Model Organisms in Drug Discovery

More documents

Recommendations

Info

viii CONTENTS 3.1 The drug discovery process . . . . . . . . . . . . . . . . . . . . . . . . . . 42 3.2 From disease to target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 3.3 Lead discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 3.4 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 3.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 4 Drosophila as a Tool for Drug Discovery Hao Li and Dan Garza ................................. 81 4.1 Drosophila as a model organism for biomedical science . . . . . 81 4.2 Research tools in Drosophila studies . . . . . . . . . . . . . . . . . . . 101 4.3 Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 4.4 Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 4.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 5 Drosophila – a Model System for Targets and Lead Identification in Cancer and Metabolic Disorders Corina Schu¨tt, Barbara Froesch and Ernst Hafen .............. 119 5.1 Evolutionary conservation of disease-related pathways in Drosophila .................................... 119 5.2 Target identification/target validation strategies. . . . . . . . . . . 129 5.3 Chemical genetics: lead identification in Drosophila ........ 142 5.4 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 5.4 Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 5.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 6 Mechanism of Action in Model Organisms: Interfacing Chemistry, Genetics and Genomics Pamela M. Carroll, Kevin Fitzgerald and Rachel Kindt. ......... 153 6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 6.2 Introduction to compound development . . . . . . . . . . . . . . . . 154 6.3 Model organisms arrive on the scene . . . . . . . . . . . . . . . . . . 156 6.4 Elucidating the mechanism of compound action . . . . . . . . . . 159 6.5 A case study for Alzheimer’s disease drug discovery . . . . . . . 162 6.6 New chemical genetic strategies: genome-wide cell-based genetic screens . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 6.7 A case study for innate immunity and inflammation drug discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 6.8 Global gene expression studies in MOA . . . . . . . . . . . . . . . . 175 6.9 Selecting and advancing compound leads using model systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 6.10 Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 6.11 Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 6.12 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
CONTENTS ix 7 Genetics and Genomics in the Zebrafish: from Gene to Function and Back Stefan Schulte-Merker ................................. 185 7.1 Zebrafish – a model system with utilities beyond the study of development. . . . . . . . . . . . . . . . . . . . . . . . . . . 185 7.2 Pathway conservation between humans and fish: what difference do 400 million years make? . . . . . . . . . . . . . 186 7.3 The zebrafish tool kit. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 7.4 Drug screening in zebrafish . . . . . . . . . . . . . . . . . . . . . . . . . 192 7.5 Organs in color: transgenic zebrafish . . . . . . . . . . . . . . . . . . 193 7.6 Genomic technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 7.7 Outlook: the future has stripes. . . . . . . . . . . . . . . . . . . . . . . 197 7.8 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 7.9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 8 Lipid Metabolism and Signaling in Zebrafish Shiu-Ying Ho, Steven A. Farber and Michael Pack ............ 203 8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 8.2 Fish as a model organism to study human physiology and disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 8.3 Lipid metabolism screen . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 8.4 Zebrafish as a model system to study prostanoid metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 8.5 Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 8.6 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 8.7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 9 Chemical Mutagenesis in the Mouse: a Powerful Tool in Drug Target Identification and Validation Andreas Russ, Neil Dear, Geert Mudde, Gabriele Stumm, Johannes Grosse, Andreas Schro¨der, Reinhard Sedlmeier, Sigrid Wattler and Michael Nehls ......................... 223 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 9.2 Chemical mutagenesis in forward and reverse genetics . . . . . 228 9.3 Reverse genetics by ENU mutagenesis . . . . . . . . . . . . . . . . . 231 9.4 Forward genetics in the discovery of new pathways . . . . . . . 235 9.5 The art of screen design: phenotyping . . . . . . . . . . . . . . . . . 242 9.6 Industrialized positional cloning. . . . . . . . . . . . . . . . . . . . . . 244 9.7 Conclusions and prospects . . . . . . . . . . . . . . . . . . . . . . . . . . 246 9.8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Page 1 and 2: Model Organisms in Drug Discovery M
Page 3 and 4: Copyright u 2003 John Wiley & Sons
Page 5: Contents List of contributors .....
Page 9 and 10: List of Contributors Hector Beltran
Page 11 and 12: LIST OF CONTRIBUTORS xiii Stefan Sc
Page 13 and 14: 1 Introduction to Model Systems in
Page 15 and 16: Organism INTEGRATING MODEL ORGANISM
Page 17 and 18: INTEGRATING MODEL ORGANISM RESEARCH
Page 19 and 20: INTEGRATING MODEL ORGANISM RESEARCH
Page 21 and 22: 10 GROWING YEAST FOR FUN AND PROFIT
Page 51 and 52: 3 Caenorhabditis elegans Functional
Page 53 and 54: THE DRUG DISCOVERY PROCESS 43 thoug
Page 55 and 56: multivulva phenotype of Ras gain-of
Page 57 and 58:
disease. These molecular targets ar
Page 59 and 60:
FROM DISEASE TO TARGET 49 Figure 3.
Page 61 and 62:
FROM DISEASE TO TARGET 51 Figure 3.
Page 63 and 64:
signaling pathway. The third catego
Page 65 and 66:
FROM DISEASE TO TARGET 55 resistant
Page 67 and 68:
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
Page 81 and 82:
10 000-15 000 human drug targets ar
Page 83 and 84:
transporter itself. The SSRIs that
Page 85 and 86:
REFERENCES 75 de Montigny, C., Blie
Page 87 and 88:
REFERENCES 77 Lewis, J. A., Wu, C.
Page 89 and 90:
REFERENCES 79 Tissenbaum, H. A. and
Page 91 and 92:
82 DROSOPHILA AS A TOOL FOR DRUG DI
Page 93 and 94:
Page 95 and 96:
Page 97 and 98:
Page 99 and 100:
Page 101 and 102:
Page 103 and 104:
Page 105 and 106:
Page 107 and 108:
Page 109 and 110:
100 DROSOPHILA AS A TOOL FOR DRUG D
Page 111 and 112:
Page 113 and 114:
Page 115 and 116:
Page 117 and 118:
Page 119 and 120:
Page 121 and 122:
Page 123 and 124:
Page 125 and 126:
Page 127 and 128:
5 Drosophila - a Model System for T
Page 129 and 130:
EVOLUTIONARY CONSERVATION OF DISEAS
Page 131 and 132:
Page 133 and 134:
Page 135 and 136:
Page 137 and 138:
TARGET IDENTIFICATION/TARGET VALIDA
Page 139 and 140:
Page 141 and 142:
Page 143 and 144:
Page 145 and 146:
Page 147 and 148:
Page 149 and 150:
Page 151 and 152:
CHEMICAL GENETICS 143 acid identity
Page 153 and 154:
3. A hit identifies a biologically
Page 155 and 156:
about their function in a multicell
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
Page 169 and 170:
ELUCIDATING THE MECHANISM OF COMPOU
Page 171 and 172:
A CASE STUDY FOR ALZHEIMER’S DISE
Page 173 and 174:
Page 175 and 176:
Page 177 and 178:
Page 179 and 180:
NEW CHEMICAL GENETIC STRATEGIES 171
Page 181 and 182:
A CASE STUDY FOR INNATE IMMUNITY 17
Page 183 and 184:
GLOBAL GENE EXPRESSION STUDIES IN M
Page 185 and 186:
As described above, the extensive i
Page 187 and 188:
REFERENCES 179 Austin, J. and Kimbl
Page 189 and 190:
REFERENCES 181 Hughes, T. R., Marto
Page 191 and 192:
REFERENCES 183 Sin, N., Meng, L., W
Page 193 and 194:
186 GENETICS AND GENOMICS IN THE ZE
Page 195 and 196:
Page 197 and 198:
Page 199 and 200:
Page 201 and 202:
Page 203 and 204:
Page 205 and 206:
Page 207 and 208:
Page 209 and 210:
8 Lipid Metabolism and Signaling in
Page 211 and 212:
FISH AS A MODEL ORGANISM 205 genes
Page 213 and 214:
LIPID METABOLISM SCREEN 207 transpo
Page 215 and 216:
LIPID METABOLISM SCREEN 209 Figure
Page 217 and 218:
the embryo media containing radioac
Page 219 and 220:
ZEBRAFISH AS A MODEL SYSTEM 213 Fig
Page 221 and 222:
ZEBRAFISH AS A MODEL SYSTEM 215 Reg
Page 223 and 224:
aspirin, which has potent inhibitor
Page 225 and 226:
REFERENCES 219 Chau, I. and Cunning
Page 227 and 228:
REFERENCES 221 Patrono, C., Patrign
Page 229 and 230:
224 CHEMICAL MUTAGENESIS IN THE MOU
Page 231 and 232:
Page 233 and 234:
Page 235 and 236:
Page 237 and 238:
Page 239 and 240:
Page 241 and 242:
Page 243 and 244:
Page 245 and 246:
Page 247 and 248:
Page 249 and 250:
Page 251 and 252:
Page 253 and 254:
Page 255 and 256:
Page 257 and 258:
252 SATURATION SCREENING OF DRUGGAB
Page 259 and 260:
Page 261 and 262:
Page 263 and 264:
Page 265 and 266:
Page 267 and 268:
Page 269 and 270:
Page 271 and 272:
Page 273 and 274:
Page 275 and 276:
Page 277 and 278:
Page 279 and 280:
Page 281 and 282:
Page 283 and 284:
Page 285 and 286:
280 INDEX bupropion 92 busulfan 143
Page 287 and 288:
282 INDEX Dscam 171 dual-energy X-r
Page 289 and 290:
284 INDEX L-685,818 16 lead discove
Page 291 and 292:
286 INDEX protein function 19-22 pr
Page 293:
288 INDEX yeast (continued) functio
show all

Model Organisms in Drug Discovery

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?