Proteomics in Drug Research

, by Hamacher, Michael; Marcus, Katrin; Stühler, Kai; van Hall, Andre; Warscheid, Bettina; Meyer, Helmut E.; Mannhold, Raimund; Kubinyi, Hugo; Folkers, Gerd

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ISBN: 9783527312269 | 3527312269
Cover: Hardcover
Copyright: 3/31/2006

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From skillful handling of the wide range of technologies to successful applications in drug discovery-this handbook has all the information professional proteomics users need.Edited by experts working at one of the hot spots in European proteomic research, the numerous contributions by experts from the pharmaceutical industry and public proteomics consortia to provide the necessary perspective on current trends and developments in this exciting field.Following an introductory chapter, the book moves on to proteomic technologies, such as protein biochips, protein-protein interactions, and proteome analysis in situ. The section on applications includes bioinformatics, Alzheimer's disease, neuroproteomics, plasma and T-cell proteomics, differential phosphoproteome analysis and biomarkers, as well as pharmacogenomics.Invaluable reading for medicinal and pharmaceutical chemists, gene technologists, molecular biologists, and those working in the pharmaceutical industry.

A Personal Foreword

xiii

Preface

List of Contributors

xvii

I. Introduction

(30)

Administrative Optimization of Proteomics Networks for Drug Development

(16)

Andre van Hall

Michael Hamacher

Introduction

(1)

Tasks and Aims of Administration

(2)

Networking

(1)

Evaluation of Biomarkers

(2)

A Network for Proteomics in Drug Development

(1)

Realization of Administrative Networking: the Brain Proteome Projects

(9)

National Genome Research Network: the Human Brain Proteome Project

(3)

Human Proteome Organisation: the Brain Proteome Project

(1)

The Pilot Phase

(2)

References

(2)

Proteomic Data Standardization, Deposition and Exchange

(12)

Sandra Orchard

Henning Hermjakob

Manuela Pruess

Rolf Apweiler

Introduction

(2)

Protein Analysis Tools

(2)

UniProt

(1)

InterPro

(1)

Proteome Analysis

(1)

International Protein Index (IPI)

(1)

Reactome

(1)

Data Storage and Retrieval

(1)

The Proteome Standards Initiative

(1)

General Proteomics Standards (GPS)

(1)

Mass Spectrometry

(2)

Molecular Interactions

(1)

Summary

(3)

References

(3)

II. Proteomic Technologies

(154)

Difference Gel Electrophoresis (DICE): the Next Generation of Two-Dimensional Gel Electrophoresis for Clinical Research

(24)

Barbara Sitek

Burghardt Scheibe

Klaus Jung

Alexander Schramm

Kai Stahler

Introduction

(2)

Difference Gel Electrophoresis: Next Generation of Protein Detection in 2-DE

(21)

Application of CyDye DIGE Minimal Fluors (Minimal Labeling with CyDye DIGE Minimal Fluors)

(1)

General Procedure

(1)

Example of Use: Identification of Kinetic Proteome Changes upon Ligand Activation of Trk-Receptors

(5)

Application of Saturation Labeling with CyDye Dige Saturation Fluors

(1)

General Procedure

(1)

Example of Use: Analysis of 1000 Microdissected Cells from PanIN Grades for the Identification of a New Molecular Tumor Marker Using CyDye Dige Saturation Fluors

(2)

Statistical Aspects of Applying DIGE Proteome Analysis

(1)

Calibration and Normalization of Protein Expression Data

(2)

Detection of Differentially Expressed Proteins

(1)

Sample Size Determination

(1)

Further Applications

(1)

References

(5)

Biological Mass Spectrometry: Basics and Drug Discovery Related Approaches

(32)

Bettina Warscheid

Introduction

(1)

Ionization Principles

(4)

Matrix-Assisted Laser Desorption/Ionization (MALDI)

(2)

Electrospray Ionization

(2)

Mass Spectrometric Instrumentation

(3)

Protein Identification Strategies

(2)

Quantitative Mass Spectrometry for Comparative and Functional Proteomics

(2)

Metabolic Labeling Approaches

(4)

15N Labeling

(1)

Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)

(2)

Chemical Labeling Approaches

(5)

Chemical Isotope Labeling at the Peptide Level

(1)

Stable Isotope Labeling at the Peptide Level

(3)

Quantitative MS for Deciphering Protein-Protein Interactions

(2)

Conclusions

(9)

References

(8)

Multidimensional Column Liquid Chromatography (LC) in Proteomics--Where Are We Now?

(24)

Egidijus Machtejevas

Klaus K. Unger

Reinhard Ditz

Introduction

(1)

Why Do We Need MD-LC/MS Methods?

(1)

Basic Aspects of Developing a MD-LC/MS Method

(8)

General

(1)

Issues to be Considered

(1)

Sample Clean-up

(1)

Choice of Phase Systems in MD-LC

(3)

Operational Aspects

(1)

State-of-the-Art--Digestion Strategy Included

(1)

Multidimensional LC MS Approaches

(2)

Applications of MD-LC Separation in Proteomics--a Brief Survey

100

(4)

Sample Clean-Up: Ways to Overcome the ``Bottleneck'' in Proteome Analysis

104

(5)

Summary

109

(4)

References

110

(3)

Peptidomics Technologies and Applications in Drug Research

113

(24)

Michael Schrader

Petra Budde

Horst Rose

Norbert Lamping

Peter Schulz-Knappe

Hans-Dieter Zucht

Introduction

114

(1)

Peptides in Drug Research

114

(6)

History of Peptide Research

114

(2)

Brief Biochemistry of Peptides

116

(1)

Peptides as Drugs

117

(1)

Peptides as Biomarkers

118

(1)

Clinical Peptidomics

118

(2)

Development of Peptidomics Technologies

120

(4)

Evolution of Peptide Analytical Methods

120

(1)

Peptidomic Profiling

121

(2)

Top-Down Identification of Endogenous Peptides

123

(1)

Applications of Differential Display Peptidomics

124

(5)

Peptidomics in Drug Development

124

(3)

Peptidomics Applied to in vivo Models

127

(2)

Outlook

129

(8)

References

130

(7)

Protein Biochips in the Proteomic Field

137

(22)

Angelika Lucking

Dolores J. Cahill

Introduction

137

(2)

Technological Aspects

139

(5)

Protein Immobilization and Surface Chemistry

139

(2)

Transfer and Detection of Proteins

141

(1)

Chip Content

142

(2)

Applications of Protein Biochips

144

(6)

Contribution to Pharmaceutical Research and Development

150

(9)

References

151

(8)

Current Developments for the In Vitro Characterization of Protein Interactions

159

(14)

Daniela Moll

Bastian Zimmermann

Frank Gesellchen

Friedrich W. Herberg

Introduction

160

(1)

The Model System: cAMP-Dependent Protein Kinase

161

(1)

Real-time Monitoring of Interactions Using SPR Biosensors

161

(2)

ITC in Drug Design

163

(2)

Fluorescence Polarization, a Tool for High-Throughput Screening

165

(2)

AlphaScreen as a Pharmaceutical Screening Tool

167

(3)

Conclusions

170

(3)

References

171

(2)

Molecular Networks in Morphologically Intact Cells and Tissue-Challenge for Biology and Drug Development

173

(12)

Walter Schubert

Manuela Friedenberger

Marcus Bode

Introduction

173

(1)

A Metaphor of the Cell

174

(2)

Mapping Molecular Networks as Patterns: Theoretical Considerations

176

(1)

Imaging Cycler Robots

177

(2)

Formalization of Network Motifs as Geometric Objects

179

(3)

Gain of Functional Information: Perspectives for Drug Development

182

(3)

References

182

(3)

III. Applications

185

(134)

From Target to Lead Synthesis

187

(22)

Stefan Mullner

Holger Stark

Paivi Niskanen

Erich Eigenbrodt

Sybille Mazurek

Hugo Fasold

Introduction

187

(3)

Materials and Methods

190

(3)

Cells and Culture Conditions

190

(1)

In Vitro Activity Testing

190

(1)

Affinity Chromatography

190

(1)

Electrophoresis and Protein Identification

191

(1)

BI Acore Analysis

191

(1)

Synthesis of Acyl Cyanides

192

(1)

Methyl 5-cyano-5-oxopentanoate

192

(1)

Methyl 6-cyano-6-oxohexanoate

193

(1)

Methyl-5-cyano-3-methyl-5-oxopentanoate

193

(1)

Results

193

(8)

Discussion

201

(8)

References

203

(6)

Differential Phosphoproteome Analysis in Medical Research

209

(14)

Elke Butt

Katrin Marcus

Introduction

210

(1)

Phosphoproteomics of Human Platelets

211

(5)

Cortactin

213

(1)

Myosin Regulatory Light Chain

213

(1)

Protein Disulfide Isomerase

214

(2)

Identification of cAMP- and cGMP-Dependent Protein Kinase Substrates in Human Platelets

216

(2)

Identification of a New Therapeutic Target for Anti-Inflammatory Therapy by Analyzing Differences in the Phosphoproteome of Wild Type and Knock Out Mice

218

(1)

Concluding Remarks and Outlook

219

(4)

References

220

(3)

Biomarker Discovery in Renal Cell Carcinoma Applying Proteome-Based Studies in Combination with Serology

223

(18)

Barbara Seliger

Roland Kellner

Introduction

224

(1)

Renal Cell Carcinoma

224

(1)

Rational Approaches Used for Biomarker Discovery

225

(1)

Advantages of Different Proteome-Based Technologies for the Identification of Biomarkers

226

(2)

Type of Biomarker

228

(1)

Proteome Analysis of Renal Cell Carcinoma Cell Lines and Biopsies

229

(5)

Validation of Differentially Expressed Proteins

234

(1)

Conclusions

235

(6)

References

235

(6)

Studies of Drug Resistance Using Organelle Proteomics

241

(18)

Catherine Fenselau

Zongming Fu

Introduction

242

(1)

The Clinical Problem and the Proteomics Response

242

(1)

Objectives and Experimental Design

243

(9)

The Cell Lines

243

(1)

Organelle Isolation

244

(1)

Criteria for Isolation

244

(1)

Plasma Membrane Isolation

245

(2)

Protein Fractionation and Identification

247

(2)

Quantitative Comparisons of Protein Abundances

249

(3)

Changes in Plasma Membrane and Nuclear Proteins in MCF-7 Cells Resistant to Mitoxantrone

252

(7)

References

254

(5)

Clinical Neuroproteomics of Human Body Fluids: CSF and Blood Assays for Early and Differential Diagnosis of Dementia

259

(20)

Jens Wiltfang

Piotr Lewczuk

Introduction

259

(1)

Neurochemical Markers of Alzheimer's Disease

260

(11)

β-Amyloid Precursor Protein (β-APP): Metabolism and Impact on AD Diagnosis

261

(2)

Tau Protein and its Phosphorylated Forms

263

(1)

Hyperphosphorylation of Tau as a Pathological Event

264

(1)

Phosphorylated Tau in CSF as a Biomarker of Alzheimer's Disease

265

(1)

Apolipoprotein E (ApoE) Genotype

266

(1)

Other Possible Factors

267

(1)

Combined Analysis of CSF Parameters

267

(3)

Perspectives: Novel Techniques to Search for AD Biomarkers--Mass Spectrometry (MS), Differential Gel Electrophoresis (DIGE), and Multiplexing

270

(1)

Conclusions

271

(8)

References

272

(7)

Proteomics in Alzheimer's Disease

279

(20)

Michael Fountoulakis

Sophia Kossida

Gert Lubec

Introduction

279

(1)

Proteomic Analysis

280

(4)

Sample Preparation

280

(2)

Two-Dimensional Electrophoresis

282

(1)

Protein Quantification

282

(1)

Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectroscopy

283

(1)

Proteins with Deranged Levels and Modifications in AD

284

(10)

Synaptosomal Proteins

290

(1)

Guidance Proteins

291

(1)

Signal Transduction Proteins

291

(1)

Oxidized Proteins

292

(1)

Heat Shock Proteins

293

(1)

Proteins Enriched in Amyloid Plaques

293

(1)

Limitations

294

(5)

References

294

(5)

Cardiac Proteomics

299

(20)

Emma McGregor

Michael J. Dunn

Heart Proteomics

300

(7)

Heart 2-D Protein Databases

300

(1)

Dilated Cardiomyopathy

300

(1)

Animal Models of Heart Disease

301

(1)

Subproteomics of the Heart

302

(1)

Mitochondria

302

(2)

PKC Signal Transduction Pathways

304

(1)

Proteomics of Cultured Cardiac Myocytes

305

(1)

Proteomic Characterization of Cardiac Antigens in Heart Disease and Transplantation

306

(1)

Markers of Acute Allograft Rejection

307

(1)

Vessel Proteomics

307

(5)

Proteomics of Intact Vessels

307

(1)

Proteomics of Isolated Vessel Cells

308

(3)

Laser Capture Microdissection

311

(1)

Concluding Remarks

312

(7)

References

312

(7)

IV. To the Market

319

(18)

Innovation Processes

321

(16)

Sven Ruger

Introduction

321

(1)

Innovation Process Criteria

322

(1)

The Concept

322

(1)

Market Attractiveness

323

(1)

Competitive Market Position

323

(1)

Competitive Technology Position

324

(1)

Strengthen the Fit

325

(1)

Reward

325

(1)

Risk

325

(1)

Innovation Process Deliverables for Each Stage

326

(1)

Stage Gate-Like Process

326

(9)

Designation as an Evaluation Project (EvP)

327

(2)

Advancement to Exploratory Project (EP)

329

(2)

For Advancement to Progressed Project (PP)

331

(3)

Advancement to Market Preparation

334

(1)

Conclusion

335

(2)

Subject Index

337

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Proteomics in Drug Research

Summary

Author Biography

Table of Contents

Supplemental Materials