Mouse as a Model Organism (eBook)

Preface 5
Contents 7
Contributors 9
1 Genomic Insulators in Transgenic Animals 15
1.1 Introduction 16
1.2 Vertebrate Insulators in Animal Transgenesis 17
1.3 Transgenes and Insulator Elements From Tyr, Wap and Gh Mouse Loci 19
1.4 Perspectives 21
References 22
2 The German Mouse Clinic -- Running an Open Access Platform 25
2.1 Introduction 26
2.2 Standardized Workflow of the Primary Screen at the German Mouse Clinic 27
2.3 Workflow and Data Management at the GMC 30
2.4 Bone and Cartilage Phenotyping in Mice 32
2.5 Neurological Screening 33
2.6 Screening of Clinical Chemical and Hematological Parameters in Genetically Modified Mice: Considerations How to Assess a Mutant Phenotype 35
2.7 Immunological and Allergological Phenotyping 37
2.7.1 Analysis of Flow Cytometric Phenotyping Data 37
2.7.2 Immunoglobulins 38
2.8 Mouse Phenotyping by Steroid Quantification 39
2.9 Mouse Phenotyping by Targeted Metabolomics 40
2.10 Cardiovascular Screening 41
2.11 Systematic Mouse Phenotyping in Search of New Gene Candidates Playing a Role in Energy Homoeostasis 42
2.12 Diabetes Mouse Phenotyping 44
2.12.1 Diabetes Pathophysiology and Gene-Environment Interactions 44
2.12.2 The German Mouse Clinic Diabetes Screen 45
2.12.3 Environmental Challenges in the Diabetes Screen 46
2.13 The Introduction of the Nuclear Magnetic Resonance Technology at the German Mouse Clinic 47
2.14 Molecular Phenotyping 47
2.15 The Histopathological Phenotyping of Mouse Models of Human Diseases in the German Mouse Clinic 48
2.15.1 Comprehensive Pathological Assessment 49
2.15.2 Background Strain Influences 49
2.15.3 Relation of the Pathology with Other Screens 50
2.15.4 Mouse Histopathology: Mirroring Human Conditions 50
2.16 Outlook 51
References 52
3 Nature and Nurture: Impacts on Mouse Phenotypes and Translational Research 59
3.1 Introduction 59
3.2 Condition: Retinal Degeneration 61
3.3 Condition: Microphthalmia 62
3.4 Condition: Glaucoma 62
3.5 Condition: Cataracts (and Corneal Opacities) 62
3.6 Condition: Presbyacusis (Age Related Hearing Loss) 63
3.7 Condition: Otitis Media (Inflammation in Middle Ear) 64
3.8 Condition: Otitis Interna (Inflammation in Inner Ear) 64
3.9 Condition: Arteritis, Polyarteritis 65
3.10 Condition: Brain (CNS), Infarction 65
3.11 Condition: Weakness, Wasting 66
3.12 Condition: Muscular Dystrophy 66
3.13 Condition: CNS, Demyelination 67
3.14 Condition: Hydrocephalus 67
3.15 Condition: CNS, Hypocallosity, Acallosity 68
3.16 Condition: Seizures 68
3.17 Condition: Neoplasia affecting CNS, vestibular system, special senses or other systems 69
3.18 Condition: Skin, Dermatitis (Mouse Ulcerative Dermatitis, MUD) 70
3.19 Condition: Barbering 70
3.20 Mouse Tumor Phenotypes 71
3.21 Condition: Hematopoietic Neoplasia 72
3.22 Condition: Lung Tumors 73
3.23 Condition: Mammary Tumors 74
3.24 Condition: Liver Tumors 77
3.25 Condition: Tumors that are Not Neoplastic (abscesses and inflammation) 78
3.26 Final Considerations 79
3.27 General Mouse Pathology Phenotyping References 79
References 80
4 The Informatics of High-Throughput Mouse Phenotyping: EUMODIC and Beyond 91
4.1 Introduction 91
4.2 Phenotyping Informatics 92
4.2.1 What Do We Need? 92
4.2.2 State of the Art 94
4.2.2.1 Protocol Data 94
4.2.2.2 Data Capture 95
4.2.2.3 Phenotype Databases 95
4.2.2.4 Data Transfer 96
4.2.2.5 Data Representation 96
4.2.2.6 Baseline Phenotype Data 96
4.2.2.7 Search Interfaces and Analysis Tools 97
4.2.2.8 Standards and Openness 97
4.2.3 Future Perspectives 99
References 100
5 Experimental Tumour Models in Mice 102
5.1 Introduction 102
5.2 The Mouse as a Model Organism in Cancer Research 103
5.3 What Constitutes an Optimal Mouse Model for Cancer Research? 104
5.4 Transplantable Tumour Models 105
5.4.1 Xenograft Models 106
5.4.2 Syngeneic Models 107
5.4.3 Orthotopic Models 107
5.5 Autochthonous Models 108
5.5.1 Spontaneous Tumour Models in Mice 109
5.5.2 Chemical Models 109
5.6 Genetic Models 110
5.6.1 Transgenic Models 111
5.6.2 Models with Targeted Gene Alterations 112
5.7 Concluding Remarks 113
References 114
6 Exploration of MMP Function in Mouse Models of Angiogenesis 118
6.1 Introduction 118
6.2 The Aortic Ring Assay 120
6.3 The Matrigel Plug Assay 122
6.4 The Transplantation Chamber Assay 122
6.5 Transgenic Mice Models of the Angiogenic Switch 123
6.6 Conclusions 125
References 125
7 Tumor-Stroma Interactions: Focus on Fibroblasts 129
7.1 Introduction 129
7.2 Fibroblasts Are Heterogeneous 130
7.3 Stroma Fibroblasts in Tumors Have Multiple Origins 130
7.4 Fibroblasts Are Activated in Tumors 131
7.5 Biomarkers for Stroma Fibroblasts and Myofibroblasts 132
7.6 Fibroblasts Affect Tumor Growth 133
7.7 Molecular Mechanisms of Tumor-Stroma Interactions 134
7.7.1 ECM 134
7.7.2 Integrins 135
7.7.3 Growth Factors 136
7.7.4 MMPs 137
7.8 Fibroblasts as Anti-cancer Targets 137
7.9 Future Directions 138
References 138
8 Experimental Procedures to Assay Invasion-Associated Activities of Primary Cultured Fibroblasts 143
8.1 Introduction 143
8.2 Isolation of Primary Cells 145
8.3 Collagen Type I Invasion 147
8.4 Matrigel Invasion 149
8.5 Monolayer Wound Healing Migration 151
8.6 Conclusion 153
References 153
9 Systemic Instigation: A Mouse Model to Study Breast Cancer as a Systemic Disease 156
9.1 The Clinical Challenges 157
9.2 The Discovery of Systemic Instigation 158
9.3 The Systemic Instigation Cascade 159
9.3.1 Instigating Tumors Facilitate Growth of Responding Tumors at Distant Anatomical Locations 159
9.3.2 Instigating Tumors Promote Metastatic Colonization 160
9.3.3 Instigating Tumors Secrete Osteopontin 161
9.3.4 Bone Marrow Cells Serve as the Intermediaries Between Instigating and Responding Tumors 163
9.3.5 Instigating Tumors Activate Bone Marrow Cells Prior to Their Mobilization 164
9.3.6 Instigating Tumors Perturb Primitive Hematopoietic Cells in the Bone Marrow 166
9.4 The Mice 166
9.5 The Experimental Applications 167
9.6 The Implications of Systemic Instigation 168
References 169
Index 174