Animal Models for the Study of Human Disease

Preface

List of Contributors

Part I: Ethics, Resources and Approaches

Chapter 1. Ethics in Biomedical Animal Research: The Key Role of the Investigator

Nature and Scope of the Chapter

The Subject Matter of Animal Research Ethics

Aspects of Animal Use and Care Relevant to Animal Research Ethics

Why Investigators are Uniquely Qualified to Engage in Ethical Assessment of Animal Research

Why Investigators Should Commit Themselves to Ethical Conduct of Animal Research

Why Investigators Play the Key Role in Assuring the Ethical Conduct of Animal Research Projects

Sources of Support and Guidance in Conducting Ethical Research

Developing Useful Ethical Guidelines

Fundamental Principles of Animal Research Ethics

Practical Ethical Guidelines for Investigators

Some Current Difficult Issues in Animal Research Ethics

General Suggestions for Investigators

References

Chapter 2. Access to Resources: A Model Organism Database for Humans

Acknowledgments

The Problem

The LAMHDI Solution

The Ideal Solution

References

Chapter 3. The Advent of the Golden Era of Animal Alternatives

Introduction

Analytical Tools for the Detection of Food-Borne Disease

An in Vitro System to Assess Adverse Effects During Development

Diseases-in-a-dish

Noninvasive Imaging and Recording

Conclusions

References

Chapter 4. Environmental Enrichment for Animals Used in Research

Acknowledgments

Introduction

Applied Science: Enrichment as a Welfare Tool

Basic Science: Enrichment and Animal Models

Enrichment and Experimental Variability

Environmental Enrichment Regulations

Implementing an Enrichment Plan

Conclusions

References

Part II: Vision

Chapter 5. Animal Models of Age-Related Macular Degeneration

Introduction

Comparative Retinal Anatomy and the Pathology of AMD

The Genetics of AMD

Inflammation in AMD

HTRA1 and LOC387715/ARMS2 in AMD

Oxidative Damage and AMD

Lipid Metabolism and AMD

Spontaneously Occurring Primate Models of AMD

Modeling Choroidal Neovascularization in Advanced AMD

Conclusion

References

Chapter 6. N-Methyl-N-Nitrosourea Animal Models for Retinitis Pigmentosa

Acknowledgments

Introduction

Time-Course Progression of MNU-Induced Retinal Degeneration

Retinal Degeneration Caused by MNU in Various Animal Species

Age-Related Photoreceptor Cell Damage and Sensitivity to MNU

Photoreceptor Cell Death, Cell Debris Removal, and RPE Cell Migration

Molecular Mechanisms in Photoreceptor Cell Death Caused by MNU

Therapeutic Trials Against MNU-Induced Photoreceptor Apoptosis

Concluding Remarks

References

Part III: Cardiac and Cardiovascular

Chapter 7. Animal Models of Myocardial Disease

Introduction

The Spectrum of Cardiovascular Disease

Choice of Animal System

Experimental Design

Ischemic Heart Disease

Systolic Heart Failure

Diastolic Heart Failure

Infective Myocarditis

Cardiomyopathies

Diabetes and Obesity-Related Heart Disease

The Future of Animal Models for Cardiovascular Disease

References

Chapter 8. Animal Models for Cardiovascular Research

Introduction

Myocardial Ischemic Models

Hypertension and Left Ventricular Hypertrophy Models

Heart Failure Models

Cardiovascular Denervation Models

Future Directions

References

Chapter 9. Cardiovascular Models: Heart Secondarily Affected by Disease

Acknowledgment

Introduction

The Heart and Diabetes Mellitus

The Heart and Renal Failure

The Heart and Dysfunctional Sympathetic Innervation

References

Chapter 10. Models for the Study of Atherosclerosis and Thrombosis

Acknowledgments

Small Versus Large: Size Matters?

Atherosclerosis

Thrombosis

Animal Models of Von Willebrand Disease

Animal Models of Venous Thrombosis

Animal Models of Plaque Rupture

Conclusions and Future Perspectives

References

Part IV: Obesity, Metabolic and Liver

Chapter 11. Animal Models of Metabolic Syndrome

Introduction and Overview

Choosing an Animal Model of MetS

Animal Models of MetS Etiology

Genetic Factors

Environmental Factors

Animal Models of MetS Pathophysiology

Conclusions

References

Chapter 12. Invertebrates in Obesity Research: A Worm’s Perspective

Obesity Worldwide

Model Organisms

Introducing the Nematode C. elegans

Lipids in C. elegans

C. elegans as a Model for Obesity Research

Fat Pathways in Mammals and Worms

Obesity in Humans and Model Organisms: A Genomic Approach

The Link Between Fat Metabolism and Other Diseases

Other Invertebrate Models in Obesity Research

Conclusion

References

Chapter 13. Animal Models of Dietary-Induced Obesity

Acknowledgments

Usefulness of Animal Models of Human Obesity

Fat-Rich Diets

Physiological Mechanisms of Fat-Rich-Diet-Induced Obesity

Behavioral Mechanisms of Dietary Obesity

Reversal of Dietary Obesity

Conclusions

References

Chapter 14. Animal Models for Manipulation of Thermogenesis

Introduction

Brown Fat

BAT and Thermogenesis in White Adipose Tissue

“Browning” of White Adipose Tissue

Skeletal Muscle

Models of Obesity

Diet-Induced Obesity and Thermogenesis

Photoperiod and Seasonality as Models of Metabolic Function

Fetal Growth Retardation and Effect on Metabolic Balance

Transgenerational Effects of Obesity

Polygenic Models of Obesity

Concluding Remarks

References

Chapter 15. Animal Models of Cholestasis

Introduction

General Concepts of Normal Bile Formation

Liver Fibrosis in Cholestatic Liver Diseases

Models for (Primary) Sclerosing Cholangitis

Models for Primary Biliary Cirrhosis

Obstructive Cholestasis

Drug-Induced Cholestasis

Inflammation-Induced Cholestasis

Biliary Atresia

Inherited Cholestatic Syndromes

Summary and Conclusions

References

Part V: Bone and Skin

Chapter 16. Animal Models of Bone Diseases-A

Acknowledgments

Introduction

Animal Models of Age-Dependent Degenerative Bone Disorders

Animal Models of Congenital Bone Disorders

Conclusions

References

Chapter 17. Animal Models of Bone Disease-B

Acknowledgments

Introduction

Criteria for Choosing Animal Models for Bone Loss and Regeneration

Common Animal Models for Skeletal Research

Genetic Mouse Models for Elucidating Mechanistic Changes

Methods Used in Evaluating Bone Structure and Strength in Animal Models

In Vitro Models of Skeletal Biology

Conclusion and Closing Remarks

References

Chapter 18. Animal Models for Implant-Associated Osteomyelitis

Acknowledgments

Introduction

General Features of Osteomyelitis Animal Models

Rabbit Osteomyelitis Models

Rat Osteomyelitis Models

Mouse Models of Osteomyelitis

Large-Animal Models of Osteomyelitis

Areas for Improvement of Animal Models of Osteomyelitis

Biomarkers of Infection

Conclusion

References

Chapter 19. Animal Models of Fibrosis in Human Disease

Introduction

Animal Models of Fibrosis in Scleroderma

Conclusions

Liver Fibrosis

Conclusions

References

Part VI: Urinary Tract, Kidney and Bowel

Chapter 20. Animal Models of Lower Urinary Tract Dysfunction

The Requirement for Animal Models

The Normal Urinary Tract

Aging Animal Models

Bladder Outflow Tract Obstruction

Stress Urinary Incontinence

Bladder Pain Syndrome

Lower Urinary Tract Disorders of Neurological Origin

Animal Models of Central Nervous System Control Over Bladder Function

Diabetes and Lower Urinary Tract Dysfunction

Urinary Tract Infections

Congenital Anomalies

Tissue Engineering and the Urinary Tract

References

Chapter 21. Animal Models of Calcium Oxalate Kidney Stone Formation

Introduction

Calcium Oxalate Crystal Deposition in Rats

Calcium Oxalate Crystal Deposition in Mice

Calcium Oxalate Crystal Deposition in Pigs

Calcium Phosphate Crystal Deposition in Rats

Calcium Phosphate Crystal Deposition in Mice

Calcium Oxalate/Calcium Phosphate Association in Animal Models

Foreign-Body Stones

Comparison Between Rat and Human Nephrolithiasis

Concluding Remarks

References

Chapter 22. Animal Models of Inflammatory Bowel Disease for Drug Discovery

Acknowledgments

Introduction

Classification of Mouse IBD Models

Etiology and Mouse IBD Models

Classical Therapy and IBD Models

Biological Therapy and IBD Models

Conclusion

References

Part VII: The Brain, Stroke, and Neuromuscular

Chapter 23. Animal Models of Stroke Versus Clinical Stroke: Comparison of Infarct Size, Cause, Location, Study Design, and Efficacy of Experimental Therapies

Acknowledgments

Introduction

Systematic Review and Meta-Analysis Method

Results

Discussion

Conclusion

References

Chapter 24. Animal Models and Methods to Study the Relationships Between Brain and Tissues in Metabolic Regulation

Introduction

General Considerations

Technical Means to Investigate the Role of the Central Nervous System

Modulating Central Nervous System Activity

Study of Cerebral Responses

Behavioral and Metabolic Responses

Conclusion

References

Chapter 25. Models of Alzheimer’s Disease

Introduction

Invertebrate Models

Nonmammalian Vertebrates

Mammalian Models

Conclusions

References

Chapter 26. Neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Animal Models for Parkinson’s Disease

Acknowledgment

Abbreviations

Introduction

Clinical Characteristics of PD and Their Relevant Symptoms in Animal Models

Molecular Pathophysiology of PD

Neurotoxins for Making PD Models

MPTP-Induced Mouse Model for PD

MPTP-Induced Common Marmoset Model for PD

Concluding Remarks

References

Chapter 27. The Importance of Olfactory and Motor Endpoints for Zebrafish Models of Neurodegenerative Disease

Introduction

Building Relevant Models

Olfactory–Neuromuscular Diseases

Conclusions

References

Part VIII: Behavior

Chapter 28. Animal Models of Drug Abuse: Place and Taste Conditioning

Acknowledgments

What is Drug Addiction and why Should we Study it?

Reward and Reinforcement

Aversive Drug Effects

The Place-Conditioning Procedure

The Flavor-Conditioning Procedure

Conclusion

References

Chapter 29. Animal Models of Reward Behavior

Acknowledgment

Reward Behavior

Examples of Reward Learning

What can be a Reward?

Factors Affecting Conditioning with Rewards

Role of Pavlovian Conditioning in Reward Learning

Conclusion

References

Chapter 30. Modeling Schizophrenia in Animals

Overview of Schizophrenia

Approaches to Creating Animal Models with Relevance to Schizophrenia

Features of Schizophrenia That Can Be Modeled in Animals

Specific Animal Models

References

Part IX: Genetics

Chapter 31. Mouse Models for the Exploration of Klinefelter’s Syndrome

Acknowledgments

Introductory Remarks

KS—an Underestimated Disease

The X Chromosome in the Male

Clinical Features of KS

Sex Chromosomal Aberrations in Male Mammals

Mouse Models for KS

Lessons from Animal Experiments

Perspectives—What Can Be Expected from Future Animal Experiments and How to Retranslate Experimental Findings into Clinical Routine—Conclusive Remarks

References

Chapter 32. Genetically Tailored Pig Models for Translational Biomedical Research

Acknowledgments

Introduction

Techniques for the Production of Genetically Engineered Pigs

Genetically Engineered Pigs as Models for Human Diseases

Conclusions

References

Chapter 33. Genetically Modified Animal Models

Introduction

Some Historical Aspects

Techniques for the Managed Creation of Genetically Modified Animal Models

Types of Genetically Modified Animals and How They Are Produced

Genetically Modified Mice as Models of Human Diseases

References

Chapter 34. Mouse Models for Human Diseases by Forward and Reverse Genetics

Acknowledgments

Genetics and Diseases

Genetic or Environmental Factors

Power of Mouse Models for Human Diseases

The Human Genome Project and Human Diseases

Basic Genetics for Developing and Using Model Mice

Mutant Mice as Disease Models

Unique Positional Cloning: High Reversion Rates of d^v and p^un Mutations

Mutagenesis for Forward Genetics

Mutagenesis for Reverse Genetics

Concluding Remarks

References

Part X: Early Life

Chapter 35. Animal Models for the Study of Infection-Associated Preterm Birth

Acknowledgment

Introduction

Infection, Inflammation, and Parturition

Practical Study: Surgical Studies in the Pregnant Sheep

References

Chapter 36. Animal Models of Febrile Seizures

Acknowledgments

Introduction

Febrile Seizure in Humans and Its Relationship to Epilepsy

Animal Models of Febrile Seizures

Other Animal Models of Early-Life Seizures

Mechanisms Underlying Hyperthermia-Induced Experimental Febrile Seizures

Neuroanatomical Changes after Experimental Febrile Seizures

Neurophysiological Changes after Experimental Febrile Seizures

Neuronal Hyperactivity after Experimental Febrile Seizures

Behavioral Changes after Experimental Febrile Seizures

Conclusions

References

Part XI: Viral Disease

Chapter 37. Human Herpesviruses and Animal Models

Acknowledgments

Introduction

CMV (HHV-5) and Other Betaherpesviruses (HHV-6 and -7)

Gammaherpesviruses (Epstein–Barr Virus and Kaposi’s Sarcoma-Associated Herpesvirus)

Herpes Simplex (HSV-1 and -2)

Varicella Zoster (HHV-4)

Recombinant Viruses and Reporter Genes

Protocols

Protocol 1. Generation of Mutants via Conventional Homologous Strategy

Protocol 2. Generation of Recombinant Virus via Manipulation of an Infectious BAC Clone

Protocol 3. Virus Titration

Protocol 4. Detection and Tracking of Cells in Response to Virus Infection

Bioluminescent Tracking of Immune Cells during Viral Brain Infection

Protocol 5. Detection of Viral Load in Target Organs of Virus-Infected Animals (CMV, HSV, and VZV)

Protocol 6. BLI of Virus Infection in an Animal Model

References

Chapter 38. Animal Models of Human Viral Diseases

Introduction

Picornaviridae

Caliciviridae

Togaviridae

Flaviviridae

Coronoviridae

Rhabdoviridae

Filoviridae

Paramyxoviridae

Orthomyxoviridae

Bunyaviridae

Arenaviridae

Reoviridae

Retroviridae

Papillomaviridae

Poxviridae

Hepadnaviridae

Conclusions

References

Part XII: Cancer

Chapter 39. Xenograft, Transgenic, and Knockout Models of Prostate Cancer

Introduction

Xenograft Models of Prostate Cancer

The LOBUND–Wistar Rat Model of Prostate Cancer

Transgenic Models of Prostate Cancer

Knockout Models of Prostate Cancer

Transgenic Models of the Tumor Microenvironment

References

Chapter 40. Animal Models for Studying Prevention and Treatment of Breast Cancer

Introduction to Animal Models of Breast Cancer

Concepts of Breast Cancer Biology

Modeling Breast Cancer in Rodents

Spontaneous and Induced Mammary Tumorigenesis in Rodents

Grafting and Transplantation Approaches

Genetically Engineered Mice Models of Breast Cancer

References

Part XIII: Sclerosis

Chapter 41. Animal Models of Systemic Sclerosis

Introduction

Bleomycin-Induced Murine Scleroderma

HOCl-Induced Murine Scleroderma

Tsk Mouse

Scl-GvHD Model

Skin Fibrosis by Exogenous Injection of Growth Factors

UCD-200 Chicken

Transgenic Mouse Models

Knockout Mouse Models

Conclusions

References

Chapter 42. Animal Models for the Study of Multiple Sclerosis

The Complex Biology of Multiple Sclerosis

Immunological Models for CNS Demyelination

Local Induction of Demyelination following Injection of Myelin Peptides

Development of MS Therapies Based on Models of Immune-Mediated Demyelinating Diseases

Viral-Mediated Models of Demyelination

Oligodendrocyte-Induced Cell Death Models of Demyelination

Toxin Models of Demyelination

Conclusions and Comments

References

Index