Synopses & Reviews
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.
Synopsis
Thrombin and thrombin receptors are involved in many physiological processes and can contribute to a variety of disease states. This book will stimulate interest in new targets of drug development and increase our understanding of the multiplicity of thrombin.
Synopsis
It has become increasingly evident in recent years that, apart from the key role that thrombin plays in the blood coagulation cascade, thrombin also elicits cellular actions via the activation of proteinase-activated receptors, which are present in many cell types. These effects of thrombin are seen in a variety of physiological as well as pathological phenomena, including vascular development and physiology, tumor progression and metastasis, neuronal functions, inflammation, angiogenesis. Thrombin: Physiology and Disease, edited by Michael E. Maragoudakis and Nikos E. Tsopanoglou, emphasizes the new developments in this important field of research and provides the basis for translating these findings into therapeutic targets."
Table of Contents
Table of contents 1. Thrombin: structure, functions and regulation 1.1. Introduction 1.2. Thrombin and Na+ 1.3. Thrombin structure 1.4. Kinetics of Na+ activation 1.5. Structures of E*, E and E:Na+ 1.6. Thrombin interaction with protein C 1.7. Thrombin interaction with the PARs 1.8. Dissociating procoagulant and anticoagulant activities 1.9. WE: a prototypic anticoagulant/antithrombotic thrombin 1.10. References 2. Thrombin: to PAR or not to PAR, and the regulation of inflammation 2.1. Introduction 2.2. Thrombin and the search for its receptor 2.3. Enzymes other than thrombin that are potential physiological regulators of PARs 2.3.1. Enzymes of the coagulation pathway 2.3.2. Proteinases of the gastrointestinal tract 2.3.3. PAR-regulating proteinases in the central nervous system 2.3.4. Immune cell-derived proteinases and PARs 2.3.5. Tumor-derived proteinases and a possible physiological role for kallikrein-related peptidases (KLKs) as PAR regulators 2.3.6. Pathogen-derived proteinases and PAR activation 2.4. Receptor dynamics and cell signaling: enzyme versus peptide-mediated activation 2.4.1. PAR-mediated signaling 2.4.2. PAR activation by enzyme versus peptide 2.5. PAR activation and the inflammation actions of thrombin 2.6. Non-PAR mechanisms of cell regulation mediated by thrombin and other proteinases 2.6.1. Signaling targets that are not "classical" receptors 2.6.2. Non-catalytic mechanisms for proteinase-mediated signaling 2.6.3. Thrombin-mediated generation of agonists from fibrin and other substrates 2.7. Therapeutic implications of thrombin action via PAR and non-PAR mechanisms 2.7.1. Targeting thrombin and other serine proteinases 2.7.2. Targeting the PARs 2.8. Summary 2.9. Acknowledgements 2.10. References 3. Regulation of thrombin receptor signaling 3.1. Introduction 3.2. Cell type specific expression of thrombin receptors 3.3. Thrombin receptor activation and signaling 3.3.1. Proteolytic mechanism of thrombin receptor activation 3.3.2. Thrombin receptor signaling to heterotrimeric G-proteins 3.3.3. Cell type specific thrombin receptor signaling 3.4. Regulation of thrombin receptor signaling 3.4.1. Thrombin receptor desensitization 3.4.2. Thrombin receptor internalization 3.4.3. Thrombin receptor down-regulation 3.5. PAR activation and signaling by other proteases 3.6. Conclusions 3.7. Acknowledgements 3.8. References 4. Thrombin-activated protein C: integrated to regulate vascular physiology 4.1. The protein C pathway is localized to the endothelial cell surface and limits thrombin generation through negative feedback 4.2. APC has protective effects in systemic inflammation that are independent of its anticoagulant function 4.3. The thrombin receptor PAR1 mediates APC signaling in tissues culture 4.4. APC and thrombin can mediate opposite cellular responses in endothelial cells through PAR1 activation 4.4.1. Barrier integrity 4.4.2. Adhesion molecule expression 4.4.3. Apoptosis 4.5. Role of the sphingosine-1 phosphate pathway in mediating protective signaling by PAR1. 4.6. Protective PAR1 signaling by APC is mechanistically coupled to PC activation by thrombin 4.7. Not PAR1- or EPCR-dependent mechanisms for signaling by the PC pathway? 4.8. Thrombin-PAR1 and APC-PAR1 signaling in in vivo models of inflammation 4.9. How can activation of the thrombin receptor PAR1 by the PC pathway be of physiological relevance? 4.9.1. PAR1 cleavage by APC is very inefficient compared with thrombin 4.9.2. What are physiological relevant concentrations of thrombin and APC? 4.9.3. Are dual roles of PAR1 dependent on kinetics of receptor activation? 4.9.4. What is the role of membrane compartmentalization of PAR1? 4.9.5. Surface-retention of APC- but not thrombin-cleaved PAR-1? 4.10. Conclusion 4.11. References 5. The role of thrombin in vascular development 5.1. Introduction 5.2. The coagulation cascade 5.3. Intrinsic pathway 5.4. Extrinsic pathway 5.4.1. Tissue factor 5.4.2. Factor VII 5.5. Common pathway 5.6. FII 5.7. Blood coagulation and vasculogenesis 5.8. Thrombin recaptors 5.9. Diversity of thrombin signaling 5.10. Conclusion 5.11. References 6. The role of thrombin in angiogenesis 6.1. Angiogenesis in health and disease 6.2. Angiogenesis and the coagulation system 6.3. Thrombin-induced angiogenesis: Involvement of coagulation-dependent pathways 6.4. Thrombin-induced angiogenesis: Involvement of coagulation-independent mechanisms 6.5. Thrombin is a protection factor for endothelial cells 6.6. Thrombin and PAR1 as targets for inhibiting angiogenesis 6.7. Conclusion 6.8. References 7. Thrombin and thrombin peptides in wound healing and tissue repair 7.1. Introduction 7.2. Proteolytic and non-proteolytic cell signaling 7.3. Biological activity of thrombin peptides 7.4. Cellular effects of TP508 7.4.1. Chemotaxis 7.4.2. Angiogenesis 7.4.3. Gene expression 7.5. Animal models of wound healing 7.6. Clinical studies 7.6.1. Diabetic foot ulcers 7.6.2. Distal radius fracture repair 7.7. Conclusions 7.8. References 8. The role of thrombin and thrombin receptors in the brain 8.1. Introduction 8.2. Thrombin in neural development and plasticity 8.3. Thrombin in neyroinflammation 8.4. Thrombin in neurodegenerative disorders 8.4.1. Thrombin in stroke 8.4.2. Thrombin and Alzheimer's disease 8.4.3. Thrombin and Parkinson's disease 8.4.4. Thrombin and multiple sclerosis 8.4.5. Thrombin and HIV 8.5. Conclusions 8.6. References 9. The role of thrombin in tumor biology 9.1. Introduction 9.2. Thrombin can stimulate tumor growth in vivo 9.2.1. Supporting evidence 9.2.2. Mechanisms of thrombin-tumor interactions 9.3. Thrombin and metastases 9.3.1. Supporting evidence 9.3.2. Mechanisms of thrombin promoting metastases 9.3.3. Thrombin and metastases: a proposed mechanism 9.4. Thrombin and tumor cell dormancy 9.4.1. Evidence for dormancy 9.4.2. The possible role of thrombin 9.5. References 10. The role of thrombin and its receptors in epithelial malignancies: lessons from a transgenic mouse model and transcriptional regulation 10.1. Morphogenesis of epithelia sheets 10.2. PAR1 over-expression directly correlates with metastatic potential: lessons from malignant and physiological invasion processes 10.3. Placenta physiological invasion 10.4. Transgenic mice of hPar1 targeted to over-express in the mammary gland tissue 10.5. Wnt-4 and wnt-7b are over-expressed in hPar1-tg mammary glands 10.6. Catenin stabilization by hPar1 10.7. hPar1 acts as a survival factor while promoting tumor progression 10.8. Transcriptional regulation of human Par1 10.9. Concluding remarks 10.10. References 11. Anti-thrombotic therapy in cancer patients 11.1. Introduction 11.2. Clinical challenges and epidemiology 11.3. Thromboprophylaxis 11.3.1. Primary surgical thromboprophylaxis 11.3.2. Prevention of VTE in non-surgical patients 11.4. Treatment of venous thromboembolism 11.5. Prevention of secondary recurrence 11.6. Anti-thrombotic and cancer survival 11.7. Conclusion 11.8. References 12. Thrombin receptor modulators: medicinal chemistry, biological evaluation and clinical application 12.1. Introduction 12.2. Proteinase-activated receptor-1 (PAR1) modulators 12.2.1. Peptide agonists and antagonists 12.2.2. Peptidomimetic antagonists 12.2.3. Non-peptide antagonists 12.2.4. Cell-penetrating pepducins 12.3. Proteinase-activated receptor-4 (PAR4) modulators 12.3.1. Peptide agonists 12.3.2. Peptide and non-peptide antagonists 12.3.3. Cell-penetrating pepducins 12.4. Potential therapeutic applications 12.4.1. Anti-thrombotic agents 12.4.2. Treatment of atherosclerosis and restenosis 12.4.3. Anticancer therapeutics 12.5. Conclusion 12.6. References 13. Novel anticoagulant therapy: principle and practice 13.1. Introduction 13.2. Anticoagulant targets that inhibit the initiation phase 13.2.1. Tissue factor/Factor VIIa complex inhibitors 13.3. Inhibitors of coagulation propagation 13.3.1. Indirect Factor Xa inhibitors 13.3.2. Selective direct Factor Xa inhibitors 13.3.3. Selective, direct Factor IXa inhibitors 13.3.4. Factor XIa inhibitors 13.4. Inhibitors of thrombin activity 13.4.1. Indirect thrombin inhibitors 13.4.2. Direct thrombin inhibitors 13.4.3. Selective oral direct thrombin inhibitors 13.5. Expert opinion and conclusions 13.6. References