Disease Modeling Unit

PROJECT SUMMARY DISEASE MODELING UNIT The goal of the Disease Modeling Unit (DMU) of The Jackson Laboratory (JAX) Center for Precision Genetics (JCPG) is to advance understanding of the mechanisms of disease pathobiology, and to provide robust platforms to test novel therapeutic interventions, through the design, creation, and phenotypic validation of complex in vivo models of human disease. Our DMU pipeline offers first-in-class genome editing technology and phenotyping expertise, and managed access to the full spectrum of JAX services, resources, and know-how. Key innovations of the DMU include use of humanization to enhance the translatability and construct validity of our models; strong capabilities in complex allele design and engineering that can support study of mutations with different functional consequences; resources and experience utilizing diverse genetic backgrounds when necessary and/or appropriate, supported by tools developed by the Bioinformatics Core; and access to high efficiency CRISPR/Cas9 genetic engineering technology. These innovations complement JAX’s exceptional behavioral, genomic, and molecular phenotyping capabilities, its institutional scale, and its expertise and commitment to supporting the Center’s mission. Over the current funding phase, the JCPG and the DMU have made enormous progress towards our goal, generating 69 confirmed alleles for 33 individual disease conditions, with several more in the pipeline. A majority of these alleles are complex, including many that incorporate extensive humanization and/or conditionality to enhance their translational potential. The large number of nominations and projects has allowed us to refine and focus our phenotyping into a discrete number of efficient phenotyping packages that reflect the common features in certain disease categories, while adding molecular phenotyping modalities to provide deeper insights into disease mechanisms and to identify disease biomarkers. We have also incorporated novel platforms and technologies developed as part of our demonstration projects in the previous cycle, including our F0 modeling platform that allows for rapid and cost-effective corroboration of novel variant- phenotype associations. We will continue to deploy JAX’s collection of cores and resources into a single, flexible, and cohesive disease modeling pipeline that can support the growing and diverse needs of the scientific and rare disease communities. The Aims of the DMU are: To deploy our sophisticated and large-scale precision model engineering capabilities to build advanced precision mouse models of rare disease in continued support of external nominations from the rare disease and scientific community (Aim 1); To characterize new models using an extensive and customizable phenotyping pipeline to uncover mechanisms of disease pathobiology and to credential new models for preclinical/co-clinical testing (Aim 2); and To apply a novel, high-throughput F0 modeling platform for rapid interrogation of novel disease-associated variants in the mouse (Aim 3).