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Report of the NIH Rat Model Repository Workshop

Introduction

This is a tremendously exciting time for scientists engaged in research aimed at the alleviation of human disease. With advances in the genome projects, including obtaining the complete sequence of the human genome within the next 3 to 5 years, the opportunity to create and utilize animal models toward this goal has never been greater. In the past 30 years more than 500,000 publications used the rat as an experimental species. The first few decades of the 21st century are likely to be dominated by assigning function to the complete genomic sequence, particularly with respect to those regions involved in common disease. While the paradigm for ascribing function to the genome is not well defined, it is clear that investigators will use comparative mapping strategies and multiple species platforms to accomplish this goal. Toward this end, the rat offers the best "functionally" characterized mammalian model system. In a number of instances, the rat offers a number of unique advantages for modeling human diseases, developing new therapeutic agents, and studying responses to environmental agents. The size of this animal, for example, makes it ideal for physiological manipulations. Several technologies can be applied in any practical way only to the rat, e.g., microdialysis. The rat is the model of choice in neurobehavioral studies and organ transplantation and is the most convenient experimental model of hypertension. Finally, toxicology has traditionally relied on the rat as a test species, and there is an extensive literature of chemical exposure in the rat. The recent development of genetic and genomic tools for the rat provides an unprecedented opportunity to take advantage of a rich and robust history of experimental studies utilizing the rat to study human disease. Since 1994 the genomic information of the rat has grown at a truly astounding pace. Currently more than 6,000 "anonymous" markers cover the majority of the genome, with many hundreds of known genes also placed within this framework. A genetic map approaching a 1–3 cM resolution, multiple large insert genomic libraries, radiation hybrid (RH) cell lines and the corresponding RH map, greater than 12 normalized cDNA libraries, allele characterization for nearly all genetic markers in 48 inbred strains of rats, and a cytogenetic map all currently exist. There is an ongoing Rat Expressed Sequence Tag (EST) Project developing full-length cDNA libraries, greater than 50,000 ESTs sequenced, and a gene-based EST map. In addition to the genomic tools for the rat, emerging genetic technologies are now being applied to the rat. The production of transgenic rats is routine in many laboratories and several commercial settings. Transgenic rats are being used to study hypertension and neoplasia, among other important public health problems. Collectively these genomic and genetic tools enable investigators to "walk" between rat and mouse and human using comparative mapping techniques, thereby providing an approach for discovery of gene function by linking physiology, genetics, and clinical phenotypes.

The rat offers significant advantages for functional studies as well as a wealth of scientific literature. Until recently, publications using the rat have outnumbered publications using the mouse by at least two to one. With the advent of homologous recombination in the mouse, the ratio has been reduced to approximately 1.5:1. Publications reporting the use of inbred rats have occurred as frequently as those using inbred mice, even though standardized rat genetic models are not as readily available to researchers. However, the full potential for the rat cannot be realized because many investigators face difficulties in obtaining genetically and microbiologically defined models. Strains obtained from other investigators often have infections that can contaminate the recipient's animal facility. In some cases, genetic quality control programs are lacking or ineffective, and colonies have become genetically contaminated, in some cases repeatedly. These errors have ruined many years of previous research and financial investment. Moreover, there is the constant potential danger of losing valuable strains because of short-term funding problems arising when a single investigator holds the animals. Pressure to have such resources available will only increase in the coming years as additional genomic and genetic tools and critical germline modification techniques, including rat embryonic stem cells and rat nuclear transfer, become available. This pressure will increase further as a primary focus of basic health care research will be to define the function of thousands of genes. Progress in these areas is clear and the future of the rat as a critical species of disease models is very bright.

To best meet the needs of the broad rat research community and to provide the foundation for consistent and well-characterized rat models for human disease, it is imperative to establish a national, central repository resource—a National Rat Genetic Resource Center (NRGRC). The main functions of this repository would be as follows: (1) Strain standardization, i.e., the repository could maintain core colonies of the most widely used inbred rat strains of high microbiological and genetic quality breeding nuclei, which could be distributed to both investigators and commercial breeders. This would reduce problems currently being encountered as a result of substrain differentiation among colonies that have been separated for several years. (2) Preservation of valuable strains, including transgenic strains, that are being produced in large numbers. The NRGRC could cryopreserve many of these strains efficiently and economically using methodology that is now routine in a few laboratories. (3) The NRGRC would be a source of genetically and microbiologically high-quality animals. (4) The NRGRC could provide information, advice, and training in the use of genetically defined rat strains. (5) The NRGRC would, by the nature of its work, be a contributor to the research and development of technological advances in cryopreservation, embryo culture, and animal maintenance. (6) The NRGRC would be charged to serve as a platform for scientific discourse and international cooperation among the community of scientists utilizing the rat as a model system by sponsoring workshops and annual symposia.

The establishment of the NRGRC will have a broad impact on many areas of categorical disease-based research. It will provide solutions to the problems presented above and is designed so as to provide for the current needs of investigators using rat models as well as anticipated increased demand as new genomic tools and new mutant resources become available. Limitations in the current genetic standardization impede research progress, compromise the value of many experiments by reducing their reproducibility, and can lead to wasteful or inefficient experiments. The ability to preserve strains not in great demand at a given time, but whose future value may prove to be great, by cryopreservation with standard microbiological and genetic quality will result in great financial savings in the long run. In short, establishment of the NRGRC will profoundly impact health care science well into the 21st century by providing a reliable source of critical models of common human disease. This resource will facilitate the translation of the wealth of previously published functional data from rat studies to be integrated with genetic and genomic data. This will help accelerate the identification of gene function.

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