Thrombin (eBook)
XII, 266 Seiten
Springer New York (Verlag)
978-0-387-09637-7 (ISBN)
In addition to its central role in blood coagulation, it has become increasingly apparent that thrombin and thrombin receptors are involved in many other physiological processes and can contribute to a variety of disease states such as tumor progression and metastasis, inflammation, neurological disorders and cardiovascular complications. This book is a collection of reviews of up-to-date information on the above topics by leaders in these fields.
This book will be of value to researchers and academic professionals both in basic and clinical science who are interested in the fields of biochemistry, biophysics, cell biology, pharmacology, cancer, inflammation, angiogenesis, cardiovascular system and neuronal system. These areas of research are prime target areas for drug development by many pharmaceutical and biotechnology companies.
In addition to its central role in blood coagulation, it has become increasingly apparent that thrombin and thrombin receptors are involved in many other physiological processes and can contribute to a variety of disease states such as tumor progression and metastasis, inflammation, neurological disorders and cardiovascular complications. This book is a collection of reviews of up-to-date information on the above topics by leaders in these fields.This book will be of value to researchers and academic professionals both in basic and clinical science who are interested in the fields of biochemistry, biophysics, cell biology, pharmacology, cancer, inflammation, angiogenesis, cardiovascular system and neuronal system. These areas of research are prime target areas for drug development by many pharmaceutical and biotechnology companies.
Preface 5
Contents 6
Contributors 8
Thrombin: Structure, Functions, and Regulation 12
1.1 Introduction 12
1.2 Thrombin and Na 13
1.3 Thrombin Structure 14
1.4 Kinetics of Na 17
1.4 Kinetics of Na+ Activation 17
1.5 Structures of E*, E, and E:Na 18
1.6 Thrombin Interaction with Protein C 19
1.7 Thrombin Interaction with the PARs 20
1.8 Dissociating Procoagulant and Anticoagulant Activities 23
1.9 WE: A Prototypic Anticoagulant/Antithrombotic Thrombin 24
References 26
Thrombin: To PAR or Not to PAR, and the Regulation of Inflammation 30
2.1 Introduction 30
2.2 Thrombin and the Search for Its Receptor 31
2.3 Enzymes Other than Thrombin That Are Potential Physiological Regulators of PARs 35
2.3.1 Enzymes of the Coagulation Pathway 35
2.3.2 Proteinases of the Gastrointestinal Tract 36
2.3.3 PAR-Regulating Proteinases in the Central Nervous System 36
2.3.4 Immune-Cell-Derived Proteinases and PARs 37
2.3.5 Tumor-Derived Proteinases and a Possible Physiological Role for Kallikrein- Related Peptidases ( KLKs) as PAR Regulators 38
2.3.6 Pathogen-Derived Proteinases and PAR Activation 39
2.4 Receptor Dynamics and Cell Signalling: Enzyme-Mediated vs. Peptide- Mediated Activation 40
2.5 PAR Activation and the Inflammatory Actions of Thrombin 44
2.6 Non-PAR Mechanisms of Cell Regulation Mediated by Thrombin and Other Proteinases 45
2.6.1 Signalling Targets That Are Not “Classical” Receptors 46
2.6.2 Non-catalytic Mechanisms for Proteinase-Mediated Signalling 46
2.6.3 Thrombin-Mediated Generation of Agonists from Fibrin and Other Substrates 47
2.7 Therapeutic Implications of Thrombin Action via PAR and Non- PAR Mechanisms 47
2.7.1 Targeting Thrombin and Other Serine Proteinases 48
2.7.2 Targeting the PARs 48
2.8 Summary 50
References 50
Regulation of Thrombin Receptor Signaling 58
3.1 Introduction 58
3.2 Cell-Type-Specific Expression of Thrombin Receptors 59
3.3 Thrombin Receptor Activation and Signaling 60
3.4 Regulation of Thrombin Receptor Signaling 63
3.5 PAR Activation and Signaling by Other Proteases 67
3.6 Conclusions 68
References 68
Thrombin and Activated Protein C: Integrated to Regulate Vascular Physiology 73
4.1 The Protein C Pathway Is Localized to the Endothelial Cell Surface and Limits Thrombin Generation Through Negative Feedback 73
4.2 APC Has Protective Effects in Systemic Inflammation That Are Independent of Its Anticoagulant Function 75
4.3 The Thrombin Receptor PAR 1 Mediates APC Signaling in Tissue Culture 75
4.4 APC and Thrombin Can Mediate Opposite Cellular Responses in Endothelial Cells Through PAR 1 Activation 77
4.4.1 Barrier Integrity 77
4.4.2 Adhesion Molecule Expression 77
4.4.3 Apoptosis 78
4.5 Role of the Sphingosine-1-Phosphate Pathway in Mediating Protective Signaling by PAR 1 79
4.6 Protective PAR 1 Signaling by APC Is Mechanistically Coupled to PC Activation by Thrombin 80
4.7 Not PAR 1 - or EPCR-Dependent Mechanisms for Signaling by the PC Pathway? 81
4.8 Thrombin-PAR 1 and APC-PAR 1 Signaling in In Vivo Models of Inflammation 82
4.9 How Can Activation of the Thrombin Receptor PAR by the PC Pathway be of Physiological Relevance? 83
4.10 Conclusion 85
References 86
The Role of Thrombin in Vascular Development 91
5.1 Introduction 91
5.2 The Coagulation Cascade 92
5.3 Intrinsic Pathway 93
5.4 Extrinsic Pathway 5.4.1 Tissue Factor 93
5.4.2 Factor VII 95
5.5 Common Pathway 96
5.6 FII 96
5.7 Blood Coagulation and Vasculogenesis 97
5.8 Thrombin Receptors 98
5.9 Diversity of Thrombin Signaling 99
5.10 Conclusion 100
References 101
The Role of Thrombin in Angiogenesis 103
6.1 Angiogenesis in Health and Disease 104
6.2 Angiogenesis and the Coagulation System 107
6.3 Thrombin-Induced Angiogenesis: Involvement of Coagulation- Dependent Pathways 109
6.4 Thrombin-Induced Angiogenesis: Involvement of Coagulation- Independent Mechanisms 112
6.5 Thrombin Is a Protection Factor for Endothelial Cells 113
6.6 Thrombin and PAR 1 as Targets for Inhibiting Angiogenesis 115
6.7 Conclusion 116
References 116
Thrombin and Thrombin Peptides in Wound Healing and Tissue Repair 124
7.1 Introduction 124
7.2 Proteolytic and Nonproteolytic Cell Signaling 125
7.3 Biological Activity of Thrombin Peptides 127
7.4 Cellular Effects of TP508 130
7.5 Animal Models of Wound Healing 132
7.6 Clinical Studies 134
7.6.1 Diabetic Foot Ulcers 135
7.6.2 Distal Radius Fracture Repair 136
7.7 Conclusions 136
References 137
The Role of Thrombin and Thrombin Receptors in the Brain 142
8.1 Introduction 142
8.2 Thrombin in Neural Development and Plasticity 144
8.3 Thrombin in Neuroinflammation 147
8.4 Thrombin in Neurodegenerative Disorders 149
8.5 Conclusions 158
References 160
The Role of Thrombin in Tumor Biology 169
9.1 Introduction 169
9.2 Thrombin Can Stimulate Tumor Growth In Vivo 170
9.3 Thrombin and Metastases 172
9.4 Thrombin and Tumor Cell Dormancy 175
References 176
The Role of Thrombin and its Receptors in Epithelial Malignancies: Lessons from a Transgenic Mouse Model and Transcriptional Regulation 181
10.1 Morphogenesis of Epithelia Sheets 182
10.2 PAR 182
10.2 PAR 1 Overexpression Directly Correlates with Metastatic Potential: Lessons from Malignant and Physiological Invasion Processes 182
10.3 Placenta Physiological Invasion 184
10.4 Transgenic Mice of hPar1 Targeted to Overexpress in the Mammary Gland Tissue 185
10.5 Wnt-4 and wnt-7b are Overexpressed in hPar1-tg Mammary Glands 186
10.6 b -Catenin Stabilization by hPar1 186
10.7 hPar1 Acts as a Survival Factor While Promoting Tumor Progression 188
10.8 Transcriptional Regulation of Human Par1 189
10.9 Concluding Remarks 193
References 193
Anti-thrombotic Therapy in Cancer Patients 197
11.1 Introduction 198
11.2 Clinical Challenges and Epidemiology 200
11.3 Thromboprophylaxis 202
11.3.1 Primary Surgical Thromboprophylaxis 203
11.3.2 Prevention of VTE in Non-Surgical Patients 204
11.4 Treatment of Venous Thromboembolism 204
11.5 Prevention of Secondary Recurrence 204
11.6 Anti-Thrombotic and Cancer Survival 205
11.7 Conclusion 206
References 206
Thrombin Receptor Modulators: Medicinal Chemistry, Biological Evaluation, and Clinical Application 212
12.1 Introduction 212
12.2 Proteinase-Activated Receptor-1 (PAR 1 ) Modulators 215
12.3 Proteinase-Activated Receptor-4 (PAR ) Antagonists 228
12.3.1 Peptide Agonists 229
12.3.2 Peptide and Nonpeptide Antagonists 229
12.3.3 Cell-Penetrating Pepducin 230
12.4 Potential Therapeutic Applications 231
12.5 Conclusion 233
References 234
Novel Anticoagulant Therapy: Principle and Practice 244
13.1 Introduction 245
13.2 Anticoagulant Targets That Inhibit the Initiation Phase 247
13.3 Inhibitors of Coagulation Propagation 249
13.3.1 Indirect Factor Xa Inhibitors 250
13.3.2 Selective Direct Factor Xa inhibitors 251
13.3.3 Selective Direct Factor IXa Inhibitors 255
13.3.4 Factor XIa Inhibitors 255
13.4 Inhibitors of Thrombin Activity 255
13.4.1 Indirect Thrombin Inhibitors: SNAC/Heparin 256
13.4.2 Direct Thrombin Inhibitors 257
13.4.3 Selective Oral Direct Thrombin Inhibitors: Ximelagatran 257
13.5 Expert Opinion and Conclusions 259
References 260
Index 265
Erscheint lt. Verlag | 2.4.2010 |
---|---|
Zusatzinfo | XII, 266 p. |
Verlagsort | New York |
Sprache | englisch |
Themenwelt | Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie |
Studium ► 1. Studienabschnitt (Vorklinik) ► Physiologie | |
Naturwissenschaften ► Biologie | |
Technik | |
Schlagworte | APC • biochemistry • Cells • Endothelium • enzymes • PAR • Physiology • proteins • receptor signaling • sphingosine-1 • Thrombin • tissue • tumor biology • Vascular Development • vascular physiology |
ISBN-10 | 0-387-09637-X / 038709637X |
ISBN-13 | 978-0-387-09637-7 / 9780387096377 |
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