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Report of the NIH Rat Model Repository Workshop

To establish criteria of strain selection, preservation, and distribution of genetically defined rats to the research and supplier communities.

The history of rat strains used for critical research on human diseases is impressive in its breadth and depth. A large number of strains are producing highly valuable insights into pathogenesis of disease, with major public health implications, including more than 170 inbred strains and many more substrains as well as a growing list of transgenic lines and congenic/ consomic lines. For example, the Maudsley strains (MR, MMR) are widely used in neurobehavioral studies, including locomotion, avoidance, and maze learning crucial in studies of neuroendocrine function and ethanol abuse, as are the four different strains of alcohol susceptible and resistant strains. In addition to their use in studying susceptibility to autoimmune diseases, the F344 and LEW strains have been used extensively in cocaine/morphine preference studies, in response to cocaine, amphetamine, and morphine, and in studies of the acquisition of cocaine self-administration. Behavioral parameters such as acoustic startle responses, stress responses, and corticotrophin-releasing hormone have also been studied in these strains. F344 has also been used for aging studies, while FBN, BN, and WKY have been used as models of longevity and neurodegeneration. The F344, LEW, and DA strains have been used extensively to study arthritis and a variety of neurodegenerative diseases. In cancer studies, rat strains have proven valuable in mammary tumor studies, particularly with respect to precancerous lesions. F344 rats develop spontaneous leukemia and prostate cancers. Importantly, modifying genes regulating the incidence of spontaneous and induced cancers are robustly available in the rat. The DA rat has also been used as a model system for multiple sclerosis. R16, LEC, and COP rats are mutant for Grc, Atp7b, and Mcs genes, respectively, and modify cancer incidence in liver, breast, and kidney. The Eker rat is an important model of renal cancer and carries a known insertional mutation that, in the heterozygous state, is associated with spontaneous renal cell carcinoma, uterine leiomyoma, and hemangiomas, whereas the homozygous state is an embryonic lethal. The rat is an important source of diabetes models with key strains including BB, LETL in studies of type I diabetes, and Zucker, ZDF, and GK important in studies of type II diabetes. For cardiovascular disease there are seven inbred strains of rats (GH, FHH, LH, Sabra, SHR, SHRSP, SS) that develop different forms of hypertension and susceptibility to end organ damage. A very large number of transgenic strains of rat are now available. These include the renin gene in hypertension, HLA-B27 in autoimmune disease, albumin promoter regulated SV40 in liver cancer, apolipoprotein A1 in lipid metabolism, and many others.

Therefore, important decisions of priorities should be made by the NRGRC. An Advisory Board should be used to help evaluate the case for entry of each strain. The NRGRC staff would screen out candidate strains that are clearly unsuitable, either because they are duplicates of those already maintained or because they are poorly documented and considered unlikely to be of any great scientific value.

All strains accepted into the NRGRC at the recommendation of the Advisory Board will be cryopreserved. Models maintained in the living state must be determined on the basis of demand at any given time.

Selection and versatility criteria for strain selection to be considered by the Advisory Board would include the following:

There should be a fee-for-service option in which the users pay for the rats obtained from the NRGRC. The nominator of a new strain to be added to the NRGRC should not be charged to have the animals accepted or cryopreserved and should have the opportunity to receive a few breeder pairs without cost as an incentive to contribute. The cost associated with adding a new strain would be covered by charging those requesting the animals for their research for the cost of providing the animals.

Cryopreservation represents a crucial element of any attempt to maintain the genetic integrity of a core of strains and stocks of rats. Cryopreservation by its nature must be done within the NRGRC and be a function of its permanent staff. Beginning in the late 1970s, rat embryos have been successfully cryopreserved and restored using different protocols. At this time, results are similar among these various protocols. These results do not indicate that one procedure is better than another. For example, one can freeze embryos at the two-cell stage (48 h) in "Minitubes" placed horizontally in an alcohol freezer with propanediol as cryoprotectant. There is the two-step method for freezing eight-cell embryos in glycerol. The Jackson Laboratory freezes a later two-cell stage in straws with propanediol as cryoprotectant. They also use the classic slow freezing with 1 M DMSO and found close to 80 percent survival as tested by developing in culture. In general, these procedures vary from 15 to 45 percent recovery efficiency. Certain publications have described a vitrification method for freezing the morula stage. The option to use several protocols in any given case should be available to the NRGRC, and the decision should be in the hands of the staff, with oversight from the Advisory Board. However, there should be standards for the overall level of success of any cryopreservation protocol in terms of the percentage of thawed embryos that develop to pups.

While it is outside the purview of this workshop, there is a clear need to improve the cryopreservation protocols and reagents for rats. The NIH is strongly urged to stimulate additional research into this area, and it is hoped that the NRGRC would play a central role in that research and development effort. Progress in this area would directly translate to reducing costs in the NRGRC by increasing the success rates.

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