Using the zinc finger nucleases (ZFN) technology for making gene modification or edits we generated 101 strains within two years. The ZFN technology is extraordinarily efficient and does not require the use of embryonic stem cells, as a result any rat strain should be able to be rapidly (3 to 6 months) modified. This R24 resource grant enables our existing infrastructure: personnel, expertise in gene editing, high throughput phenotyping, distribution channels resulting in an economies of scale that can be leverage to generate novel and important rat models to more investigators. The unique rat models already developed by our existing program, have demonstrated: 1) that the infrastructure is already in place to meet our objectives;2) these gene modified strains can be used to validate a gene underlying a quantitative trait locus, testing a GWAS result, follow-up studies to define function of a predicted gene, or developing a model to study the physiology/mechanisms of a gene;3) our economy of scale;4) a full distribution system in place;and 5) over a decade of resources development (data, rats, genetic and genomic reagents) for the rat. To assure the resource meets community needs, we will establish an External Advisory Board (EAB) that will assess our progress, and conduct a scientific merit review process to select the genes and use of the resources of the R24 nominated by the scientific community (Aim 1). We plan to generate 250 gene targeted rat models (Aim 2), to provide a menu of phenotypic characterization that are available, but not required (Aim 3), and cryopreserved sperm from each line, along with a tissue and fibroblast primary culture bank for each strain, as well as distribute all the animals and reagents to the community (Aim 4).
Specific aims 1 -4 are expected to generate a cost effective and powerful collection of rat models for the community that will accelerate discovery and increase the field's understanding ofthe mechanisms involved in complex diseases. The scientific community has already nominated more than 343 genes demonstrating that the resources developed in this R24 will be of significant value to many investigators. The EAB will assure transparency and that this resource serves the community.
|Flister, Michael J; Endres, Bradley T; Rudemiller, Nathan et al. (2014) CXM: a new tool for mapping breast cancer risk in the tumor microenvironment. Cancer Res 74:6419-29|