A short commentary on rat biomedical models
A wide variety of animal models are used in biomedical research to help us understand human biology. Below is a plot commonly used animal models in research. Mouse and rats are the most commonly used animal models, while other larger animals are less frequently used. And a fun fact- a guinea pig is actually not a rodent- as described in this 1996 Nature paper!
Rats are utilized in fields relating to cardiology, neurology, infectious disease, and cancer. As stated by Ellenbroek and Youn et al. (2016), rats are not big mice, and they can provide advantages over mouse models such as larger brain and body size for ease of surgical techniques, imaging, and catheter/needle placement for drug administration . There are a variety of rat models that are being utilized in cancer research. Recently described models of cancer in rats include studying the role of estrogen in prostate carcinogensis in NBL rats , as well as testing anti-metastatic drug ranolazine on prostate tumors in rats . Additionally, immunodeficient rats are also in the process of being developed. Immunodeficient animal models are critical in the field of cancer research because they allow for the growth of human tumor tissue.
He et al. (2019) generated a Rag1-/- Rag2-/- IL2Rg-/Y (SD-RG) rat model . Rag1/2 (recombination activating genes) are required for proper VDJ recombination, needed for T and B cell development. IL2Rg is a signaling component required for T, B, and NK cell development. Thus, their rat model lacks T, B, and NK cells providing an environment permissible for human xenotransplantation. The group decided to mutate both Rag1 and Rag2 due to T cell leakiness problems in single Rag1-/- [6,7] and Rag2-/-  rats. The researchers successfully established human lung PDXs by subcutaneous implantation of tissue, and additionally show that xenografts propagated faster in the SD-RG rat model than the commonly used NOD scid gamma mice . In order to improve this model, the authors discuss that introduction of a human Sirpa gene would allow for further humanization studies to be performed. Optimization of these rat models would provide biomedical models to a larger alternative animal model to mice.
And of course, check out these references:
1. D’Erchia AM, Gissi C, Pesole G, Saccone C, Arnason U. The guinea-pig is not a rodent. Nature. 1996;381: 597–600. doi:10.1038/381597a0
2. Ellenbroek B, Youn J. Rodent models in neuroscience research: is it a rat race? Dis Model Mech. 2016;9: 1079–1087. doi:10.1242/dmm.026120
3. Ozten N, Vega K, Liehr J, Huang X, Horton L, Cavalieri EL, et al. Role of Estrogen in Androgen-Induced Prostate Carcinogenesis in NBL Rats. Horm Cancer. 2019;10: 77–88. doi:10.1007/s12672-019-00360-7
4. Bugan I, Kucuk S, Karagoz Z, Fraser SP, Kaya H, Dodson A, et al. Anti-metastatic effect of ranolazine in an in vivo rat model of prostate cancer, and expression of voltage-gated sodium channel protein in human prostate. Prostate Cancer Prostatic Dis. 2019; doi:10.1038/s41391-019-0128-3
5. He D, Zhang J, Wu W, Yi N, He W, Lu P, et al. A novel immunodeficient rat model supports human lung cancer xenografts. FASEB J Off Publ Fed Am Soc Exp Biol. 2019;33: 140–150. doi:10.1096/fj.201800102RR
6. Zschemisch N-H, Glage S, Wedekind D, Weinstein EJ, Cui X, Dorsch M, et al. Zinc-finger nuclease mediated disruption of Rag1 in the LEW/Ztm rat. BMC Immunol. 2012;13: 60. doi:10.1186/1471-2172-13-60
7. Menoret S, Fontaniere S, Jantz D, Tesson L, Thinard R, Remy S, et al. Generation of Rag1-knockout immunodeficient rats and mice using engineered meganucleases. FASEB J Off Publ Fed Am Soc Exp Biol. 2013;27: 703–711. doi:10.1096/fj.12-219907
8. Noto FK, Adjan-Steffey V, Tong M, Ravichandran K, Zhang W, Arey A, et al. Sprague Dawley <em>Rag2</em>-Null Rats Created from Engineered Spermatogonial Stem Cells Are Immunodeficient and Permissive to Human Xenografts. Mol Cancer Ther. 2018;17: 2481 LP – 2489. doi:10.1158/1535-7163.MCT-18-0156