Model Organisms in Drug Discovery

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218 LIPID METABOLISM AND SIGNALING IN ZEBRAFISH mutations from mutagenized sperm offer the promise of generating libraries of mutant alleles that can be assayed in live fish generated through in vitro fertilization (Draper et al., 2001; Wienholds et al., 2002). This methodology, commonly referred to as ‘TILLING’ (McCallum et al., 2000), offers the chance to perform a comprehensive analysis of genes regulating prostanoid synthesis and activity. 8.6 Summary Recent work has shown that it is possible to assay phospholipid metabolism and prostanoid synthesis in zebrafish (Farber et al., 1991; Grosser et al., 2002). These preliminary studies suggest that important questions of lipid biology are amenable to large-scale, high-throughput analyses in this model system. Lipid metabolism now can be added to the growing list of vertebrate developmental and physiological processes that can be assayed in zebrafish. The potential to identify novel genes (or novel functions of known genes) that regulate the metabolism of dietary lipids or the generation of lipid signaling molecules has important pharmacological implications. By using this strategy, ultimately it may be possible to devise combined biochemical and physiological assays of small-molecule modulators of lipid metabolism. Such studies may provide a rapid and accurate screening methodology of great pharmacological value. As an example, a recent pilot screen of 640 bioavailable compounds from a chemical library (Prestwick Chemicals) identified several compounds that inhibit the accumulation of gall bladder fluorescence in zebrafish larvae fed the quenched lipid reporter PED6 (A. Rubinstein, Zygogen, Inc., personal communication). Multiple developmental and physiological pathways are predicted to have an impact on PED6 processing. Some of these, such as lipid absorption and transport, have important clinical implications and their analysis may prove to be tractable using zebrafish-based assays. 8.7 References Amatruda, J. F., Shepard, J. L., Stern, H. M. and Zon, L. I. (2002). Zebrafish as a cancer model system. Cancer Cell 1, 229–231. Babin, P. J. and Vernier, J. M. (1989). Plasma lipoproteins in fish. J. Lipid Res. 30, 467– 489. Barut, B. A. and Zon, L. I. (2000). Realizing the potential of zebrafish as a model for human disease. Physiol. Genom. 2, 49–51. Calder, P. C. (2001). Polyunsaturated fatty acids, inflammation, and immunity. Lipids 36, 1007–1024. Chan, J., Bayliss, P. E., Wood, J. M. and Roberts, T. M. (2002). Dissection of angiogenic signaling in zebrafish using a chemical genetic approach. Cancer Cell 1, 257–267.
REFERENCES 219 Chau, I. and Cunningham, D. (2002). Cyclooxygenase inhibition in cancer – a blind alley or a new therapeutic reality? N. Engl. J. Med. 346, 1085–1087. Chawla, A., Repa, J. J., Evans, R. M. and Mangelsdorf, D. J. (2001). Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866–1870. Chen, W., Burgess, S., Golling, G., Amsterdam, A. and Hopkins, N. (2002). Highthroughput selection of retrovirus producer cell lines leads to markedly improved efficiency of germ line-transmissible insertions in zebra fish. J. Virol. 76, 2192–2198. Claria, J. and Serhan, C. N. (1995). Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell–leukocyte interactions. Proc. Natl. Acad. Sci. USA 92, 9475–9479. Crofford, L. J. (2001). Rational use of analgesic and antiinflammatory drugs. N. Engl. J. Med. 345, 1844–1846. Dennis, E. A. (1997). The growing phospholipase A2 superfamily of signal transduction enzymes. Trends Biochem. Sci. 22, 1–2. Donovan, A., Brownlie, A., Zhou, Y., Shepard, J., Pratt, S. J., Moynihan, J., Paw, B. H., et al. (2000). Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403, 776–781. Draper, B. W., Morcos, P. A. and Kimmel, C. B. (2001). Inhibition of zebrafish fgf8 premRNA splicing with morpholino oligos: a quantifiable method for gene knockdown. Genesis 30, 154–156. Driever, W., Solnica-Krezel, L., Schier, A. F., Neuhauss, S. C., Malicki, J., Stemple, D. L., Stainier, D. Y., et al. (1996). A genetic screen for mutations affecting embryogenesis in zebrafish. Development 123, 37–46. Farber, S. A., Buyukuysal, R. L. and Wurtman, R. J. (1991). Why do phospholipid levels decrease with repeated stimulation? A study of choline-containing compounds in rat striatum following electrical stimulation. Ann. NY Acad. Sci. 640, 114–117. Farber, S. A., Olson, E. S., Clark, J. D. and Halpern, M. E. (1999). Characterization of Ca 2+ -dependent phospholipase A2 activity during zebrafish embryogenesis. J. Biol. Chem. 274, 19338–19346. Farber, S. A., Pack, M., Ho, S. Y., Johnson, I. D., Wagner, D. S., Dosch, R., Mullins, M. C., et al. (2001). Genetic analysis of digestive physiology using fluorescent phospholipid reporters. Science 292, 1385–1388. Fisher, S., Amacher, S. L. and Halpern, M. E. (1997). Loss of cerebum function ventralizes the zebrafish embryo. Development 124, 1301–1311. FitzGerald, G. A. and Loll, P. (2001). COX in a crystal ball: current status and future promise of prostaglandin research. J. Clin. Invest. 107, 1335–1337. Fitzpatrick, F. A. and Soberman, R. (2001). Regulated formation of eicosanoids. J. Clin. Invest. 107, 1347–1351. Fritsche, R., Schwerte, T. and Pelster, B. (2000). Nitric oxide and vascular reactivity in developing zebrafish, Danio rerio. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R2200–2207. Garg, A. (1998). Dyslipoproteinemia and diabetes. Endocrinol. Metab. Clin. North Am. 27, 613–625, ix–x. Goodwin, B. and Kliewer, S. A. (2002). Nuclear receptors. I. Nuclear receptors and bile acid homeostasis. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G926–931. Grosser, T., Yusuff, S., Cheskis, E., Pack, M. A. and FitzGerald, G. A. (2002). Developmental expression of functional cyclooxygenases in zebrafish. Proc. Natl. Acad. Sci. USA 99, 8418–8423. Gupta, R. A. and Dubois, R. N. (2001). Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat. Rev. Cancer 1, 11–21.
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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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LEAD DISCOVERY 65 previous section,
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LEAD DISCOVERY 67 Figure 3.5 Distri
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Compound learning set for assay val
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10 000-15 000 human drug targets ar
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transporter itself. The SSRIs that
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REFERENCES 75 de Montigny, C., Blie
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REFERENCES 77 Lewis, J. A., Wu, C.
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REFERENCES 79 Tissenbaum, H. A. and
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82 DROSOPHILA AS A TOOL FOR DRUG DI
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100 DROSOPHILA AS A TOOL FOR DRUG D
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5 Drosophila - a Model System for T
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EVOLUTIONARY CONSERVATION OF DISEAS
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TARGET IDENTIFICATION/TARGET VALIDA
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CHEMICAL GENETICS 143 acid identity
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3. A hit identifies a biologically
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about their function in a multicell
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REFERENCES 149 Han, Z. S., Enslen,
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REFERENCES 151 Rintelen, F., Stocke
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6 Mechanism of Action in Model Orga
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INTRODUCTION TO COMPOUND DEVELOPMEN
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MODEL ORGANISMS ARRIVE ON THE SCENE
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ELUCIDATING THE MECHANISM OF COMPOU
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ELUCIDATING THE MECHANISM OF COMPOU
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A CASE STUDY FOR ALZHEIMER’S DISE
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Page 193 and 194: 186 GENETICS AND GENOMICS IN THE ZE
Page 209 and 210: 8 Lipid Metabolism and Signaling in
Page 211 and 212: FISH AS A MODEL ORGANISM 205 genes
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Page 223: aspirin, which has potent inhibitor
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270 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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