalier, G. (1997). Drosophila Cells in Culture. San Diego, CA: Academic Press. EPA. (1998). OPPTS Harmonized Test Guidelines, Series 870 Health Effects Test Guidelines, 870.5275 Sex-linked Recessive Lethal Test in Drosophila melanogaster (August, 1998). Washington, DC: US Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances. Fischer, J. A., Giniger, E., Maniatis, T. and Ptashne, M. (1988). GAL4 activates transcription in Drosophila. Nature 332, 853–856. Fortier, E. and Belote, J. M. (2000). Temperature-dependent gene silencing by an expressed inverted repeat in Drosophila. Genesis 26, 240–244. Fossett, N. and Schulz, R. A. (2001). Functional conservation of hematopoietic factors in Drosophila and vertebrates. Differentiation 69, 83–90. Foureman, P., Mason, J. M., Valencia, R. and Zimmering, S. (1994a). Chemical mutagenesis testing in Drosophila. IX. Results of 50 coded compounds tested for the National Toxicology Program. Environ. Mol. Mutagen. 23, 51–63. Foureman, P., Mason, J. M., Valencia, R. and Zimmering, S. (1994b). Chemical mutagenesis testing in Drosophila. X. Results of 70 coded chemicals tested for the National Toxicology Program. Environ. Mol. Mutagen. 23, 208–227. Furlong, E. E., Andersen, E. C., Null, B., White, M. P. and Scott, M. P. (2001a). Patterns of gene expression during Drosophila mesoderm development. Science 293, 1629–1633. Furlong, E. E., Profitt, D. and Scott, H. P. (2001b). Automated sorting of live transgenic embryos. Nat. Biotechnol. 19, 153–156. Gilbert, D. G. (2002). euGenes: a eukaryote genome information system. Nucleic Acids Res. 30, 145–148. Gisselbrecht, S. S., Bayes, J., Etchin, J., Dell’Orfano, B., Ferrante, A. and Michelson, A. M. (2002). A rapid and efficient approach to vital enhancer trap screening in Drosophila embryos. Dros. Res. Conf. Proc. 43, 143.
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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.
Page 69 and 70: profiles. The C. elegans gene expre
Page 71 and 72: emerging technologies. Forward gene
Page 73 and 74: The compound library LEAD DISCOVERY
Page 75 and 76: LEAD DISCOVERY 65 previous section,
Page 77 and 78: LEAD DISCOVERY 67 Figure 3.5 Distri
Page 79 and 80: Compound learning set for assay val
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Page 83 and 84: transporter itself. The SSRIs that
Page 85 and 86: REFERENCES 75 de Montigny, C., Blie
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Page 89 and 90: REFERENCES 79 Tissenbaum, H. A. and
Page 91 and 92: 82 DROSOPHILA AS A TOOL FOR DRUG DI
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Page 127 and 128: 5 Drosophila - a Model System for T
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 157 and 158: REFERENCES 149 Han, Z. S., Enslen,
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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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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