Transgenic animals as models for human disease

Transgenic animals, especially mice, have been used quite extensively as models for various human diseases. At first, the level of scientific inquiry was driven by the need to establish the model. In many cases, these models may be considered quite crude because of their limitations. More recently, transgenic models of disease have become more refined and are currently being used to study the pathological mechanisms behind the disease rather than to just provide a model of the disease. Using some examples from the recent literature, we will document the current level and complexity of inquiry using transgenic animals. New techniques and techniques that may prove promising will be discussed. This revised version was published online in August 2006 with corrections to the Cover Date.     

Transgenic animal models of cardiovascular disease

Transgenic experimentation has become a crucial part of hypertension and atherosclerosis research, and is growing more important in several other areas of cardiovascular disease. It has recently made a particular contribution to understanding the role of the renin-angiotensin system in controlling hypertension. The study of blood pressure regulation, cardiac hypertrophy, atherogenesis and thrombosis are also benefiting from the transgenic approach.     

Transgenic mouse models of Alzheimer's disease

Recent advances in the understanding of the genetic basis of Alzheimer's disease have enabled the production of transgenic mouse models of the disease. Utilizing both cDNA- and genomic-based approaches, these mouse models for Alzheimer's disease have already provided valuable insights into the pathogenesis of the disease and potential therapeutic interventions.     

Transgenic models of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. A mouse model of this disease has been generated by the introduction of exon 1 of the human HD gene carrying highly expanded CAG repeats into the mouse germ line (R6 lines). Transgenic mice develop a progressive neurological phenotype with a movement disorder and weight loss similar to that in HD. We have previously identified neuronal inclusions in the brains of these mice that have subsequently been established as the pathological hallmark of polyglutamine disease. Inclusions are present before symptoms, which in turn occur long before any selective neuronal cell death can be identified. We have extended the search for inclusions to skeletal muscle, which, like brain, contains terminally differentiated cells. We have conducted an investigation into the skeletal muscle atrophy that occurs in the R6 lines, (i) to provide possible insights into the muscle bulk loss observed in HD patients, and (ii) to conduct a parallel analysis into the consequence of inclusion formation to that being performed in brain. The identification of inclusions in skeletal muscle might be additionally useful in monitoring the ability of drugs to prevent inclusion formation in vivo.     

Transgenic models for cytokine-induced neurological disease

Considerable evidence supports the idea that cytokines are important mediators of pathophysiologic processes within the central nervous system (CNS). Numerous studies have documented the increased production of various cytokines in the human CNS in a variety of neurological and neuropsychiatric disorders. Deciphering cytokine actions in the intact CNS has important implications for our understanding of the pathogenesis and treatment of these disorders. One approach to address this problem that has been used widely employs transgenic mice with CNS-targeted production of different cytokines. Transgenic production of cytokines in the CNS of mice allows not only for the investigation of complex cellular responses at a localized level in the intact brain but also more closely recapitulates the expression of these mediators as found in disease states. As discussed in this review, the findings show that these transgenic animals exhibit wide-ranging structural and functional deficits that are linked to the development of distinct neuroinflammatory responses which are relatively specific for each cytokine. These cytokine-induced alterations often recapitulate those found in various human neurological disorders not only underscoring the relevance of these models but also reinforcing the clinicopathogenetic significance of cytokines in diseases of the CNS.     

Transgenic animals as models for human diseasereport of an EC Study Group

ContributorsThis report results from the discussion of an Expert Group convened in Edinburgh on 29–30 October 1992 for a workshop on that subject sponsored and organized by the Commission of the European Communities, Directorate General XII (CEC-DG XII). The experts taking part in the workshop were: R. Lathe and J.J. Mullins, Coordinators (AFRC Centre for Genome Research, University of Edinburgh); G.N. Fracchia, Secretary (Medical Research-Pharmaceuticals, CEC-DG XII, Brussels); and the participants; C. Babinet (Dept d'Immunologie, Institut Pasteur, Paris); P. Eliard (EFPIA, Brussels); C. Benoist (LGME du CNRS/INSERM, Strasbourg); G. Bianchi (Ospedale San Raffaele, Universita di Milano, Milan); E. Boncinelli (DIBIT, Ospedale San Raffaele, Milan); G. Brem (Universitat München); G. Cossu (Institute of Histology, School of Medicine, University of Rome); N. Dillon (MRC National Institute for Medical Research, London); V. Episkopou (Dept of Biochemistry & Molecular Genetics, St Mary's Hospital Medical School, London); M. Evans (Wellcome/CRC Institute, Cambridge); R. Forster (Italfarmaco Research Centre, Cinisello Balsamo, Milan); D. Ganten (Max-Delbrück-Zentrum für Molekulare Medizin, Berlin); A. Gossler (Max-Delbrück-Laboratorium in der Max-Planck-Gesellschaft, Köln); J. Gray (Dept Psychology, Institute of Psychiatry, London); R. Hammer (Howard Hughes Medical Institute, University of Texas, Dallas, USA); A. Hobden (Genetics Unit, Glaxo Group Research Ltd, Middlesex); G. Kollias (Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens); D. Lamy (Transgène SA, Strasbourg); D. Lincoln (MRC Reproductive Biology Unit, Edinburgh); J. Mallet (CNRS/LNCM, Gif-sur-Yvette); D. Melton (ICMB, University of Edinburgh, Edinburgh); J.M. Moalic (U127 INSERM, Hôpital Laraboisire, Paris); S. Mockrin (Dept Health & Human Services, National Institutes of Health, Bethesda, MA, USA); J. Ottesen (Biopharmaceuticals Division, Dept of Gene Technology and Virology, Novo Industrie, Denmark); D. Porteous (MRC Human Genetics Unit, Western General Hospital, Edinburgh); P. Rae (Pharmaceutical Division, Miles, West Haven, USA); F. Theuring (Schering AG, Pharmaceutical Research, Berlin); G. Tremp (Rhone-Poulenc Rorer SA, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine); H. Van der Putten (Dept Biotechnology, Ciba-Geigy AG, Basel); R. Wolf (ICRF Molecular Pharmacology Group, Biochemistry Dept, Edinburgh). Further supporting documentation and commentary were received from P. Dement (Amsterdam), U. Habenicht (Berlin), P. Grüss (Gottingen), M. Lyon (Oxford), C.C.J. Miller (London), W.-D. Schleuning (Berlin) and R. Williamson (London) and their contributions are gratefully acknowledged.     

浅谈转基因克隆动物技术

根据现有理论和技术发展趋势,提出了转基因克隆动物的概念,即将克隆动物与转基因克隆动物技术有机地结合起来,认为转基因克隆动物制作 技术将有望成为下一世纪创建遗传工程动物的主导性技术。     

Transgenic animals in biomedical research.

The advent of transgenic technology, in which foreign genetic information is stably introduced into the mammalian germ line, has dramatically enhanced our basic knowledge of physiologic and pathologic processes. Transgenic animals created by these genetic manipulations are being used to provide insights into gene regulation, development, pathogenesis, and the treatment of disease. Furthermore, transgenic biotechnology holds great promise for the creation of genetically superior livestock and the industrial production of precious pharmaceuticals. It is evident now that the study and use of transgenic animals will significantly improve the human condition.     

Transgenic models of Alzheimer's disease: Better utilization of existing models through viral transgenesis

Animal models have been used for decades in the Alzheimer's disease (AD) research field and have been crucial for the advancement of our understanding of the disease. Most models are based on familial AD mutations of genes involved in the amyloidogenic process, such as the amyloid precursor protein (APP) and presenilin 1 (PS1). Some models also incorporate mutations in tau (MAPT) known to cause frontotemporal dementia, a neurodegenerative disease that shares some elements of neuropathology with AD. While these models are complex, they fail to display pathology that perfectly recapitulates that of the human disease. Unfortunately, this level of pre-existing complexity creates a barrier to the further modification and improvement of these models. However, as the efficacy and safety of viral vectors improves, their use as an alternative to germline genetic modification is becoming a widely used research tool. In this review we discuss how this approach can be used to better utilize common mouse models in AD research. This article is part of a Special Issue entitled: Animal Models of Disease.     

转基因动物在输血医学中的应用

转基因动物技术是在动物整体水平研究和表达目的基因的生物技术,其基本特点是：分子及细胞水平操作,组织及整体水平表达,是常规分子生物学理论和技术的拓展和延伸,也是现代生物高技术研究和开发的热点之一。本简述了转基因动物在输血医学领域的应用及其发展前景,包括利用转基因动物生物反应器制备人血浆蛋白和人血红蛋白、建立血传播病毒的感染模型和血液相关遗传模型以及转基因动物与输血医学的基础研究等。     

Alzheimer's disease: Transgenic models to test new chemicals and pharmaceuticals

Alzheimer's disease is the most common form of senile dementia and is predicted to become even more prevalent as the proportion of elderly in the population increases over the next few decades. As yet, there are no effective treatments for the disorder. A major limitation to identifying new drugs and therapeutic targets for Alzheimer's disease has been the absence of an animal model displaying typical Alzheimer's pathology. Transgenic technology is now providing a powerful new approach for the development of animal models of Alzheimer's disease.     

Transgenic farm animals get off the ground

Transgenic Research -     

Transgenic animals: current and alternative strategies

Transgenic animal technology is one of the most fascinating technologies developed in the last two decades. It allows us to address questions in life sciences that no other methods have achieved. The impact on biomedical and biological research, as well as commercial interests are overwhelming. The questions accompanying this fast growing technology and its diversified applications attract the attention from a variety of entities. Still, one of the most fundamental problems remaining is the search for an efficient and reliable gene delivery system for creating transgenic animals. The traditional method of pronuclear microinjection has displayed great variability in success among species. While an acceptable efficiency in the production of transgenic mice has been attained, the relative low efficiency (<1%) in creating transgenic livestock has become one of the barriers for its application. In the past decades, improvements in producing transgenic livestock have made a slow progression, however, the recent advancement in cloning technology and the ability to create transgenic livestock in a highly efficient manner, have opened the gate to a new era in transgenic technology. Discoveries of new gene delivery systems have created an enthusiastic atmosphere that has made this technology so unique. This review focuses on gene delivery strategies as well as various approaches that may assist the advancement of transgenic efficiency in large animals.