Systems Biomedicine (eBook)

Front Cover 1
Systems Biomedicine: Concepts and Perspectives 4
Copyright Page 5
Contents 6
Overview 8
SECTION I: FOUNDATIONS OF SYSTEMS BIOLOGY 12
Chapter 1. Foundations for Systems Biomedicine: An Introduction 14
INTRODUCTION 14
EXPERIMENTAL STRATEGIES IN SYSTEMS BIOLOGY 17
SYSTEMS BIOMEDICINE 18
CIRCADIAN CYCLES AS A RELEVANT MODEL FOR SYSTEMS BIOMEDICINE 20
CONCLUSION 22
References 23
Chapter 2. Genomic Technologies for Systems Biology 26
INTRODUCTION 27
DNA SEQUENCING: HIGH-THROUGHPUT SEQUENCING TECHNOLOGIES 28
APPLICATIONS OF SEQUENCING IN SYSTEMS BIOLOGY: THE TRANSCRIPTOME AND TRANSCRIPTIONAL REGULATION 35
INTERACTION ANALYSIS: TWO-HYBRID SCREENS 44
GENE-BASED PERTURBATION STUDIES: TRANSGENIC KNOCKOUTS 45
References 54
Chapter 3. Proteomics Technologies 56
INTRODUCTION 56
CELL-BASED PROTEOMICS 57
PROTEOMICS OF BIOLOGICAL FLUIDS 59
MICROARRAY-BASED APPROACHES 61
COMPUTATIONAL ASPECTS OF PROTEOMICS 63
CONCLUSION 64
References 64
Chapter 4. Cellular Regulatory Networks 68
INTRODUCTION 69
PART I. TRANSCRIPTIONAL NETWORKS 69
PART II. PROTEIN PHOSPHORYLATION NETWORKS 95
ACKNOWLEDGEMENTS 110
References 111
Chapter 5. The Interface of MicroRNAs and Transcription Factor Networks 120
TRANSCRIPTION NETWORK IN CELLULAR SYSTEMS 121
MICRORNA BIOGENESIS AND FUNCTION 122
A STEM CELL MODEL FOR THE TRANSCRIPTIONAL CONTROL OF MIRNAS 124
LESSONS FROM THE MIRNA REGULATORY LANDSCAPE 126
ENGINEERING MIRNA NETWORKS 130
THE ROADMAP TO SYSTEMS BIOLOGY: DECONVOLUTING COMPLEXITIES 140
CONCLUDING REMARKS 141
References 143
Chapter 6. Protein Networks in Integrin-mediated Adhesions 150
INTRODUCTION 151
PROBLEM 152
SOLUTION 152
CONCLUSION 161
ACKNOWLEDGEMENTS 162
References 162
Chapter 7. Systems Biology and Stem Cell Biology 164
INTRODUCTION 165
TRANSCRIPTION NETWORKS 167
COMPUTATIONAL TOOLS FOR NETWORK CONSTRUCTION AND MODELING 172
GENETIC PERTURBATION OF THE ES CELL SYSTEMS TO DISSECT REGULATORY PATHWAYS 174
EPIGENETIC AND CHROMATIN FEATURES OF PLURIPOTENT STEM CELLS 177
MICRORNAs PROVIDE ANOTHER LAYER OF REGULATORY CONTROL 179
FORWARDING ENGINEERING OF ES CELL REGULATORY NETWORK 180
CONCLUDING REMARKS 181
References 182
SECTION II: COMPUTATIONAL MODELING IN SYSTEMS BIOLOGY 186
Chapter 8. Computational Challenges in Systems Biology 188
INTRODUCTION 189
DIFFERENT LEVELS OF MODELS OF BIOCHEMICAL SYSTEMS 192
CHALLENGES IN BUILDING BIOCHEMICAL MODELS 195
CHALLENGES IN BUILDING MATHEMATICAL MODELS 201
CHALLENGES IN BUILDING COMPUTATIONAL MODELS 210
CASE STUDY: MODELING THE REGULATION OF CALCIUM DYNAMICS IN RAW 264.7 CELLS 215
FUTURE DIRECTIONS AND CONCLUDING REMARKS 222
ACKNOWLEDGEMENTS 224
References 224
Chapter 9. High-level Modeling of Biological Networks 236
INTRODUCTION 237
PARTIAL-LEAST-SQUARES MODELING OF SIGNALING NETWORKS 239
BAYESIAN MODELING OF TRANSCRIPTIONAL NETWORKS 246
AGENT-BASED MODELING OF CELLULAR NETWORKS 250
References 256
Chapter 10. Systems Analysis for Systems Biology 260
INTRODUCTION 261
SENSITIVITY ANALYSIS 262
APPLICATIONS 269
ACKNOWLEDGEMENTS 281
References 282
Chapter 11. The Virtual Cell Project 284
INTRODUCTION 285
THE VIRTUAL CELL DATABASE 286
MODELING PROCESS IN THE VIRTUAL CELL–BIOMODEL INTERFACE 289
NUMERICAL ALGORITHMS IN VIRTUAL CELL 293
WEB-BASED DEPLOYMENT AND CLIENT–SERVER ARCHITECTURE 296
CONCLUSION AND FUTURE PROSPECTS 296
ACKNOWLEDGEMENT 298
References 298
Chapter 12. Software Tools for Systems Biology 300
INTRODUCTION 301
A BRIEF SURVEY OF COMMONLY USED TOOLS 304
DEDICATED TOOLS FOR STOCHASTIC SIMULATION 314
STANDARDS 316
DATABASES 319
TEST SUITES 320
FUTURE PROSPECTS 320
ACKNOWLEDGEMENTS 321
References 321
SECTION III: APPLICATIONS OF SYSTEMS BIOLOGY 326
Chapter 13. Physiome Mark-up Languages for Systems Biology: Model Modularization and Re-use 328
INTRODUCTION 329
CONCEPTUAL MODULARIZATION 330
COMPONENT-BASED IMPLEMENTATION 332
IMPLICATIONS OF MODULARITY 335
INCORPORATING CELLML MODELS INTO TISSUE AND ORGAN MODELS 336
References 338
Chapter 14. Systems Approaches to Developmental Patterning 340
INTRODUCTION 340
SPECIFICATION CUES 341
PROCESSING, REFINING AND INTEGRATING SIGNALS DOWNSTREAM OF SPECIFICATION CUES 352
CONCLUSIONS 357
ACKNOWLEDGMENTS 358
References 358
Chapter 15. Applications of Immunologic Modeling to Drug Discovery and Development 362
INTRODUCTION 363
INFECTIOUS DISEASES 366
CANCER 371
ALLERGIC AND AUTOIMMUNE DISEASES 378
CONCLUSION 383
ACKNOWLEDGEMENTS 384
References 384
Chapter 16. Systems Pharmacology in Cancer 388
FROM MOLECULE TO SYSTEM 388
COMPLEXITY OF HUMAN DISEASES AND DRUG ACTION: THE NEED FOR A SYSTEMS APPROACH TO PHARMACOLOGY HIGHLIGHTED 389
TARGET-BASED THERAPY AND ITS LIMITATIONS 390
COMBINATION THERAPY AND SYNTHETIC LETHALITY 393
DECONVOLUTING MECHANISMS 396
PERTURBATION ANALYSIS OF CONSTRAINED SYSTEMS TO DISCOVER NEW ANTI-CANCER DRUGS 397
NETWORKS, ROBUSTNESS AND CANCER THERAPEUTIC STRATEGIES 399
MINING THE REGULATORY PROGRAM IN THE CANCER TRANSCRIPTOME FOR NOVEL TARGETS 401
INTEGRATING EXPERIMENTAL AND PRIMARY TUMOR EXPRESSION DATA FOR NOVEL BIOMARKERS FOR THERAPEUTIC EFFICACY 404
GENE SIGNATURES TO REVEAL THE DRUG ACTION–GENE FUNCTION CONNECTIVITY MAP 405
CONCLUDING REMARKS 406
References 407
Chapter 17. Systems Biology in Drug Discovery: Using Predictive Biomedicine to Guide Development Choices for Novel Agents in Cancer 410
INTRODUCTION 411
SYSTEMS BIOLOGY IN DRUG DISCOVERY 412
CONCLUDING REMARKS 423
References 423
Chapter 18. Quantitative Biology and Clinical Trials: A Perspective 426
THE ROLE OF CLINICAL TRIALS IN MODERN MEDICINE 426
CLINICAL TRIALS OF THERAPEUTICS 428
UNDERSTANDING THE PROBLEM 430
ANOTHER VIEW OF "SYSTEMS" BIOMEDICINE 432
CONCLUSION AND SUMMARY 433
References 434
Index 436
A 436
B 436
C 437
D 439
E 439
F 440
G 440
H 441
I 441
J 442
K 442
L 442
M 442
N 444
O 444
P 444
Q 446
R 446
S 446
T 448
U 449
V 449
W 450
X 450
Y 450
Z 450