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Rats — An ideal animal model of human disease

Annalise Barnette
Jun 21, 2017

A list of interesting rat facts The concept of the ‘lab rat’ likely developed over 150 years ago when rats were the predominant animal model of human disease. They were the first mammalian species to be domesticated for use in the laboratory. As a result, most in vivo assays were originally developed and optimized in the rat ( Iannaccone and Jacob 2009). However, in the past 30 years, the mouse has rapidly overtaken the rat as the preferred animal research model.

The shift in popularity among scientists from the rat to the mouse model is largely due to the development of targeted gene manipulation and the introduction of the first transgenic mouse model in 1987 (Capecchi 2001, Thomas and Capecchi, 1987). Transgenic mice closely model the function and physiology of human diseases and allow scientists to monitor the effect of individual genes on disease. The much delayed sequencing of the rat genome and the capacity to isolate rat embryonic stem cells limited the generation of transgenic rat models and perpetuated the preference for transgenic mouse models of human disease.

Although transgenic mice have helped to advance scientific discovery, the rat is still considered an ideal research model for certain research areas (Iannaccone and Jacob 2009). Because rats are significantly larger than mice, they are well suited for performing surgeries, for drug studies requiring serial blood draws, as well as for transplantation studies. In addition, their physiology has been shown to be closer to humans, and there is a large body of historical physiology data available in rats that are not easily adapted to mice (Ellenbroek and Youn 2016, Iannaccone and Jacob 2009).

Rats have also been shown to be more advanced in terms of cognition and memory (Ellenbroek and Youn 2016). They are capable of learning a wider variety of tasks, which is important for cognitive research. Accordingly, a number of landmark studies on learning and memory were originally performed in rats (Quillfeldt 2016). 

The lack of transgenic rat models has therefore been a major limitation in further applying the rat to specific research problems.

The publication of the rat genome in 2004 and the availability of new gene editing tools such as clustered regularly interspaced short palindromic repeats (CRISPR) and zinc-finger nucleases have addressed this limitation (Gibbs et al. 2004, Shao et al. 2014, Geurts et al. 2010 ). There are now some transgenic rat models available, mainly for neuroscience research, and it is likely that more models will be developed in the coming years.

One of the most recently developed genetic rat models was designed to study Phelan-McDermid syndrome (Harony-Nicolas et al. 2017). This disorder is characterized as demonstrating high rates of autism, severe language delay, intellectual disability, and attention deficits. The rat model is deficient in the protein Shank-3, which mimics the human Shank-3 mutation that is associated with Phelan-McDermid syndrome. The study using these Shank-deficient rats is the first to demonstrate that individuals with Phelan-McDermid syndrome may benefit from oxytocin treatment, and this is currently being investigated in clinical trials at the Seaver Autism Center for Research and Treatment at Mount Sinai. The rat was an ideal model for generating this discovery because of its enhanced cognitive and social ability, which, compared to mice, better resembles that of humans (Iannaccone and Jacob 2009).

In the area of immunology research, there are several frequently used rat models that mimic autoimmune diseases such as multiple sclerosis and diabetes mellitus (Storch et al. 1998, King 2012, Takeda et al. 2017). Specifically for diabetes research, rat models have proven useful for understanding the mechanisms of the disease, as they provide a larger scale of tissue samples than can be attained from the mouse. They also include a greater variety of type 2 diabetes models that more accurately mimic the disease in humans, compared to mouse models (Takeda et al. 2017).

The most important reason for using animal models in research is to model human physiology and function as well as to advance our understanding of human diseases. The rat has proven invaluable in achieving this goal and will continue to play an important role as new rat models of disease become available.

To support scientists using rat models to achieve their research goals, Bio-Rad offers an extensive range of anti-rat monoclonal and polyclonal antibodies targeted against key markers in research areas such as immunology, neurology, transplantation, toxicology, and pathology.

References

Capecchi MR (2001). Generating mice with targeted mutations. Nat Med 7, 1086-1090.

Ellenbroek B and Youn J (2016). Rodent models in neuroscience research: is it a rat race? Dis Model Mech 9, 1079-1087.

Geurts AM et al. (2010). Generation of gene-specific mutated rats using zinc-finger nucleases. Methods Mol Biol 597, 211-225.

Gibbs RA et al. (2004). Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428, 493-521.

Harony-Nicolas H et al. (2017). Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat. eLife 6, e18904.

Iannnaccone PM and Jacob HJ (2009). Rats! Dis Model Mech 2, 206-210.

King AJ (2012). The use of animal models in diabetes research. Br J Pharmacol 166, 877-894.

Shao Y et al. (2014). CRISPR/Cas-mediated genome editing in the rat via direct injection of one-cell embryos. Nat Protoc 9, 2493-2512.

Storch MK et al. (1998). Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol 8, 681-694.

Quillfeldt JA (2016). Behavioral methods to study learning and memory in rats. In Rodent Model as Tools in Ethical Biomedical Research, Andersen ML and Tufik S, ed. (Switzerland: Springer International Publishing), pp. 271-311.

Takeda Y et al. (2017). Relationship between immunological abnormalities in rat models of diabetes mellitus and the amplification circuits for diabetes. J Diabetes Res 2017, 4275851.

Thomas KR and Capecchi MR (1987). Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51, 503-512.

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