National Center of Rabbit Models for Translational Research

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

PROJECT SUMMARY: Rabbits offer great potential as translationally relevant models of human disease for many biomedical research applications thanks to their evolutionarily closeness to humans, favorable reproduction features, relatively long lifespan which allows for clinically relevant studies, a body size that is similar to that of human infants allowing for more relevant surgical models, and an economically feasible housing cost in a research setting. Rabbit models have been critical to diverse scientific breakthroughs, such as the development of in vitro fertilization techniques, the HPV vaccine, and a multitude of antibodies for various scientific applications. Over the last 30 years, rabbits have been surpassed by mice in part due to ease of generating genetically engineered mice from embryonic stem cells (ESCs), which are not available in rabbits. CRISPR/Cas9 has made it possible to generate gene edited (GE) rabbit models analogous to those in mice for use in research. Other GE large animal models including pigs and non-human primates have also been generated, but the extended generation times, cost of housing, and high level of technical care required greatly limit how widely they can be utilized. GE rabbits overcome many of these barriers and allow for the development and expansion colonies in limited space and in a short time frame, making them a large animal that is practical for wider adoption. More than 50 GE rabbit models have been published thus far highlighting their usefulness, yet the cost of generating these models can be significantly higher than mice and rats. We have developed a genome editing pipeline coupled with an improved rabbit reference genome for efficient generation of GE rabbits. We have generated more than 40 different translationally relevant GE rabbit lines, including whole body knockouts, humanization of disease associated alleles, and targeted knock-ins of proteins of interest. Our lab has expansive expertise in characterizing these GE rabbits to study human disease and have demonstrated that for multiple diseases rabbits are superior to rodents due to increased translational relevance. However, rabbit models have increased costs and require advanced technical skills to generate which has limited the overall number of GE rabbits generated and distribution of models. A centralized resource to produce and distribution of GE rabbits would help overcome this limitation and increase the implementation of rabbits in biomedical research. The overall mission of this grant is to leverage our expertise to create the National Center of Rabbit Models for Translational Research (NCRMTR) and expand access to GE rabbit models across the United States for biomedical research. We propose to generate rabbit models with direct translational relevance to human diseases including cardiovascular, ocular, neurologic, immunology and infectious diseases. This proposed centralized NIH resource center would improve the generation of translationally relevant GE rabbits. We also aim to increase the dissemination and maintenance of these rabbit models to the wider research community.